Ras vaccine compositions and methods of use

Abstract

The present disclosure provides a therapy with vaccine compositions including multiepitopic polypeptides, recombinant nucleic acids encoding multiepitopic polypeptides and methods of use thereof. Also provided herein are T-cell receptors (TCRs) that can recognize one or more epitopes of the multiepitopic polypeptides. The therapy provided herein can comprise (i) a TCR, a recombinant nucleic acid encoding the TCR, or cells comprising the TCR or the recombinant nucleic acid encoding the TCR, and (ii) a vaccine composition described herein. The methods and compositions provided herein can be used for the treatment of cancer.

Description

WSGR Docket No.50401-795.601 RAS VACCINE COMPOSITIONS AND METHODS OF USE CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 638,565, filed on April 25, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Cancer is a leading cause of death worldwide, accounting for nearly one in six deaths globally. While cell-based immunotherapies have led to advances in treatment options for cancer, they are often limited in their long-term efficacy. There is a need for methods and compositions to improve the efficacy of cell-based immunotherapy. SUMMARY

[0003] Provided herein is a method of treating a subject with a disease or condition comprising administering to the subject a therapy comprising (i) a multiepitopic polypeptide, (ii) a recombinant nucleic acid encoding the multiepitopic polypeptide, or (iii) a cell comprising the multiepitopic polypeptide or the recombinant nucleic acid encoding the multiepitopic polypeptide, wherein the multiepitopic polypeptide does not comprise a full-length RAS polypeptide and comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence, wherein the first RAS epitope sequence and the second RAS epitope sequence are different, and wherein presentation of the first and / or second RAS epitope sequence as a peptide:MHC complex by antigen presenting cells (APCs) of the subject administered the therapy is higher than the presentation of the first and / or second RAS epitope sequence as the peptide:MHC complex by the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide.

[0004] Also provided herein is a method of treating a subject with a disease or condition comprising administering to the subject a therapy comprising (i) a multiepitopic polypeptide, (ii) a recombinant nucleic acid encoding the multiepitopic polypeptide, or (iii) a cell comprising the multiepitopic polypeptide or the recombinant nucleic acid encoding the multiepitopic polypeptide, wherein the multiepitopic polypeptide does not comprise a full-length RAS polypeptide and comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence, wherein the first RAS epitope sequence and the second RAS epitope sequence are different, and wherein the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker.

[0005] In some embodiments, the full-length RAS polypeptide is a full-length KRAS, NRAS or HRAS polypeptide, wherein the first RAS amino acid sequence is a first KRAS, NRAS or HRASWSGR Docket No.50401-795.601 amino acid sequence, and wherein the second RAS amino acid sequence is a second KRAS, NRAS or HRAS amino acid sequence.

[0006] In some embodiments, the method of any one of the preceding embodiments further comprises administering the subject a T-cell receptor (TCR), a recombinant nucleic acid encoding the TCR, or a cell comprising the TCR or the recombinant nucleic acid encoding the TCR.

[0007] In some embodiments, the first RAS epitope sequence and the second RAS epitope sequence is separated by a linker.

[0008] In some embodiments, the first RAS amino acid sequence is the first epitope sequence and / or the second RAS amino acid sequence is the second epitope sequence.

[0009] In some embodiments, the first RAS amino acid sequence comprises a first RAS mutation, and / or the second RAS amino acid sequence comprises a second RAS mutation different from the first RAS mutation.

[0010] In some embodiments, the first RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

[0011] In some embodiments, the second RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

[0012] In some embodiments, the first RAS amino acid sequence is processed into one or more epitopes comprising the first RAS mutation within a cell.

[0013] In some embodiments, the first RAS mutation is G12V, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 58-62 and 65-72.

[0014] In some embodiments, the first RAS mutation is G12D, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 28, 75-79.

[0015] In some embodiments, the first RAS mutation is G12C, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096.

[0016] In some embodiments, the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 7 to 12 consecutive amino acids from the full-length RAS polypeptide.

[0017] In some embodiments, the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 13 to 25 consecutive amino acids from the full-length RAS polypeptide.

[0018] In some embodiments, the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker.

[0019] In some embodiments, the first RAS amino acid sequence comprises the first RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the first RAS epitope sequence from the full-length RAS polypeptide.WSGR Docket No.50401-795.601

[0020] In some embodiments, the second RAS amino acid sequence comprises the second RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the second RAS epitope sequence from the full-length RAS polypeptide.

[0021] In some embodiments, the multiepitopic polypeptide does not comprise more than 12 or more consecutive amino acids from the full-length RAS polypeptide, or the multiepitopic polypeptide does not comprise more than 25 or more consecutive amino acids from the full-length RAS polypeptide.

[0022] In some embodiments, the TCR recognizes and binds to a peptide:MHC complex, the peptide:MHC complex comprising (i) the first or the second RAS epitope sequence, and (ii) a human MHC encoded by an HLA allele.

[0023] In some embodiments, the multiepitopic polypeptide is a RAS polypeptide comprising the first RAS epitope sequence and the second RAS epitope sequence.

[0024] In some embodiments, the linker is a cleavable linker.

[0025] Also provided herein is a method of treating a subject with a disease or condition comprising administering to the subject (a) a RAS polypeptide, (b) a recombinant nucleic acid encoding the RAS polypeptide, or (c) a cell comprising the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide, wherein the RAS polypeptide comprises a RAS epitope sequence, wherein the subject has been previously administered a T-cell receptor (TCR), a recombinant nucleic acid encoding the TCR, or a cell comprising the TCR or the recombinant nucleic acid encoding the TCR, wherein the TCR recognizes and binds to a peptide:MHC complex, the peptide:MHC complex comprising (i) the RAS epitope sequence, and (ii) a human MHC encoded by an HLA allele.

[0026] Also provided herein is a method of treating a subject with a disease or condition comprising administering to the subject a T-cell receptor (TCR), a recombinant nucleic acid encoding the TCR, or a cell comprising the TCR or the recombinant nucleic acid encoding the TCR, wherein the TCR recognizes and binds to a peptide:MHC complex, the peptide:MHC complex comprising (i) a RAS epitope sequence, and (ii) a human MHC encoded by an HLA allele, wherein the subject has been previously administered (a) a RAS polypeptide, (b) a recombinant nucleic acid encoding the RAS polypeptide, or (c) a cell comprising the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide, wherein the RAS polypeptide comprises the RAS epitope sequence.

[0027] Also provided herein is a method of treating a subject with a disease or condition comprising, administering to the subject (i) a RAS polypeptide, (ii) a recombinant nucleic acid encoding the RAS polypeptide, or (iii) a cell comprising the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide, wherein the RAS polypeptide comprises a RAS epitope sequence; and administering to the subject a TCR, a recombinant nucleic acid encoding the TCR, or a cell comprising the TCR or the recombinant nucleic acid encoding the TCR, wherein the TCR recognizesWSGR Docket No.50401-795.601 and binds to a peptide:MHC complex, the peptide:MHC complex comprising (i) the RAS peptide sequence, and (ii) a human MHC encoded by an HLA allele.

[0028] In some embodiments, administering in (a) is performed concurrently with administering in (b).

[0029] In some embodiments, administering in (a) is prior to administering in (b).

[0030] In some embodiments, administering in (a) is subsequent to administering in (b).

[0031] In some embodiments, the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide is administered at least 1 day, 2 days, 5 days, 10 days, 20 days, 30 days, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years or more after the subject has been administered the TCR or the recombinant nucleic acid encoding the TCR.

[0032] In some embodiments, the TCR or the recombinant nucleic acid encoding the TCR is administered at least 1 day, 2 days, 5 days, 10 days, 20 days, 30 days, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years or more after the subject has been administered the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide.

[0033] In some embodiments, the cell is an immune cell.

[0034] In some embodiments, the T-cell receptor (TCR) or the recombinant nucleic acid encoding the TCR is expressed by an immune cell.

[0035] In some embodiments, the TCR is a soluble TCR.

[0036] In some embodiments, the method of any one of the preceding embodiments further comprises administering two or more different TCRs or recombinant nucleic acids encoding the two or more different TCRs, or cells comprising the two or more different TCRs or the recombinant nucleic acids encoding the two or more different TCRs and wherein the two or more different TCRs comprise a first TCR and a second TCR.

[0037] In some embodiments, the two or more different TCRs are expressed on surface of two different immune cells.

[0038] In some embodiments, the first TCR and the second TCR bind to different peptide:MHC complexes, each peptide:MHC complex comprising (i) an epitope sequence and (ii) a human MHC encoded by an HLA allele.

[0039] In some embodiments, the two or more different TCRs or recombinant nucleic acids encoding the two or more different TCRs are administered separately or co-administered in a same mixture.

[0040] In some embodiments, the first TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12V mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA- C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, and the second TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12DWSGR Docket No.50401-795.601 mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA- B*07:02, HLA-C*08:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA- A*68:01.

[0041] In some embodiments, the first TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12V mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA- C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, and the second TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12C mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA- DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03.

[0042] In some embodiments, the first TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12D mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA- A*11:01, and HLA-A*68:01., and the second TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12C mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA- C*03:03.

[0043] In some embodiments, the first TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 58-62 and 65-72 and an MHC encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA- A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA- DRB1*07:01, HLA-A*03:02, and HLA-A*03:05 and the second TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 28, 75- 79 and an MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA-A*68:01; the first TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72 and an MHC encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA- B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, and, HLA-A*03 and the second TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096 and an MHC encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA- A*68:01, and HLA-C*03:03; or the first TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 28, 75-79 and an MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA-C*03:04,WSGR Docket No.50401-795.601 HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA-A*68:01 and the second TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096 and an MHC encoded by an HLA allele selected from the group consisting HLA-DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03.

[0044] In some embodiments, the RAS polypeptide does not comprise a full-length RAS protein sequence.

[0045] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NOs: 58 or 59.

[0046] In some embodiments, the HLA allele is selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*03:02, HLA-A*03:05, HLA-B*40:01, and HLA-A*68:01.

[0047] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NO: 60.

[0048] In some embodiments, the HLA allele is HLA-C*01:02.

[0049] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NOs: 61 or 62.

[0050] In some embodiments, the HLA allele is HLA-C*03:03, or HLA-C*03:04.

[0051] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NOs: 58 or 59.

[0052] In some embodiments, the MHC allele is HLA-A*11:01.

[0053] In some embodiments, the RAS epitope sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 65-71.

[0054] In some embodiments, the MHC allele is HLA-DRB1*07:01.

[0055] In some embodiments, the RAS epitope sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 58 or 72.

[0056] In some embodiments, the MHC allele is selected from the group consisting of HLA- A*03:01, HLA-A*03:02, and HLA-A*03:05.

[0057] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NO: 75.

[0058] In some embodiments, the MHC allele is selected from the group consisting of HLA- B*07:02, HLA-C*08:02, HLA-C*03:04, and HLA-C*05:01.

[0059] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NO: 76.

[0060] In some embodiments, the MHC allele is selected from the group consisting of HLA-A*-3:01, HLA-A*11:01, and HLA-A*68:01.

[0061] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NO: 77.

[0062] In some embodiments, the MHC allele is HLA-A*11:01.WSGR Docket No.50401-795.601

[0063] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NOs: 78 or 79.

[0064] In some embodiments, the MHC allele is HLA-C*08:02.

[0065] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NO: 29.

[0066] In some embodiments, the MHC allele is HLA-DRB1*11:01.

[0067] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NO: 81 or 1096.

[0068] In some embodiments, the MHC allele is selected from the group consisting of HLA-A*3:01, HLA-A*11:01, and HLA-A*68:01.

[0069] In some embodiments, the RAS epitope sequence comprises a sequence of SEQ ID NO: 82.

[0070] In some embodiments, the MHC allele is HLA-C*03:03.

[0071] In some embodiments, the RAS polypeptide is a multiepitopic polypeptide, and wherein the multiepitopic polypeptide does not comprise a full-length RAS polypeptide and comprises two or more different RAS epitope sequences.

[0072] In some embodiments, the multiepitopic polypeptide comprises at least 3, 4, 5, or more different RAS epitope sequences.

[0073] In some embodiments, the two or more different RAS epitope sequences are separated by linker sequences.

[0074] In some embodiments, antigen presenting cells (APCs) of the subject administered the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide comprising the multiepitopic polypeptide present more of a RAS epitope sequence as a peptide:MHC complex compared to the APCs of a subject administered a full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide.

[0075] In some embodiments, T cells of the subject administered the multiepitopic polypeptide or a recombinant nucleic acid encoding the multiepitopic polypeptide exhibit increased expansion compared to T cells of a subject administered a full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide.

[0076] In some embodiments, the multiepitopic polypeptide comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence, and wherein the first RAS epitope sequence and the second RAS epitope sequence are different or wherein the first RAS amino acid sequence and the second RAS amino acid sequence comprise different RAS mutations.

[0077] In some embodiments, the first RAS epitope sequence and the second RAS epitope sequence is separated by a linker.WSGR Docket No.50401-795.601

[0078] In some embodiments, the first amino acid sequence is the first epitope sequence and / or the second amino acid sequence is the second epitope sequence.

[0079] In some embodiments, the first amino acid sequence consists of the first epitope sequence, and / or the second amino acid sequence consists of the second epitope sequence.

[0080] In some embodiments, the first RAS amino acid sequence comprises a first RAS mutation, and / or the second RAS amino acid sequence comprises a second RAS mutation different from the first RAS mutation.

[0081] In some embodiments, the first RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

[0082] In some embodiments, the second RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

[0083] In some embodiments, the first RAS amino acid sequence is processed into one or more epitopes comprising the first RAS mutation within a cell.

[0084] In some embodiments, the first RAS mutation is G12V, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72.

[0085] In some embodiments, the first RAS mutation is G12D, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 28, 75-79.

[0086] In some embodiments, the first RAS mutation is G12C, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096.

[0087] In some embodiments, the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 7 to 12 consecutive amino acids from the full-length RAS polypeptide.

[0088] In some embodiments, the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 13 to 25 consecutive amino acids from the full-length RAS polypeptide.

[0089] In some embodiments, the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker.

[0090] In some embodiments, the first amino acid sequence comprises the first RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the first RAS epitope sequence from the full-length RAS polypeptide.

[0091] In some embodiments, the second amino acid sequence comprises the second RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the second RAS epitope sequence from the full-length RAS polypeptide.

[0092] In some embodiments, the multiepitopic polypeptide does not comprise more than 12 or more consecutive amino acids from the full-length RAS polypeptide, or the multiepitopic polypeptide does not comprise more than 25 or more consecutive amino acids from the full-length RAS polypeptide.WSGR Docket No.50401-795.601

[0093] In some embodiments, the first RAS epitope sequence and the second RAS epitope sequence are presentable by different HLA alleles, are presented by different HLA alleles, bind to different HLA alleles, are predicted to bind to different HLA alleles, or are predicted to be presented by different HLA alleles.

[0094] In some embodiments, a first RAS epitope sequence (i) binds to or is predicted to bind to a first HLA allele with a KD of less than 100 nM and (ii) to binds to or is predicted to bind to a second HLA allele with a KD of more than 500 nM.

[0095] In some embodiments, the first amino acid sequence is operably linked to the second amino acid sequence via a linker.

[0096] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0097] In some embodiments, the multiepitopic polypeptide comprises a first amino acid sequence comprising a first RAS epitope sequence, operably linked to a second amino acid sequence comprising a second RAS epitope sequence, operably linked to a third amino acid sequence comprising a third RAS epitope sequence.

[0098] In some embodiments, the first RAS epitope sequence, the second RAS epitope sequence, and / or the third RAS epitope sequence comprises a RAS mutation selected from the group consisting of G12V, G12D, and G12C, and wherein the first RAS epitope sequence, the second RAS epitope sequence, and the third RAS epitope sequence comprise different RAS mutations.

[0099] In some embodiments, the first RAS epitope sequence comprises a G12V mutation.

[0100] In some embodiments, the second RAS epitope sequence comprises a G12D mutation.

[0101] In some embodiments, the third RAS epitope sequence comprises a G12C mutation.

[0102] In some embodiments, (i) the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA- A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA- DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA- B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA- A*03:05, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-WSGR Docket No.50401-795.601 B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, (ii) the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA- C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA- C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, and (iii) the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA- DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA- A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA- A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03.

[0103] In some embodiments, the subject does not express an HLA allele that recognizes each RAS epitope sequence of the multiepitopic polypeptide.

[0104] In some embodiments, the subject only expresses HLA alleles that recognize a subset of RAS epitope sequences of the multiepitopic polypeptide.

[0105] In some embodiments, the RAS polypeptide comprises one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

[0106] In some embodiments, the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

[0107] In some embodiments, the RAS polypeptide comprises two, three, four, or five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

[0108] In some embodiments, the RAS polypeptide comprises two, three, four, or five copies of each sequence of SEQ ID NOs: 27-29.WSGR Docket No.50401-795.601

[0109] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 27, operably linked to a sequence of SEQ ID NO: 29, and operably linked to a sequence of SEQ ID NO: 28.

[0110] In some embodiments, the sequence of SEQ ID NO: 27 is operably linked to the sequence of SEQ ID NOs: 29 via a linker, and the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 28 via a linker.

[0111] In some embodiments, the linker is a cleavable linker.

[0112] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0113] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NOs: 29, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO: 27.

[0114] In some embodiments, the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 28 via a linker, and the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 27 via a linker.

[0115] In some embodiments, the linker is a cleavable linker.

[0116] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0117] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 28, operably linked to a sequence of SEQ ID NO: 27, and operably linked to a sequence of SEQ ID NO: 29.

[0118] In some embodiments, the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 27 via a linker, and the sequence of SEQ ID NO: 27 is operably linked to a sequence of SEQ ID NO: 29 via a linker.

[0119] In some embodiments, the linker is a cleavable linker.

[0120] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0121] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 27, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO: 29.

[0122] In some embodiments, the sequence of SEQ ID NO: 27 is operably linked to the sequence of SEQ ID NO: 28 via a linker, and the sequence of SEQ ID NO: 28 is operably linked to a sequence of SEQ ID NO: 29 via a linker.

[0123] In some embodiments, the linker is a cleavable linker.

[0124] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0125] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 28, operably linked to a sequence of SEQ ID NO: 29, and operably linked to a sequence of SEQ ID NO: 27.WSGR Docket No.50401-795.601

[0126] In some embodiments, the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 29 via a linker, and the sequence of SEQ ID NO: 29 is operably linked to a sequence of SEQ ID NO: 27 via a linker.

[0127] In some embodiments, the linker is a cleavable linker.

[0128] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0129] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 29, operably linked to a sequence of SEQ ID NO: 27, and operably linked to a sequence of SEQ ID NO: 28.

[0130] In some embodiments, the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 27 via a linker, and the sequence of SEQ ID NO: 27 is operably linked to a sequence of SEQ ID NO: 28 via a linker.

[0131] In some embodiments, the linker is a cleavable linker.

[0132] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0133] In some embodiments, the RAS polypeptide comprises at least two copies of a multiepitopic polypeptide, and wherein each copy comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 29, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO: 27.

[0134] In some embodiments, the RAS polypeptide comprises three copies of the multiepitopic polypeptide.

[0135] In some embodiments, the RAS polypeptide comprises five copies of the multiepitopic polypeptide.

[0136] In some embodiments, the RAS polypeptide further comprises a secretory domain (Sec) sequence at the N terminus of the multiepitopic polypeptide.

[0137] In some embodiments, the Sec sequence comprises a sequence of SEQ ID NO: 32.

[0138] In some embodiments, the Sec sequence is operably linked to the multiepitopic polypeptide via a linker.

[0139] In some embodiments, the linker comprises a sequence of SEQ ID NO: 30 or 112.

[0140] In some embodiments, the RAS polypeptide further comprises an MHC class I trafficking domain (MITD) sequence at the C terminus of the multiepitopic polypeptide.

[0141] In some embodiments, the MITD sequence comprises a sequence of SEQ ID NO: 33.

[0142] In some embodiments, the multiepitopic polypeptide is operably linked to the MITD sequence via a linker.

[0143] In some embodiments, the linker comprises a sequence of SEQ ID NO: 30 or 112.WSGR Docket No.50401-795.601

[0144] In some embodiments, the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 25.

[0145] In some embodiments, the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 26.

[0146] In some embodiments, the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 113.

[0147] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

[0148] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14- 23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

[0149] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two, three, four, or five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

[0150] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two, three, four, or five copies of each sequence of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

[0151] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 14- 16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109.

[0152] In some embodiments, the sequence selected from the group consisting of SEQ ID NOs: 14- 16, 84, 92, 96, 100, 104, and 108 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence.

[0153] In some embodiments, the linker sequence encodes a cleavable linker.

[0154] In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13.

[0155] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20- 23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting ofWSGR Docket No.50401-795.601 SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108.

[0156] In some embodiments, the sequence selected from the group consisting of SEQ ID NOs: 20- 23, 88, 94, 98, 102, 106, and 110 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 via a linker sequence.

[0157] In some embodiments, the linker sequence encodes a cleavable linker.

[0158] In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13.

[0159] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 17- 19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110.

[0160] In some embodiments, the sequence selected from the group consisting of SEQ ID NOs: 17- 19, 86, 93, 97, 101, 105, and 109 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 is operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 via a linker sequence.

[0161] In some embodiments, the linker sequence is a cleavable linker.

[0162] In some embodiments, the linker sequence comprises a sequence of selected from the group consisting of SEQ ID NOs: 5, 6, 8-13.

[0163] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises at least two copies of a string of sequences, and wherein each string of sequences comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17- 19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108.

[0164] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of the string of sequences.

[0165] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of the string of sequences.WSGR Docket No.50401-795.601

[0166] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding a secretory (Sec) sequence at the 5’end of the string of sequences.

[0167] In some embodiments, the sequence encoding the Sec sequence comprises a sequence of SEQ ID NO: 3.

[0168] In some embodiments, the sequence encoding the Sec sequence is operably linked to the string of sequences via a linker sequence.

[0169] In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

[0170] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding an MITD sequence at the 3’ end of the string of sequences.

[0171] In some embodiments, the sequence encoding the MITD domain comprises a sequence of SEQ ID NO: 24 or 90.

[0172] In some embodiments, the string of sequences is operably linked to the sequence encoding the MITD sequence via a linker sequence.

[0173] In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

[0174] In some embodiments, the recombinant nucleic acid is codon-optimized.

[0175] In some embodiments, the recombinant nucleic acid is an RNA.

[0176] In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 2, 91, 95, 99, 103, 107, 111.

[0177] In some embodiments, the subject expresses more of the RAS epitope when administered with the codon-optimized recombinant nucleic acid than administered with wild-type recombinant nucleic acid.

[0178] In some embodiments, the TCR comprises a TCR beta chain construct and a TCR alpha chain construct, wherein the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 57.

[0179] In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence with at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NO: 52 or SEQ ID NO: 53.

[0180] In some embodiments, the TCR beta chain construct comprises a complementarity determining region 1 (CDR1) having an amino acid sequence set forth in SEQ ID NO: 55 and a complementarity determining region 2 (CDR2) having an amino acid sequence set forth in SEQ ID NO: 56.WSGR Docket No.50401-795.601

[0181] In some embodiments, the TCR alpha chain construct comprises a CDR1, a CDR2, and a CDR3, wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 46, the CDR2 has an amino acid sequence set forth in SEQ ID NO: 47, and the CDR3 has an amino acid sequence set forth in SEQ ID NO: 48.

[0182] In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NO: 43 or SEQ ID NO: 44.

[0183] In some embodiments, the TCR comprises: (a) a beta chain having an amino acid sequence set forth in SEQ ID NO: 49 or SEQ ID NO: 51, or an amino acid sequence that is at least 80% identical to SEQ ID NO: 49 or SEQ ID NO: 51, and (b) an alpha chain having an amino acid sequence set forth in SEQ ID NO: 40 or SEQ ID NO: 42, or an amino acid sequence that is at least 80% identical to SEQ ID NO: 40 or SEQ ID NO: 42.

[0184] In some embodiments, the TCR is selected from the TCRs presented in Tables 8A-8D.

[0185] In some embodiments, binding of the TCR to the peptide:MHC complex results in production of a cytokine by the immune cell.

[0186] In some embodiments, the cytokine is IFN-γ, TNF-α, IL-2, IL-18, or any combination thereof.

[0187] Also provided herein is a recombinant nucleic acid encoding a RAS polypeptide comprising a multiepitopic polypeptide, wherein the multiepitopic polypeptide does not comprise a full-length RAS polypeptide and comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence, wherein the first RAS epitope sequence and the second RAS epitope sequence are different, and wherein the first RAS amino acid sequence and the second RAS amino acid sequence are linked via a linker.

[0188] In some embodiments, presentation of the first and / or second RAS epitope sequence as a peptide:MHC complex by antigen presenting cells (APCs) of the subject administered the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide is higher than the presentation of the first and / or second RAS epitope sequence as the peptide:MHC complex by the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide.

[0189] In some embodiments, the first RAS amino acid sequence is the first epitope sequence and / or the second RAS amino acid sequence is the second epitope sequence.

[0190] In some embodiments, the first RAS amino acid sequence consists of the first epitope sequence, and / or the second RAS amino acid sequence consists of the second epitope sequence.

[0191] In some embodiments, the first RAS amino acid sequence comprises a first RAS mutation, and / or the second RAS amino acid sequence comprises a second RAS mutation different from the first RAS mutation.WSGR Docket No.50401-795.601

[0192] In some embodiments, the first RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

[0193] In some embodiments, the second RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

[0194] In some embodiments, the first RAS amino acid sequence is processed into one or more epitopes comprising the first RAS mutation within a cell.

[0195] In some embodiments, the first RAS mutation is G12V, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72.

[0196] In some embodiments, the first RAS mutation is G12D, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 28, 75-79.

[0197] In some embodiments, the first RAS mutation is G12C, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096.

[0198] In some embodiments, the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 7 to 12 consecutive amino acids from the full-length RAS polypeptide.

[0199] In some embodiments, the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 13 to 25 consecutive amino acids from the full-length RAS polypeptide.

[0200] In some embodiments, the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker.

[0201] In some embodiments, the first RAS amino acid sequence comprises the first RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the first RAS epitope sequence from the full-length RAS polypeptide.

[0202] In some embodiments, the second RAS amino acid sequence comprises the second RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the second RAS epitope sequence from the full-length RAS polypeptide.

[0203] In some embodiments, the multiepitopic polypeptide does not comprise more than 12 or more consecutive amino acids from the full-length RAS polypeptide, or the multiepitopic polypeptide does not comprise more than 25 or more consecutive amino acids from the full-length RAS polypeptide.

[0204] In some embodiments, the RAS polypeptide further comprises a Secretory (Sec) sequence at the N terminus of the multiepitopic polypeptide.

[0205] In some embodiments, the Sec sequence comprises a sequence of SEQ ID NO: 32.

[0206] In some embodiments, the Sec sequence is operably linked to the multiepitopic polypeptide via a linker.

[0207] In some embodiments, the linker comprises a sequence of SEQ ID NO: 30 or 112.

[0208] In some embodiments, the RAS polypeptide further comprises an MHC class I trafficking signal (MITD) sequence at the C terminus of the multiepitopic polypeptide.WSGR Docket No.50401-795.601

[0209] In some embodiments, the MITD sequence comprises a sequence of SEQ ID NO: 33.

[0210] In some embodiments, the multiepitopic polypeptide is operably linked to the MITD sequence via a linker.

[0211] In some embodiments, the linker comprises a sequence of SEQ ID NO: 30 or 112.

[0212] In some embodiments, the multiepitopic polypeptide comprises at least 3, 4, 5, or more different RAS epitope sequences.

[0213] In some embodiments, the first RAS epitope sequence and the second RAS epitope sequence are presentable by different HLA alleles, are presented by different HLA alleles, bind to different HLA alleles, are predicted to bind to different HLA alleles, or are predicted to be presented by different HLA alleles.

[0214] In some embodiments, the first RAS epitope sequence (i) binds to or is predicted to bind to a first HLA allele with a KD of less than 100 nM and (ii) to binds to or is predicted to bind to a second HLA allele with a KD of more than 500 nM.

[0215] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0216] In some embodiments, the multiepitopic polypeptide comprises a first amino acid sequence comprising a first RAS epitope sequence, operably linked to a second amino acid sequence comprising a second RAS epitope sequence, operably linked to a third amino acid sequence comprising a third RAS epitope sequence.

[0217] In some embodiments, (i) the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA- A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA- DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA- B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA- A*03:05, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA- B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, (ii) the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01,WSGR Docket No.50401-795.601 HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA- C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02,binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA- C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, and (iii) the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA- DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA- A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA- A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03.

[0218] In some embodiments, the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2])x-CT seq, where x is an integer from 1 to 10.

[0219] In some embodiments, the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2]-cleavable linker2-[Antigen3])x-CT seq, where x is an integer from 1 to 10.

[0220] In some embodiments, the NT seq comprises a Secretory (Sec) sequence and a N-terminal linker sequence.

[0221] In some embodiments, the CT seq comprises a C-terminal linker and a MITD sequence.

[0222] In some embodiments, the Antigen1, Antigen2, or Antigen3 is comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 27-29.

[0223] In some embodiments, the cleavable linker1 or cleavable linker2 is selected from the group consisting of SEQ ID NOs: 30 and 31.

[0224] In some embodiments, the N-terminal linker sequence or the C-terminal linker sequence is selected from the group consisting of SEQ ID NOs: 30 and 31.WSGR Docket No.50401-795.601

[0225] In some embodiments, the RAS polypeptide comprises one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

[0226] In some embodiments, the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

[0227] In some embodiments, the RAS polypeptide comprises two, three, four, or five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

[0228] In some embodiments, the RAS polypeptide comprises two, three, four, or five copies of each sequence of SEQ ID NOs: 27-29.

[0229] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 27, operably linked to a sequence of SEQ ID NO: 29, and operably linked to a sequence of SEQ ID NO: 28.

[0230] In some embodiments, the sequence of SEQ ID NO: 27 is operably linked to the sequence of SEQ ID NO: 29 via a linker, and the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 28 via a linker.

[0231] In some embodiments, the linker is a cleavable linker.

[0232] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0233] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 29, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO: 27.

[0234] In some embodiments, the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 28 via a linker, and the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 27 via a linker.

[0235] In some embodiments, the linker is a cleavable linker.

[0236] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0237] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 28, operably linked to a sequence of SEQ ID NO: 27, and operably linked to a sequence of SEQ ID NO: 29.

[0238] In some embodiments, the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 27 via a linker, and the sequence of SEQ ID NO: 27 is operably linked to a sequence of SEQ ID NO: 29 via a linker.

[0239] In some embodiments, the linker is a cleavable linker.

[0240] In some embodiments, the linker comprises a sequence of SEQ ID NO: 31.

[0241] In some embodiments, the RAS polypeptide comprises at least two copies of a multiepitopic polypeptide, and wherein each copy comprises, from N terminus to C terminus, a sequence of SEQ IDWSGR Docket No.50401-795.601 NO: 29, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO: 27.

[0242] In some embodiments, the RAS polypeptide comprises three copies of the multiepitopic polypeptide.

[0243] In some embodiments, the RAS polypeptide comprises five copies of the multiepitopic polypeptide.

[0244] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

[0245] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NO:s 14- 23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

[0246] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two, three, four, or five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

[0247] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two, three, four, or five copies of each sequence of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

[0248] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 14- 16, 84, 92, 96, 100, 104, and 108 , operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109.

[0249] In some embodiments, the sequence selected from the group consisting of SEQ ID NOs: 14- 16, 84, 92, 96, 100, 104, and 108 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence.

[0250] In some embodiments, the linker sequence encodes a cleavable linker.

[0251] In some embodiments, the linker sequence comprises a sequence of selected from the group consisting of SEQ ID NOs: 5, 6, 8-13.

[0252] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20- 23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting ofWSGR Docket No.50401-795.601 SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108.

[0253] In some embodiments, the sequence selected from the group consisting of SEQ ID NOs: 20- 23, 88, 94, 98, 102, 106, and 110 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 via a linker sequence.

[0254] In some embodiments, the linker sequence encodes a cleavable linker.

[0255] In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13.

[0256] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 17- 19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110.

[0257] In some embodiments, the sequence selected from the group consisting of SEQ ID NOs: 17- 19, 86, 93, 97, 101, 105, and 109 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 is operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 via a linker sequence.

[0258] In some embodiments, the linker sequence is a cleavable linker.

[0259] In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13.

[0260] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises at least two copies of a string of sequences, and wherein each string of sequences comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17- 19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108.

[0261] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of the string of sequences.

[0262] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of the string of sequences.WSGR Docket No.50401-795.601

[0263] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding a Sec sequence at the 5’ end of the string of sequences.

[0264] In some embodiments, the sequence encoding the Sec sequence comprises a sequence of SEQ ID NO: 3.

[0265] In some embodiments, the sequence encoding the Sec sequence is operably linked to the string of sequences via a linker sequence.

[0266] In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

[0267] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding an MITD sequence at the 3’ end of the string of sequences.

[0268] In some embodiments, the sequence encoding the MITD sequence comprises a sequence of SEQ ID NO: 24 or 90.

[0269] In some embodiments, the string of sequences is operably linked to the sequence encoding the MITD sequence via a linker sequence.

[0270] In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

[0271] Also provided herein is a recombinant nucleic acid having at least 60% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 2, 91, 95, 99, 103, 107, 111.

[0272] Also provided herein is a recombinant nucleic acid having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 2, 91, 95, 99, 103, 107, 111.

[0273] Also provided herein is a polypeptide encoded by the recombinant nucleic acid of any one of the preceding embodiments.

[0274] Also provided herein is a pharmaceutical composition comprising the recombinant nucleic acid of any one of the preceding embodiments or the polypeptide of any one of the preceding embodiments, and a pharmaceutically acceptable carrier.

[0275] Also provided herein is the recombinant nucleic acid of any one of the preceding embodiments, polypeptide of any one of the preceding embodiments, or the pharmaceutical composition of any one of the preceding embodiments for use in therapy.

[0276] Also provided herein is use of the recombinant nucleic acid of any one of the preceding embodiments, the polypeptide of any one of the preceding embodiments, or the pharmaceutical composition of any one of the preceding embodiments, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof. INCORPORATION BY REFERENCEWSGR Docket No.50401-795.601

[0277] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0278] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0279] FIGs.1-2 depict an exemplary vaccine construct containing three different antigenic KRAS protein mutants. FIG.1 is a cartoon depicting the protein domains and linkers encoded by the construct. FIG.2 shows the fully annotated sequence of the exemplary construct.

[0280] FIGs.3A-3D depict results from a T cell activation experiment measuring IFN-γ secretion by T cells incubated with monocyte-derived dendritic cells (moDCs) transfected with the construct shown in FIG.1, a construct containing three repeats of the antigenic KRAS mutants, an irrelevant construct, or with no moDCs. FIG.3A depicts results using T cells expressing a TCR recognizing KRAS G12V mutant presented by HLA-DRB1:07:01, left and right panels are from different T cell donors. FIG.3B depicts results using T cells expressing a TCR recognizing KRAS G12V mutant presented by HLA-A11:01, left and right panels are from different T cell donors. FIG.3C depicts results using T cells expressing a TCR recognizing KRAS G12D mutant presented by HLA-A11:01, left and right panels are from different T cell donors. FIG.3D depicts results using T cells expressing a TCR recognizing KRAS G12D mutant presented by HLA-C08:02, left and right panels are from different T cell donors.

[0281] FIG.4 depicts results from a T cell activation experiment measuring IFN-γ secretion by T cells incubated with monocyte-derived dendritic cells (moDCs) transfected with the constructs described in Table 6. Left and right panels depict results obtained using two different T cell donors. DETAILED DESCRIPTION Definitions

[0282] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0283] An antigen is a foreign substance to the body that induces an immune response. A “neoantigen” refers to a class of tumor antigens which arise from tumor-specific changes in proteins. Neoantigens encompass, but are not limited to, tumor antigens which arise from, for example, aWSGR Docket No.50401-795.601 substitution in a protein sequence, a frame shift mutation, a fusion polypeptide, an in-frame deletion, an insertion, and expression of an endogenous retroviral polypeptide.

[0284] A “neoepitope” refers to an epitope that is not present in a reference, such as a non-diseased cell, e.g., a non-cancerous cell or a germline cell, but is found in a diseased cell, e.g., a cancer cell. This includes situations where a corresponding epitope is found in a normal non-diseased cell or a germline cell but, due to one or more mutations in a diseased cell, e.g., a cancer cell, the sequence of the epitope is changed so as to result in the neoepitope.

[0285] A “mutation” refers to a change of or a difference in a nucleic acid sequence (e.g., a nucleotide substitution, addition or deletion) compared to a reference nucleic acid. A “somatic mutation” can occur in any of the cells of the body except the germ cells (sperm and egg) and are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. In some embodiments, a mutation is a non-synonymous mutation. A “non-synonymous mutation” refers to a mutation, for (e.g., a nucleotide substitution), which does result in an amino acid change such as an amino acid substitution in the translation product. A “frameshift” occurs when a mutation disrupts the normal phase of a gene’s codon periodicity (also known as “reading frame”), resulting in translation of a non-native protein sequence. It is possible for different mutations in a gene to achieve the same altered reading frame.

[0286] “Antigen processing” or “processing” refers to the degradation of a polypeptide or antigen into procession products, which are fragments of said polypeptide or antigen (e.g., the degradation of a polypeptide into peptides) and the association of one or more of these fragments (e.g., via binding) with MHC molecules for presentation by cells, for example, antigen presenting cells, to specific T cells.

[0287] An “antigen presenting cell” (APC) refers to a cell which presents peptide fragments of protein antigens in association with MHC molecules on its cell surface. The term includes professional antigen presenting cells (e.g., B lymphocytes, monocytes, dendritic cells, Langerhans cells) as well as other antigen presenting cells (e.g., keratinocytes, endothelial cells, astrocytes, fibroblasts, oligodendrocytes). In some cases, the APC can be a cancer cell.

[0288] The term “affinity” refers to a measure of the strength of binding between two members of a binding pair (e.g., a human leukocyte antigen (HLA)-binding peptide and a class I or II HLA, or a peptide-HLA complex and a T cell receptor (TCR)). KD refers to the dissociation constant between two members of a binding pair and has units of molarity. KA refers to the affinity constant between two members of a binding pair is the inverse of the dissociation constant. Affinity may be determined experimentally, for example by surface plasmon resonance (SPR) using commercially available Biacore SPR units. Koff refers to the off-rate constant of two members of a binding pair, (e.g., the off- rate constant of an HLA-binding peptide and a class I or II HLA, or a peptide-HLA complex and aWSGR Docket No.50401-795.601 TCR). Konrefers to the on-rate constant of two members of a binding pair, (e.g., the on-rate constant of an HLA-binding peptide and a class I or II HLA, or a peptide-HLA complex and a TCR).

[0289] Throughout this disclosure, “binding data” results may be expressed in terms of an “IC50.” Affinity may also be expressed as the inhibitory concentration 50 (IC50), or the concentration at which 50% of a first member of a binding pair (e.g., a peptide) is displaced. Likewise, ln(IC50) refers to the natural log of the IC50. For example, an IC50may be the concentration of a tested peptide in a binding assay at which 50% inhibition of binding of a labeled reference peptide is observed. Given the conditions in which the assays are run (e.g., limiting HLA protein concentrations and / or labeled reference peptide concentrations), these values can approximate KDvalues. Assays for determining binding are well known in the art and are described in detail, for example, in PCT publications WO 94 / 20127 and WO 94 / 03205, and other publications such Sidney et al., Current Protocols in Immunology 18.3.1 (1998); Sidney, et al., J. Immunol.154:247 (1995); and Sette, et al., Mol. Immunol.31:813 (1994). Alternatively, binding can be expressed relative to binding by a reference standard peptide. Binding can also be determined using other assay systems including those using: live cells (e.g., Ceppellini et al., Nature 339:392 (1989); Christnick et al., Nature 352:67 (1991); Busch et al., Int. Immunol.2:443 (1990); Hill et al., J. Immunol.147:189 (1991); del Guercio et al., J. Immunol.154:685 (1995)), cell free systems using detergent lysates (e.g., Cerundolo et al., J. Immunol.21:2069 (1991)), immobilized purified MHC (e.g., Hill et al., J. Immunol.152, 2890 (1994); Marshall et al., J. Immunol.152:4946 (1994)), ELISA systems (e.g., Reay et al., EMBO J. 11:2829 (1992)), surface plasmon resonance (e.g., Khilko et al., J. Biol. Chem.268:15425 (1993)); high flux soluble phase assays (Hammer et al., J. Exp. Med.180:2353 (1994)), and measurement of class I MHC stabilization or assembly (e.g., Ljunggren et al., Nature 346:476 (1990); Schumacher et al., Cell 62:563 (1990); Townsend et al., Cell 62:285 (1990); Parker et al., J. Immunol.149:1896 (1992)).

[0290] The term “derived” when used to discuss an epitope is a synonym for “prepared.” A derived epitope can be isolated from a natural source, or it can be synthesized according to standard protocols in the art. Synthetic epitopes can comprise artificial amino acid residues “amino acid mimetics,” such as D isomers of natural occurring L amino acid residues or non-natural amino acid residues such as cyclohexylalanine. A derived or prepared epitope can be an analog of a native epitope. The term “derived from” refers to the origin or source, and may include naturally occurring, recombinant, unpurified, purified or differentiated molecules or cells. For example, an expanded or induced antigen specific T cell may be derived from a T cell. For example, an expanded or induced antigen specific T cell may be derived from an antigen specific T cell in a biological sample. For example, a matured APC (e.g., a professional APC) may be derived from a non-matured APC (e.g., an immature APC). For example, an APC may be derived from a monocyte (e.g., a CD14+ monocyte). For example, aWSGR Docket No.50401-795.601 dendritic cell may be derived from a monocyte (e.g., a CD14+ monocyte). For example, an APC may be derived from a bone marrow cell.

[0291] An “epitope” is the collective features of a molecule (e.g., a peptide’s charge and primary, secondary and tertiary structure) that together form a site recognized by another molecule (e.g., an immunoglobulin, T cell receptor, HLA molecule, or chimeric antigen receptor). For example, an epitope can be a set of amino acid residues involved in recognition by a particular immunoglobulin; a Major Histocompatibility Complex (MHC) receptor; or in the context of T cells, those residues recognized by a T cell receptor protein and / or a chimeric antigen receptor. Epitopes can be prepared by isolation from a natural source, or they can be synthesized according to standard protocols in the art. Synthetic epitopes can comprise artificial amino acid residues, amino acid mimetics, (such as D isomers of naturally-occurring L amino acid residues or non-naturally-occurring amino acid residues). Throughout this disclosure, epitopes may be referred to in some cases as peptides or peptide epitopes. In certain embodiments, there is a limitation on the length of a peptide of the present disclosure. The embodiment that is length-limited occurs when the protein or peptide comprising an epitope described herein comprises a region (i.e., a contiguous series of amino acid residues) having 100% sequence identity with a native sequence. In order to avoid the definition of epitope from reading, e.g., on whole natural molecules, there is a limitation on the length of any region that has 100% sequence identity with a native peptide sequence. Thus, for a peptide comprising an epitope described herein and a region with 100% sequence identity with a native peptide sequence, the region with 100% sequence identity to a native sequence generally has a length of: less than or equal to 600 amino acid residues, less than or equal to 500 amino acid residues, less than or equal to 400 amino acid residues, less than or equal to 250 amino acid residues, less than or equal to 100 amino acid residues, less than or equal to 85 amino acid residues, less than or equal to 75 amino acid residues, less than or equal to 65 amino acid residues, and less than or equal to 50 amino acid residues. In certain embodiments, an “epitope” described herein is comprised by a peptide having a region with less than 51 amino acid residues that has 100% sequence identity to a native peptide sequence, in any increment down to 5 amino acid residues; for example 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid residues.

[0292] A “T cell epitope” refers to a peptide sequence bound by an MHC molecule in the form of a peptide-MHC (pMHC) complex. A peptide-MHC complex can be recognized and bound by a TCR of a T cell (e.g., a cytotoxic T-lymphocyte or a T-helper cell).

[0293] A “T cell” includes CD4+ T cells and CD8+ T cells. The term T cell also includes both T helper 1 type T cells and T helper 2 type T cells. T cells may be generated by the method described in the application, for a clinical application. T cells or adoptive T cells referred to here, such as for aWSGR Docket No.50401-795.601 clinical application are cells isolated from a biological source, manipulated and cultured ex vivo and prepared into a drug candidate for a specific therapy such as a cancer, e.g., melanoma. When drug candidate cells pass specific qualitative and quantitative criteria for fitness for a clinical application, the drug candidate may be designated a drug product. In some cases, a drug product is selected from a number of drug candidates. In the context of this application, a drug product is a T cell, more specifically, a population of T cells, or more specifically a population of T cells with heterogeneous characteristics and subtypes. For example, a drug product, as disclosed herein may have a population of T cells comprising CD8+ T cells, CD4+ T cells, with cells at least above a certain exhibiting antigen specificity, a certain percentage of each exhibiting a memory phenotype, among others.

[0294] An “immune cell” refers to a cell that plays a role in the immune response. Immune cells are of hematopoietic origin, and include lymphocytes, such as B cells and T cells; natural killer cells; myeloid cells, such as monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes.

[0295] An “immunogenic” peptide or an “immunogenic” epitope or an “immunogenic” peptide epitope is a peptide that binds to an HLA molecule and induces a cell-mediated or humoral response, for example, a cytotoxic T lymphocyte (CTL) response, a helper T lymphocyte (HTL) response and / or a B lymphocyte response. Immunogenic peptides described herein are capable of binding to an HLA molecule and thereafter induce a cell-mediated or humoral response (e.g., a CTL (cytotoxic) response, or a HTL response) to the peptide.

[0296] A “protective immune response” or “therapeutic immune response” refers to a CTL and / or an HTL response to an antigen derived from a pathogenic antigen (e.g., a tumor antigen), which in some way prevents or at least partially arrests disease symptoms, side effects or progression. The immune response can also include an antibody response which has been facilitated by the stimulation of helper T cells.

[0297] A “T cell receptor” (“TCR”) refers to a molecule, whether natural or partly or wholly synthetically produced, found on the surface of T lymphocytes (T cells) that recognizes an antigen bound to a major histocompatibility complex (MHC) molecule. The ability of a T cells to recognize an antigen associated with various diseases (e.g., cancers) or infectious organisms is conferred by its TCR, which is made up of both an alpha (α) chain and a beta (β) chain or a gamma (γ) and a delta (δ) chain. The proteins which make up these chains are encoded by DNA, which employs a unique mechanism for generating the tremendous diversity of the TCR. This multi-subunit immune recognition receptor associates with the CD3 complex and binds peptides presented by the MHC class I and II proteins on the surface of antigen-presenting cells (APCs). Binding of a TCR to a peptide on an APC is a central event in T cell activation.

[0298] As used herein, a “chimeric antigen receptor” or “CAR” refers to an antigen binding protein in that includes an immunoglobulin antigen binding domain (e.g., an immunoglobulin variableWSGR Docket No.50401-795.601 domain) and a T cell receptor (TCR) constant domain. As used herein, a “constant domain” of a TCR polypeptide includes a membrane-proximal TCR constant domain, a TCR transmembrane domain and / or a TCR cytoplasmic domain, or fragments thereof. For example, in some embodiments, a CAR is a monomer that includes a polypeptide comprising an immunoglobulin heavy chain variable domain linked to a TCRβ constant domain. In some embodiments, the CAR is a dimer that includes a first polypeptide comprising an immunoglobulin heavy or light chain variable domain linked to a TCRα or TCRβconstant domain and a second polypeptide comprising an immunoglobulin heavy or light chain variable domain (e.g., a κ or λ variable domain) linked to a TCRβ or TCRα constant domain.

[0299] “Major Histocompatibility Complex” or “MHC” is a cluster of genes that plays a role in control of the cellular interactions responsible for physiologic immune responses. The terms “major histocompatibility complex” and the abbreviation “MHC” can include any class of MHC molecule, such as MHC class I and MHC class II molecules, and relate to a complex of genes which occurs in all vertebrates. In humans, the MHC complex is also known as the human leukocyte antigen (HLA) complex. Thus, a “Human Leukocyte Antigen” or “HLA” refers to a human Major Histocompatibility Complex (MHC) protein (see, e.g., Stites, et al., Immunology, 8TH Ed., Lange Publishing, Los Altos, Calif. (1994). For a detailed description of the MHC and HLA complexes, see, Paul, Fundamental Immunology, 3rd Ed., Raven Press, New York (1993).

[0300] The major histocompatibility complex in the genome comprises the genetic region whose gene products expressed on the cell surface are important for binding and presenting endogenous and / or foreign antigens and thus for regulating immunological processes. MHC proteins or molecules are important for signaling between lymphocytes and antigen presenting cells or diseased cells in immune reactions. MHC proteins or molecules bind peptides and present them for recognition by T- cell receptors. The proteins encoded by the MHC can be expressed on the surface of cells, and display both self-antigens (peptide fragments from the cell itself) and non-self-antigens (e.g., fragments of invading microorganisms) to a T-cell. MHC binding peptides can result from the proteolytic cleavage of protein antigens and represent potential lymphocyte epitopes. (e.g., T cell epitope and B cell epitope). MHCs can transport the peptides to the cell surface and present them there to specific cells, such as cytotoxic T-lymphocytes, T-helper cells, or B cells. The MHC region can be divided into three subgroups, class I, class II, and class III. MHC class I proteins can contain an α-chain and β2- microglobulin (not part of the MHC encoded by chromosome 15). They can present antigen fragments to cytotoxic T-cells. MHC class II proteins can contain α- and β-chains and they can present antigen fragments to T-helper cells. MHC class III region can encode for other immune components, such as complement components and cytokines. The MHC can be both polygenic (there are several MHC class I and MHC class II genes) and polymorphic (there are multiple alleles of each gene).WSGR Docket No.50401-795.601

[0301] A “receptor” refers to a biological molecule or a molecule grouping capable of binding a ligand. A receptor may serve, to transmit information in a cell, a cell formation or an organism. A receptor comprises at least one receptor unit, for example, where each receptor unit may consist of a protein molecule. A receptor has a structure which complements that of a ligand and may complex the ligand as a binding partner. The information is transmitted in particular by conformational changes of the receptor following complexation of the ligand on the surface of a cell. In some embodiments, a receptor is to be understood as meaning in particular proteins of MHC classes I and II capable of forming a receptor / ligand complex with a ligand, in particular a peptide or peptide fragment of suitable length. A “ligand” refers to a molecule which has a structure complementary to that of a receptor and is capable of forming a complex with this receptor. In some embodiments, a ligand is to be understood as meaning a peptide or peptide fragment which has a suitable length and suitable binding motifs in its amino acid sequence, so that the peptide or peptide fragment is capable of forming a complex with MHC proteins such as MHC class I or MHC class II proteins. In some embodiments, a “receptor / ligand complex” is also to be understood as meaning a “receptor / peptide complex” or “receptor / peptide fragment complex”, including a peptide- or peptide fragment- presenting MHC molecule such as MHC class I or MHC class II molecules.

[0302] A “native” or a “wild type” sequence refers to a sequence found in nature. The term “naturally occurring” as used herein refers to the fact that an object can be found in nature. For example, a peptide or nucleic acid that is present in an organism (including viruses) and can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally occurring.

[0303] The terms “peptide” and “peptide epitope” are used interchangeably with “oligopeptide” in the present specification to designate a series of residues connected one to the other, typically by peptide bonds between the α-amino and carboxyl groups of adjacent amino acid residues. A “synthetic peptide” refers to a peptide that is obtained from a non-natural source, e.g., is man-made. Such peptides can be produced using such methods as chemical synthesis or recombinant DNA technology. “Synthetic peptides” include “fusion proteins.”

[0304] The term “motif” refers to a pattern of residues in an amino acid sequence of defined length, for example, a peptide of less than about 15 amino acid residues in length, or less than about 13 amino acid residues in length, for example, from about 8 to about 13 amino acid residues (e.g., 8, 9, 10, 11, 12, or 13) for a class I HLA motif and from about 6 to about 25 amino acid residues (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) for a class II HLA motif, which is recognized by a particular HLA molecule. Motifs are typically different for each HLA protein encoded by a given human HLA allele. These motifs differ in their pattern of the primary and secondary anchor residues. In some embodiments, an MHC class I motif identifies a peptide of 7, 89,WSGR Docket No.50401-795.601 10, 11, 12 or 13 amino acid residues in length. In some embodiments, an MHC class II motif identifies a peptide of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 amino acid residues in length. A “cross-reactive binding” peptide refers to a peptide that binds to more than one member of a class of a binding pair members (e.g., a peptide bound by both a class I HLA molecule and a class II HLA molecule).

[0305] The term “residue” refers to an amino acid residue or amino acid mimetic residue incorporated into a peptide or protein by an amide bond or amide bond mimetic, or that is encoded by a nucleic acid (DNA or RNA). The nomenclature used to describe peptides or proteins follows the conventional practice. The amino group is presented to the left (the amino- or N-terminus) and the carboxyl group to the right (the carboxy- or C-terminus) of each amino acid residue. When amino acid residue positions are referred to in a peptide epitope, they are numbered in an amino to carboxyl direction with the first position being the residue located at the amino terminal end of the epitope, or the peptide or protein of which it can be a part. In the formulae representing selected specific embodiments of the present disclosure, the amino- and carboxyl-terminal groups, although not specifically shown, are in the form they can assume at physiologic pH values, unless otherwise specified. In the amino acid structure formulae, each residue is generally represented by standard three letter or single letter designations. The L-form of an amino acid residue is represented by a capital single letter or a capital first letter of a three-letter symbol, and the D-form for those amino acid residues having D-forms is represented by a lower case single letter or a lower case three letter symbol. However, when three letter symbols or full names are used without capitals, they can refer to L amino acid residues. Glycine has no asymmetric carbon atom and is simply referred to as “Gly” or “G”. The amino acid sequences of peptides set forth herein are generally designated using the standard single letter symbol. (A, Alanine; C, Cysteine; D, Aspartic Acid; E, Glutamic Acid; F, Phenylalanine; G, Glycine; H, Histidine; I, Isoleucine; K, Lysine; L, Leucine; M, Methionine; N, Asparagine; P, Proline; Q, Glutamine; R, Arginine; S, Serine; T, Threonine; V, Valine; W, Tryptophan; and Y, Tyrosine.)

[0306] A “conservative amino acid substitution” is one in which one amino acid residue is replaced with another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of a phenylalanine for a tyrosine is a conservativeWSGR Docket No.50401-795.601 substitution. Methods of identifying nucleotide and amino acid conservative substitutions which do not eliminate peptide function are well-known in the art.

[0307] “Pharmaceutically acceptable” refers to a generally non-toxic, inert, and / or physiologically compatible composition or component of a composition. A “pharmaceutical excipient” or “excipient” comprises a material such as an adjuvant, a carrier, pH-adjusting and buffering agents, tonicity adjusting agents, wetting agents, preservatives, and the like. A “pharmaceutical excipient” is an excipient which is pharmaceutically acceptable.

[0308] According to the present disclosure, the term “vaccine” relates to a pharmaceutical preparation (pharmaceutical composition) or product that upon administration induces an immune response, for example, a cellular or humoral immune response, which recognizes and attacks a pathogen or a diseased cell such as a cancer cell. A vaccine may be used for the prevention or treatment of a disease. The term “individualized cancer vaccine” or “personalized cancer vaccine” “personal cancer vaccine” concerns a particular cancer patient and means that a cancer vaccine is adapted to the needs or special circumstances of an individual cancer patient.

[0309] The terms “polynucleotide” and “nucleic acid” are used interchangeably herein and refer to polymers of nucleotides of any length, and include DNA and RNA, for example, mRNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. In some embodiments, the polynucleotide and nucleic acid can be in vitro transcribed mRNA. In some embodiments, the polynucleotide that is administered using the methods of the present disclosure is mRNA.

[0310] The terms “isolated” or “biologically pure” refer to material which is substantially or essentially free from components which normally accompany the material as it is found in its native state. Thus, isolated peptides described herein do not contain some or all of the materials normally associated with the peptides in their in situ environment. For example, an “isolated” epitope can be an epitope that does not include the whole sequence of the protein from which the epitope was derived. For example, a naturally-occurring polynucleotide or peptide present in a living animal is not isolated, but the same polynucleotide or peptide, separated from some or all of the coexisting materials in the natural system, is isolated. Such a polynucleotide could be part of a vector, and / or such a polynucleotide or peptide could be part of a composition, and still be “isolated” in that such vector or composition is not part of its natural environment. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the DNA molecules described herein, and further include such molecules produced synthetically. In some embodiments, a polypeptide, antibody, polynucleotide, vector, cell, or composition which is isolated is substantially pure. The term “substantially pure” as used hereinWSGR Docket No.50401-795.601 refers to material which is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0311] The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variations thereof. In some embodiments, two nucleic acids or polypeptides described herein are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, 99% nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists over a region of the sequences that is at least about 10, at least about 20, at least about 40-60 residues, at least about 60-80 residues in length or any integral value there between. In some embodiments, identity exists over a longer region than 60-80 residues, such as at least about 80-100 residues, and in some embodiments the sequences are substantially identical over the full length of the sequences being compared, such as an amino acid sequence of a peptide or a coding region of a nucleotide sequence.

[0312] The term “subject” refers to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, canines, felines, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.

[0313] The terms “effective amount” or “therapeutically effective amount” or “therapeutic effect” refer to an amount of a therapeutic effective to “treat” a disease or disorder in a subject or mammal. The therapeutically effective amount of a drug has a therapeutic effect and as such can prevent the development of a disease or disorder; slow down the development of a disease or disorder; slow down the progression of a disease or disorder; relieve to some extent one or more of the symptoms associated with a disease or disorder; reduce morbidity and mortality; improve quality of life; or a combination of such effects.

[0314] The terms “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that preventWSGR Docket No.50401-795.601 or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.

[0315] The term “depleted” when used to describe a cell sample (e.g., a peripheral blood mononuclear cell (PBMC) sample) refers to a cell sample in which a subpopulation of cells has been removed or depleted. For example, an immune cell sample depleted of CD25 expressing cells refers to an immune cell sample in which CD25 expressing cells have been removed or depleted. For example, one or more binding agents can be used to remove or deplete one or more cells or cell types from a sample. For example, CD14+ cells can be depleted or removed from a PBMC sample, such as by using an antibody that binds to CD14.

[0316] The “stimulation” refers to a response induced by binding of a stimulatory molecule with its cognate ligand thereby mediating a signal transduction event. For example, stimulation of a T cell can refer to binding of a TCR of a T cell to a peptide-MHC complex. For example, stimulation of a T cell can refer to a step within protocol 1 or protocol 2 in which PBMCs are cultured together with peptide loaded APCs.

[0317] The term “enriched” refers to a composition or fraction wherein an object species has been partially purified such that the concentration of the object species is substantially higher than the naturally occurring level of the species in a finished product without enrichment. The term “induced cell” refers to a cell that has been treated with an inducing compound, cell, or population of cells that affects the cell’s protein expression, gene expression, differentiation status, shape, morphology, viability, and the like.

[0318] A “reference” can be used to correlate and / or compare the results obtained in the methods of the present disclosure from a diseased specimen. Typically, a “reference” may be obtained on the basis of one or more normal specimens, in particular specimens which are not affected by a disease, either obtained from an individual or one or more different individuals (e.g., healthy individuals), such as individuals of the same species. A “reference” can be determined empirically by testing a sufficiently large number of normal specimens.

[0319] As used herein, a tumor unless otherwise mentioned, is a cancerous tumor, and the terms cancer and tumor are used interchangeably throughout the document. While a tumor is a cancer of solid tissue, several of the compositions and methods described herein are in principle applicable to cancers of the blood, leukemia. Overview

[0320] After infusion of T cells (e.g., ex vivo activated T cells, or T-cell receptor engineered T cells (TCR-T cells)) into a patient with cancer, the cells can circulate until they encounter their cognate epitope, typically on a tumor cell. In the case of solid tumors, this can be challenging because the TWSGR Docket No.50401-795.601 cells can infiltrate the tumor and survive the harsh tumor microenvironment. Partly due to this challenge, infused T cell numbers and frequency may decline relatively rapidly after infusion. Additionally, the dose of infused TCR-T cells may be important in clinical response across several studies.

[0321] One strategy to support the engraftment, expansion and persistence of infused T cells after infusion can include administering a vaccine that encodes the target antigen. In this case, however, the vaccine design can differ and may be a determinant of the success of this approach. The vaccine may encode for the full-length protein to be presented on the surface of cells. The vaccine strings designed to lead to optimal cleavage of the target epitopes can lead to more (e.g., 10-100 times more) of the desired epitope being presented on major histocompatibility complex (MHC) molecules encoded by HLA alleles than when the full-length RAS protein is used. The full-length RAS polypeptide can be a full-length KRAS, NRAS or HRAS polypeptide. This method can enable the vaccine to induce robust display of the target epitope in a patient and subsequent stimulation of transferred T cells, whereas the dose attainable with the full-length RAS protein may be insufficient in some cases.

[0322] The vaccine may encode targets epitopes presented by MHC molecules encoded by HLA- A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA- C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-DRB1*11:01, HLA-A*03:02, HLA-B*07:02, HLA-C*08:02, HLA-C*03:04, HLA-C*05:01, and HLA-A*03:05. Provided herein are vaccine constructs to present at least the target epitope on each of these HLA alleles. There are multiple considerations, including the order of the epitopes, the number of times each epitope is encoded, the codon optimization approach, and the mRNA format. A series of in vitro and in vivo assays have been defined to prioritize and select the best vaccine design, starting by choosing the best codon optimization approach and then selecting the best order of the epitopes. This information can be used to evaluate the approach in vivo. For example, a mouse model for this approach can utilize mice expressing human HLA and MHC. HLA-engineered tumor cells can also be utilized to evaluate the approach. RAS Vaccines

[0323] The present disclosure provides RAS vaccines comprising RAS polypeptides or recombinant nucleic acids encoding RAS polypeptides that, when expressed, can result in presentation of one or more epitopes of RAS by one or more MHC molecules encoded by one or more HLA alleles.

[0324] Provided herein is a recombinant nucleic acid encoding a RAS polypeptide comprising a multiepitopic polypeptide. In some embodiments, the RAS polypeptide does not comprise a full- length RAS polypeptide. In some embodiments, the RAS polypeptide comprises a first RAS amino acid sequence comprising a first RAS epitope sequence. In some embodiments, the RAS polypeptide comprises a second RAS amino acid sequence comprising a second RAS epitope sequence. In someWSGR Docket No.50401-795.601 embodiments, the first RAS epitope sequence and the second RAS epitope sequence are different. In some embodiments, the first RAS epitope sequence and the second RAS epitope sequence are linked via a linker. In some embodiments, presentation of the first and / or second RAS epitope sequence as a peptide:MHC complex by the antigen presenting cells (APCs) of the subject administered the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide is higher than the presentation of the first and / or second RAS epitope sequence as the peptide:MHC complex by the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide. In some embodiments, the first RAS amino acid sequence is the first epitope sequence. In some embodiments, the second RAS amino acid sequence is the second epitope sequence. In some embodiments, the first RAS amino acid sequence is the first epitope sequence and the second RAS amino acid sequence is the second epitope sequence. In some embodiments, the first RAS amino acid sequence consists of the first epitope sequence. In some embodiments, the second RAS amino acid sequence consists of the second epitope sequence. In some embodiments, the first RAS amino acid sequence consists of the first epitope sequence and the second RAS amino acid sequence consists of the second epitope sequence. In some cases, each different RAS epitope sequence is separated by a linker.

[0325] In some embodiments, the first RAS amino acid sequence comprises a first RAS mutation. In some embodiments, the second RAS amino acid sequence comprises a second RAS mutation. In some embodiments, the second RAS mutation is different from the first RAS mutation. In some embodiments, the second RAS mutation is same as the first RAS mutation. In some embodiments, the first RAS amino acid sequence comprises a first RAS mutation, and the second RAS amino acid sequence comprises a second RAS mutation different from the first RAS mutation. In some embodiments, the first RAS amino acid sequence comprises a first RAS mutation, and the second RAS amino acid sequence comprises a second RAS mutation same as the first RAS mutation.

[0326] In some embodiments, the first RAS mutation is selected from the group consisting of G12V, G12D, and G12C. In some embodiments, the second RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

[0327] In some embodiments, the first RAS amino acid sequence is processed into one or more epitopes comprising the first RAS mutation within a cell. In some embodiments, the first RAS mutation is G12V, and the one or more epitopes are selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72. In some embodiments, the first RAS mutation is G12D, and the one or more epitopes are selected from the group consisting of SEQ ID NOs: 28, 75-79. In some embodiments, the first RAS mutation is G12C, and the one or more epitopes are selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096. In some embodiments, the first RAS epitope sequence first RAS epitope sequence consists of from 5 to 18, from 6 to 17, from 5 to 16, from 7 toWSGR Docket No.50401-795.601 12, or from 8 to 10 consecutive amino acids from the full length RAS polypeptide. In some embodiments, the second RAS epitope sequence consists of from 5 to 18, from 6 to 17, from 5 to 16, from 7 to 12, or from 8 to 10 consecutive amino acids from the full length RAS polypeptide.

[0328] In some embodiments, the first RAS epitope sequence consists of from 8 to 30, from 9 to 29, from 10 to 28, from 11 to 27, from 12 to 26, from 13 to 25, from 14 to 24, or from 15 to 23 consecutive amino acids from the full length RAS polypeptide. In some embodiments, the second RAS epitope sequence consists of from 8 to 30, from 9 to 29, from 10 to 28, from 11 to 27, from 12 to 26, from 13 to 25, from 14 to 24, or from 15 to 23 consecutive amino acids from the full length RAS polypeptide.

[0329] In some embodiments, the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker. In some embodiments, the first RAS amino acid sequence comprises the first RAS epitope sequence and one, two, three, four, five or more residues flanking the N-terminus or C-terminus of the first RAS epitope sequence from the full length RAS polypeptide. In some embodiments, the second RAS amino acid sequence comprises the second RAS epitope sequence and one, two, three, four, five or more residues flanking the N-terminus or C-terminus of the second RAS epitope sequence from the full-length RAS polypeptide.

[0330] In some embodiments the multiepitopic polypeptide does not comprise more than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more consecutive amino acids from the full-length RAS polypeptide. In some embodiments, the multiepitopic polypeptide does not comprise more than 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more consecutive amino acids from the full-length RAS polypeptide.

[0331] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding a secretory (Sec) sequence. In some embodiments, the Sec sequence is at the N terminus of the multiepitopic polypeptide. In some embodiments the Sec sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80% , at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 32. In some embodiments the Sec sequence comprises a sequence of SEQ ID NO: 32. In some embodiments, the Sec sequence is operably linked to the multiepitopic polypeptide via a linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 30. In some embodiments, the linker comprises a sequence of SEQ ID NO: 30. In some embodiments, the Sec sequence is operably linked to the multiepitopic polypeptide via a linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 112. In some embodiments, the linker comprises a sequence of SEQ ID NO: 112. In some embodiments, the linker comprises a sequence having at least 60%, at leastWSGR Docket No.50401-795.601 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 31. In some embodiments, the linker comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 30. In some cases, the linker comprises a sequence of SEQ ID NO: 31.

[0332] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding an MHC I Trafficking Domain (MITD) sequence. In some embodiments, the sequence encoding an MITD sequence is at the C terminus of the multiepitopic polypeptide. In some embodiments, the MITD sequence comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 33. In some embodiments, the MITD sequence comprises a sequence of SEQ ID NO: 33. In some embodiments, the multiepitopic polypeptide is operably linked to the MITD domain. In some embodiments, the multiepitopic polypeptide is operably linked to the MITD domain via a linker sequence. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 30. In some embodiments, the linker comprises a sequence of SEQ ID NO: 30. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 112. In some embodiments, the linker comprises a sequence of SEQ ID NO: 112.

[0333] In some embodiments, the multiepitopic polypeptide comprises a RAS polypeptide. In some embodiments, the sequence of the multiepitopic polypeptide is the same RAS epitope sequence. In some embodiments, the sequence of the multiepitopic polypeptide is a different RAS epitope sequence. In some embodiments, the multiepitopic polypeptide comprises at least 2 different RAS epitope sequences. In some embodiments, the multiepitopic polypeptide comprises at least 3 different RAS epitope sequences. In some embodiments, the multiepitopic polypeptide comprises at least 4 different RAS epitope sequences. In some embodiments, the multiepitopic polypeptide comprises at least 5 different RAS epitope sequences. In some embodiments, the multiepitopic polypeptide comprises at least 6 different RAS epitope sequences. In some embodiments, the multiepitopic polypeptide comprises at least 8 different RAS epitope sequences. In some embodiments, the multiepitopic polypeptide comprises at least 9 different RAS epitope sequences. In some embodiments, the multiepitopic polypeptide comprises at least 10 or more different RAS epitope sequences. In some embodiments, the multiepitopic polypeptide is a RAS polypeptide comprising the first RAS epitope sequence and the second RAS epitope sequence.

[0334] In some embodiments, the multiepitopic polypeptide comprises a first RAS epitope sequence, operably linked to a second RAS epitope sequence. In some embodiments, the first RAS epitopeWSGR Docket No.50401-795.601 sequence and the second RAS epitope sequence are the same. In some embodiments, the first RAS epitope sequence and the second RAS epitope sequence are different. In some embodiments, the first RAS epitope sequence and second RAS epitope sequence are presentable by different HLA alleles. In some embodiments, the first RAS epitope sequence and second RAS epitope sequence are presented by different HLA alleles. In some embodiments, the first RAS epitope sequence and second RAS epitope sequence are predicted to bind to different HLA alleles. In some embodiments, the first RAS epitope sequence and second RAS epitope sequence are predicted to be presented by different HLA alleles.

[0335] In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD less than 500nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD less than 400nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD less than 300nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele. In some embodiments, a first RAS epitope sequence is predicted to bind to a first HLA allele. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD less than 200nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD less than 100nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD less than 50nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD less than 1nM. In some embodiments, a first RAS epitope sequence binds to a second HLA allele. In some embodiments, a first RAS epitope sequence is predicted to bind to a second HLA allele. In some embodiments, a first RAS epitope sequence binds to a second HLA allele with a KD of more than 200nM. In some embodiments, a first RAS epitope sequence binds to a second HLA allele with a KD of more than 300nM. In some embodiments, a first RAS epitope sequence binds to a second HLA allele with a KD of more than 500nM. In some embodiments, a first RAS epitope sequence binds to a second HLA allele with a KD of more than 600nM. In some embodiments, a first RAS epitope sequence binds to a second HLA allele with a KD of more than 700nM. In some embodiments, a first RAS epitope sequence binds to a second HLA allele with a KD of more than 800nM. In some embodiments, a first RAS epitope sequence binds to a second HLA allele with a KD of more than 900nM. In some embodiments, a first RAS epitope sequence binds to a second HLA allele with a KD of more than 1000nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD of less than 1nM and binds to second HLA allele with a KD of more than 200nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD of less than 50nM and binds to second HLA allele with a KD of more than 300nM. In some embodiments, a first RAS epitope sequence binds to a first HLA allele with a KD of less than 100nM and binds to second HLA allele with a KD of more than 500nM. In some embodiments, a firstWSGR Docket No.50401-795.601 RAS epitope sequence binds to a first HLA allele with a KD of less than 200 nM and binds to second HLA allele with a KD of more than 600 nM.

[0336] In some embodiments, the linker comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 31. In some embodiments, the linker comprises a sequence of SEQ ID NO: 31. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 112. In some embodiments, the linker comprises a sequence of SEQ ID NO: 112.

[0337] In some embodiments, the multiepitopic polypeptide comprises a first RAS epitope sequence, operably linked to a second RAS epitope sequence, operably linked to a third RAS epitope sequence.

[0338] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*11:01 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*11:01 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*11:01 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*11:01 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*11:01 allele.

[0339] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*03:01 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*03:01 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*03:01 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*03:01 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*03:01 allele.

[0340] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*30:01 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*30:01 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*30:01 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*30:01 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*30:01 allele.WSGR Docket No.50401-795.601

[0341] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*68:01 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*68:01 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*68:01 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*68:01 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*68:01 allele.

[0342] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-B allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-B*40:01 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-B*40:01 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- B*40:01 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-B*40:01 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-B*40:01 allele.

[0343] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C*01:02 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-C*01:02 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- C*01:02 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-C*01:02 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-C*01:02 allele.

[0344] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C*03:03 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-C*03:03 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- C*03:03 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-C*03:03 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-C*03:03 allele.

[0345] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C*03:04 allele. In some embodiments, the first RAS epitopeWSGR Docket No.50401-795.601 sequence is presented by an MHC molecule encoded by an HLA-C*03:04 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- C*03:04 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-C*03:04 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-C*03:04 allele.

[0346] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-DRB1 allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-DRB1*07:01 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-DRB1*07:01 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA-DRB1*07:01 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-DRB1*07:01 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA- DRB1*07:01 allele.

[0347] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*03:02 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*03:02 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*03:02 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*03:02 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*03:02 allele.

[0348] In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*03:05 allele. In some embodiments, the first RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*03:05 allele. In some embodiments, the first RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*03:05 allele. In some embodiments, the first RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*03:05 allele. In some embodiments, the first RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*03:05 allele.

[0349] In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-B allele. In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-B*07:02 allele. In some embodiments, the second RAS epitope sequence is presented by an MHC molecule encoded by an HLA-B*07:02 allele. In some embodiments, the second RAS epitope sequence binds to an MHC molecule encoded by an HLA-WSGR Docket No.50401-795.601 B*07:02 allele. In some embodiments, the second RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-B*07:02 allele. In some embodiments, the second RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-B*07:02 allele.

[0350] In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C allele. In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C*03:04 allele. In some embodiments, the second RAS epitope sequence is presented by an MHC molecule encoded by an HLA-C*03:04 allele. In some embodiments, the second RAS epitope sequence binds to an MHC molecule encoded by an HLA- C*03:04 allele. In some embodiments, the second RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-C*03:04 allele. In some embodiments, the second RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-C*03:04 allele.

[0351] In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C allele. In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C*05:01 allele. In some embodiments, the second RAS epitope sequence is presented by an MHC molecule encoded by an HLA-C*05:01 allele. In some embodiments, the second RAS epitope sequence binds to an MHC molecule encoded by an HLA- C*05:01 allele. In some embodiments, the second RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-C*05:01 allele. In some embodiments, the second RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-C*05:01 allele.

[0352] In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*-3:01 allele. In some embodiments, the second RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*-3:01 allele. In some embodiments, the second RAS epitope sequence binds to an MHC molecule encoded by an HLA-A*- 3:01 allele. In some embodiments, the second RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*-3:01 allele. In some embodiments, the second RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*-3:01 allele.

[0353] In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*-11:01 allele. In some embodiments, the second RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*-11:01 allele. In some embodiments, the second RAS epitope sequence binds to an MHC molecule encoded by an HLA-A*- 11:01 allele. In some embodiments, the second RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*-11:01 allele. In some embodiments, the second RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*-11:01 allele.WSGR Docket No.50401-795.601

[0354] In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*-68:01 allele. In some embodiments, the second RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*-68:01 allele. In some embodiments, the second RAS epitope sequence binds to an MHC molecule encoded by an HLA-A*- 68:01 allele. In some embodiments, the second RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*-68:01 allele. In some embodiments, the second RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*-68:01 allele.

[0355] In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C allele. In some embodiments, the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C*08:02 allele. In some embodiments, the second RAS epitope sequence is presented by an MHC molecule encoded by an HLA-C*08:02 allele. In some embodiments, the second RAS epitope sequence binds to an MHC molecule encoded by an HLA- C*08:02 allele. In some embodiments, the second RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-C*08:02 allele. In some embodiments, the second RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-C*08:02 allele.

[0356] In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-DRB allele. In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-DRB1*11:01 allele. In some embodiments, the third RAS epitope sequence is presented by an MHC molecule encoded by an HLA-DRB1*11:01 allele. In some embodiments, the third RAS epitope sequence binds to an MHC molecule encoded by an HLA-DRB1*11:01 allele. In some embodiments, the third RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-DRB1*11:01 allele. In some embodiments, the third RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA- DRB1*11:01 allele.

[0357] In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*3:01 allele. In some embodiments, the third RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*3:01 allele. In some embodiments, the third RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*3:01 allele. In some embodiments, the third RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*3:01 allele. In some embodiments, the third RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*3:01 allele.

[0358] In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the third RAS epitope sequence is presentable byWSGR Docket No.50401-795.601 an MHC molecule encoded by an HLA-A*11:01 allele. In some embodiments, the third RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*11:01 allele. In some embodiments, the third RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*11:01 allele. In some embodiments, the third RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*11:01 allele. In some embodiments, the third RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*11:01 allele.

[0359] In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A allele. In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-A*68:01 allele. In some embodiments, the third RAS epitope sequence is presented by an MHC molecule encoded by an HLA-A*68:01 allele. In some embodiments, the third RAS epitope sequence binds to an MHC molecule encoded by an HLA- A*68:01 allele. In some embodiments, the third RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-A*68:01 allele. In some embodiments, the third RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-A*68:01 allele.

[0360] In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C allele. In some embodiments, the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA-C*03:03 allele. In some embodiments, the third RAS epitope sequence is presented by an MHC molecule encoded by an HLA-C*03:03 allele. In some embodiments, the third RAS epitope sequence binds to an MHC molecule encoded by an HLA- C*03:03 allele. In some embodiments, the third RAS epitope sequence is predicted to bind to an MHC molecule encoded by an HLA-C*03:03 allele. In some embodiments, the third RAS epitope sequence is predicted to be presented by an MHC molecule encoded by an HLA-C*03:03 allele.

[0361] In some embodiments, the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2])x-CT seq, where x is an integer from 1 to 50. In some embodiments, the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2])x-CT seq, where x is an integer from 1 to 25. In some embodiments, the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1- [Antigen2])x-CT seq, where x is an integer from 1 to 10.

[0362] In some embodiments, the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2]-cleavable linker2-[Antigen3])x-CT seq, where x is an integer from 1 to 50. In some embodiments, the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2]-cleavable linker2-[Antigen3])x-CT seq, where x is an integer from 1 to 25. In some cases, the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2]-cleavable linker2-[Antigen3])x-CT seq, where x is an integer from 1 to 10.WSGR Docket No.50401-795.601

[0363] In some embodiments, the NT seq comprises a secretory (Sec) sequence and a N-terminal linker sequence. In some embodiments, the CT seq comprises a C-terminal linker and a MITD sequence. In some embodiments, the Antigen1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 27-29. In some embodiments, the Antigen2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 27-29. In some embodiments, the Antigen3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 27- 29. In some cases, the cleavable linker1 or cleavable linker2 comprise a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to any one of SEQ ID NOs: 30 or 31. In some embodiments, the cleavable linker1 or cleavable linker2 is selected from the group consisting of SEQ ID NOs: 30 and 31. In some embodiments, the N-terminal linker sequence is selected from the group consisting of SEQ ID NOs: 30 and 31. In some embodiments, the C-terminal linker sequence is selected from the group consisting of SEQ ID NOs: 30 and 31.

[0364] In some embodiments, the RAS polypeptide comprises a sequence with at least 60% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises a sequence with at least 70% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises a sequence with at least 80% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises a sequence with at least 90% sequence identity to SEQ ID NO: 75. In some embodiments, the RAS polypeptide comprises a sequence of SEQ ID NO: 27.

[0365] In some embodiments, the RAS polypeptide comprises a sequence with at least 60% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises a sequence with at least 70% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises a sequence with at least 80% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises a sequence with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises a sequence of SEQ ID NO: 28.

[0366] In some embodiments, the RAS polypeptide comprises a sequence with at least 60% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises a sequence with at least 70% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises a sequence with at least 80% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises a sequence with at least 90% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises a sequence of SEQ ID NO: 29.

[0367] In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 60% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 70% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at leastWSGR Docket No.50401-795.601 80% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 27.

[0368] In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 60% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 70% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 80% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 28.

[0369] In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 60% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 70% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 80% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 29.

[0370] In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 60% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 70% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 80% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 90% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 27.

[0371] In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 60% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 70% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 80% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 28.

[0372] In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 60% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 70% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 80% sequence identity to SEQWSGR Docket No.50401-795.601 ID NO: 29. In some embodiments, the RAS polypeptide comprises two copies of a sequence with at least 90% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 29.

[0373] In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 60% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 70% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 80% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 90% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 27.

[0374] In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 60% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 70% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 80% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 28.

[0375] In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 60% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 70% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 80% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises three copies of a sequence with at least 90% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 29.

[0376] In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 60% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 70% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 80% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 90% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 27.

[0377] In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 60% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 70% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 80% sequenceWSGR Docket No.50401-795.601 identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 28.

[0378] In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 60% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 70% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 80% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises four copies of a sequence with at least 90% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 29.

[0379] In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 60% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 70% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 80% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 90% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 27.

[0380] In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 60% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 70% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 80% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 28.

[0381] In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 60% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 70% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 80% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises five copies of a sequence with at least 90% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 29.

[0382] In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 60% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 70% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at leastWSGR Docket No.50401-795.601 80% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 90% sequence identity to SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence of SEQ ID NO: 27.

[0383] In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 60% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 70% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 80% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence of SEQ ID NO: 28.

[0384] In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 60% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 70% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 80% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence with at least 90% sequence identity to SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises six or more copies of a sequence of SEQ ID NO: 29.

[0385] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 27, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 29, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 28.

[0386] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 27, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 29 via a linker, and the sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 29 operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 28 via a linker. In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus,WSGR Docket No.50401-795.601 the sequence of SEQ ID NO: 27, operably linked to the sequence of SEQ ID NO: 29 via a linker, and the sequence of SEQ ID NO: 29 operably linked to the sequence of SEQ ID NO: 28 via a linker. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 31. In some embodiments, the linker comprises a sequence of SEQ ID NO: 31. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 112. In some embodiments, the linker comprises a sequence of SEQ ID NO: 112.

[0387] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 29, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 28, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 27. In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, the sequence of SEQ ID NO: 29, operably linked to the sequence of SEQ ID NO: 28, operably linked to the sequence of SEQ ID NO: 27.

[0388] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 29, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 28 via a linker, and the sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 28 operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 27 via a linker. In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, the sequence of SEQ ID NO: 29, operably linked to the sequence of SEQ ID NO: 28 via a linker, and the sequence of SEQ ID NO: 28 operably linked to the sequence of SEQ ID NO: 27 via a linker. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 31. In someWSGR Docket No.50401-795.601 embodiments, the linker comprises a sequence of SEQ ID NO: 31. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 112. In some embodiments, the linker comprises a sequence of SEQ ID NO: 112.

[0389] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 28, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 27, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 29. In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, the sequence of SEQ ID NO: 28, operably linked to the sequence of SEQ ID NO: 27, operably linked to the sequence of SEQ ID NO: 29.

[0390] In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 28, operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 27 via a linker, and the sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 27 operably linked to a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence of SEQ ID NO: 29 via a linker. In some embodiments, the RAS polypeptide comprises, from N terminus to C terminus, the sequence of SEQ ID NO: 28, operably linked to the sequence of SEQ ID NO: 27 via a linker, and the sequence of SEQ ID NO: 27 operably linked to the sequence of SEQ ID NO: 29 via a linker. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 31. In some embodiments, the linker comprises a sequence of SEQ ID NO: 31. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 112. In some embodiments, the linker comprises a sequence of SEQ ID NO: 112.WSGR Docket No.50401-795.601

[0391] In some embodiments, the RAS polypeptide comprises two copies of a multiepitopic polypeptide. In some embodiments each copy of the multiepitopic polypeptide comprises, from N to C terminus, a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 29, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 28, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 27.

[0392] In some embodiments, the RAS polypeptide comprises three copies of a multiepitopic polypeptide. In some embodiments each copy of the multiepitopic polypeptide comprises, from N to C terminus, a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 29, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 28, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 27.

[0393] In some embodiments, the RAS polypeptide comprises four copies of a multiepitopic polypeptide. In some embodiments each copy of the multiepitopic polypeptide comprises, from N to C terminus, a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 29, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 28, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 27.

[0394] In some embodiments, the RAS polypeptide comprises five copies of a multiepitopic polypeptide. In some embodiments each copy of the multiepitopic polypeptide comprises, from N to C terminus, a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 29, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 28, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 27.

[0395] In some embodiments, the RAS polypeptide comprises six copies of a multiepitopic polypeptide. In some embodiments each copy of the multiepitopic polypeptide comprises, from N to C terminus, a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 29, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 28, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 27.

[0396] In some embodiments, the RAS polypeptide comprises seven copies of a multiepitopic polypeptide. In some embodiments each copy of the multiepitopic polypeptide comprises, from N to C terminus, a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 29, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 28, operably linked to a sequence with at least 80% sequence identity to a sequence of SEQ ID NO: 27.

[0397] Also provided herein are recombinant nucleic acids encoding multiepitopic polypeptides.

[0398] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more sequences with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.WSGR Docket No.50401-795.601

[0399] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 14.

[0400] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 15.

[0401] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ IDWSGR Docket No.50401-795.601 NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 16.

[0402] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 17.

[0403] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 18.

[0404] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RASWSGR Docket No.50401-795.601 polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 19.

[0405] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 20.

[0406] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 21.

[0407] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to aWSGR Docket No.50401-795.601 sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 22.

[0408] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 23.

[0409] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 84.

[0410] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleicWSGR Docket No.50401-795.601 acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 86.

[0411] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 88.

[0412] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 92.

[0413] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70%WSGR Docket No.50401-795.601 sequence identity to a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 93.

[0414] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 94.

[0415] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 96.

[0416] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 97. In some embodiments, theWSGR Docket No.50401-795.601 recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 97.

[0417] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 98.

[0418] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 100.

[0419] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequenceWSGR Docket No.50401-795.601 having at least 60% sequence identity to a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 101.

[0420] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 102.

[0421] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 104.

[0422] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 105. In someWSGR Docket No.50401-795.601 embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 105.

[0423] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 106.

[0424] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 108.

[0425] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, atWSGR Docket No.50401-795.601 least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 109.

[0426] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 70% sequence identity to a sequence of SEQ ID NO: 110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises a sequence of SEQ ID NO: 110.

[0427] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of one or more sequences with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100- 102, 104-106, 108-110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to aWSGR Docket No.50401-795.601 sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%,WSGR Docket No.50401-795.601 at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RASWSGR Docket No.50401-795.601 polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 110.

[0428] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of one or more sequences with at least 90% sequence identity to any one sequence selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104- 106, 108-110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQWSGR Docket No.50401-795.601 ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence with at least 90% sequence identity to a sequence of SEQ ID NO: 110.

[0429] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14- 23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ IDWSGR Docket No.50401-795.601 NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 105. In some embodiments,WSGR Docket No.50401-795.601 the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of a sequence of SEQ ID NO: 110.

[0430] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptideWSGR Docket No.50401-795.601 comprises two copies of a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises two copies of a sequence of SEQ ID NO: 110.

[0431] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 88.WSGR Docket No.50401-795.601 In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of a sequence of SEQ ID NO: 110.

[0432] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acidWSGR Docket No.50401-795.601 encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of a sequence of SEQ ID NO: 110.

[0433] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of aWSGR Docket No.50401-795.601 sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 101. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 108. In some embodiments, the recombinantWSGR Docket No.50401-795.601 nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of a sequence of SEQ ID NO: 110.

[0434] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 14. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 15. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 16. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 17. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 18. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 19. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 20. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 21. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 22. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 23. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 84. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 86. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 88. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 92. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 93. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 94. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 96. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 97. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 98. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 100. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 101.WSGR Docket No.50401-795.601 In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 102. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 104. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 105. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 106. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 109. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of a sequence of SEQ ID NO: 110.

[0435] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, and operably linked to a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 17-19, 86, 93, 97, 101, 105, and 109.

[0436] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, and operably linked to a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 17-19, 86, 93, 97, 101, 105, and 109.

[0437] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, and operably linked to a sequence selected from the group consisting of SEQ ID NO: 17-19, 86, 93, 97, 101, 105, and 109.

[0438] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selectedWSGR Docket No.50401-795.601 from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, via a linker sequence and the sequence a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 operably linked to a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity the sequence selected from the group consisting of SEQ ID NO: 17- 19, 86, 93, 97, 101, 105, and 109 via a linker sequence.

[0439] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 90% sequence identity the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence a sequence having at least 90% sequence identity the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, via a linker sequence and the sequence having at least 90% sequence identity the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence a sequence having at least 90% sequence identity the sequence selected from the group consisting of SEQ ID NO: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence.

[0440] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, via a linker sequence and the sequence of any one of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 operably linked to a sequence selected from the group consisting of SEQ ID NO: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence.

[0441] In some embodiments, the linker sequence encodes a cleavable linker. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 5. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 6. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 8. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequenceWSGR Docket No.50401-795.601 identity to a sequence of SEQ ID NO: 9. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 10. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 11. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 12. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 13. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 5. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 6. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 8. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 9. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 10. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 11. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 12. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 13.

[0442] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 80% sequence identity the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence having at least 80% sequence identity the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence having at least 80% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 14-16, 84, 92, 96, 100, 104, and 108.

[0443] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 14-16, 84, 92, 96, 100, 104, and 108.

[0444] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs:WSGR Docket No.50401-795.601 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NO: 14-16, 84, 92, 96, 100, 104, and 108.

[0445] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, via a linker sequence and the sequence a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 14-16, 84, 92, 96, 100, 104, and 108, via a linker sequence.

[0446] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence a sequence having at least 90% sequence identity to any one of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, via a linker sequence and the sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 14-16, 84, 92, 96, 100, 104, and 108, via a linker sequence.

[0447] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, via a linker sequence and the sequence of any one of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence selected from the group consisting of SEQ ID NO: 14-16, 84, 92, 96, 100, 104, and 108, via a linker sequence.

[0448] In some embodiments, the linker sequence encodes a cleavable linker. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 5. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, orWSGR Docket No.50401-795.601 100% sequence identity to a sequence of SEQ ID NO: 10. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 6. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 14. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 8. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 9. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 10. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 11. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 12. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 13. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 5. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 6. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 8. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 10. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 11. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 12. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 13.

[0449] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, and operably linked to a sequence a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, atWSGR Docket No.50401-795.601 least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 20-23, 88, 94, 98, 102, 106, and 110.

[0450] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, and operably linked to a sequence a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 20-23, 88, 94, 98, 102, 106, and 110.

[0451] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, and operably linked to a sequence selected from the group consisting of SEQ ID NO: 20-23, 88, 94, 98, 102, 106, and 110.

[0452] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, via a linker sequence and the sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 20-23, 88, 94, 98, 102, 106, and 110, via a linker sequence.

[0453] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-19, via a linker sequence and the sequence having at least 90% sequence identity to any one of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NO: 20-23, 88, 94, 98, 102, 106, and 110, via a linker sequence.WSGR Docket No.50401-795.601

[0454] In some cases, the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence of any one of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, via a linker sequence and the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence selected from the group consisting of SEQ ID NO: 20-23, 88, 94, 98, 102, 106, and 110, via a linker sequence.

[0455] In some embodiments, the linker sequence encodes a cleavable linker. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 5. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 6. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 8. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 9. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 10. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 11. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 12. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 13. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 8. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 5. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 6. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 8. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 9. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 10. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 11. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 12. In some embodiments, the linker sequence comprises a sequence of SEQ ID NO: 13.WSGR Docket No.50401-795.601

[0456] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises at least two copies of a string of sequences. In some embodiments, each string of sequences comprises, 5’ end to 3’ end, a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108. In some embodiments, each string of sequences comprises, from 5’ end to 3’ end, a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence a sequence having at least 90% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108. In some embodiments, each string of sequences comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of the string of sequences. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises four copies of the string of sequences. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of the string of sequences. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises six copies of the string of sequences. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises seven copies of the string of sequences. In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide comprises eight copies of the string of sequences.

[0457] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding a secretory (Sec) sequence. In some embodiments, the Sec sequence is at the 5’ end of the string of sequences. In some embodiments, the Sec sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 3. In someWSGR Docket No.50401-795.601 embodiments the Sec sequence comprises a sequence of SEQ ID NO: 3. In some embodiments, the sequence encoding the Sec sequence is operably linked to the string of sequences via a linker sequence. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89. In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

[0458] In some embodiments, the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding an MHC I Trafficking Domain (MITD) sequence. In some embodiments, the sequence encoding an MITD sequence is at the 3’ end of the string of sequences. In some embodiments the MITD sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 24 or 90. In some embodiments the MITD sequence comprises a sequence of SEQ ID NO: 24 or 90. In some embodiments, the string of sequences is operably linked to the sequence encoding the MITD domain. In some embodiments, the string of sequences is operably linked to the sequence encoding the MITD domain via a linker sequence. In some embodiments, the linker sequence comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to the sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89. In some embodiments, the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

[0459] Provided herein is a recombinant nucleic acid comprising a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 1. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 2. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 91. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 95. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 99. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%,WSGR Docket No.50401-795.601 at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 103. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 107. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 111.

[0460] In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 1. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 2. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 91. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 95. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 99. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 103. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 107. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence of SEQ ID NO: 111. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 1. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 2. In some embodiments, the recombinant nucleic acid comprises a sequence of SEQ ID NO: 1. In some embodiments, the recombinant nucleic acid comprises a sequence of SEQ ID NO: 2. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 91. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 95. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 99. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 103. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 107. In some embodiments, the recombinant nucleic acid comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 111. Immune Cells

[0461] The present disclosure provides immune cells (e.g., T cells) expressing a T cell receptor (TCR) or a chimeric antigen receptor. T cell receptors can also comprise endogenous T cell receptorsWSGR Docket No.50401-795.601 that have been activated. Immune cells expressing a TCR can be activated and / or expanded using methods such as NEO-STIM. T cell receptors can comprise receptors encoded by recombinant nucleic acids that are specific for a RAS polypeptide or fragment thereof.

[0462] Provided herein is a recombinant nucleic acid encoding a TCR. In some embodiments, the TCR comprises a TCR beta chain construct. In some embodiments the TCR comprises a TCR alpha chain construct. In some embodiments, the TCR comprises a TCR beta chain construct and a TCR alpha chain construct. In some embodiments, the TCR binds to a peptide:MHC complex. In some embodiments, the peptide:MHC complex comprises a RAS epitope sequence having at least 5 consecutive amino acids of a sequence selected from the group consisting of SEQ ID NO: 27, 58-62 and 65-72 and a human MHC encoded by an HLA allele selected from the group consisting of HLA- A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA- C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05. In some embodiments, the peptide:MHC complex comprises a RAS epitope sequence having at least 7 consecutive amino acids of a sequence selected from the group consisting of SEQ ID NO: 27, 58-62 and 65-72 and a human MHC encoded by an HLA allele selected from the group consisting of HLA- A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA- C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05. In some embodiments, the peptide:MHC complex comprises a RAS epitope sequence having at least 5 consecutive amino acids of a sequence selected from the group consisting of SEQ ID NO: 28, 75-79 and a human MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA-A*68:01. In some embodiments, the peptide:MHC complex comprises a RAS epitope sequence having at least 7 consecutive amino acids of a sequence selected from the group consisting of SEQ ID NO: 28, 75-79 and a human MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA-A*68:01. In some embodiments, the peptide:MHC complex comprises a RAS epitope sequence having at least 5 consecutive amino acids of a sequence selected from the group consisting of SEQ ID NO: 29, 81, 82, and 1096 and a human MHC encoded by an HLA allele selected from the group consisting of HLA- DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03. In some embodiments, the peptide:MHC complex comprises a RAS epitope sequence having at least 7 consecutive amino acids of a sequence selected from the group consisting of SEQ ID NO: 29, 81, 82, and 1096 and a human MHC encoded by an HLA allele selected from the group consisting of HLA- DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03.

[0463] In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at leastWSGR Docket No.50401-795.601 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 58. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 59. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 60. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 61. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 62. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 65. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 66. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 67. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 68. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 69. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 70. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 71. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 72. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 75. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequenceWSGR Docket No.50401-795.601 identity to a sequence of SEQ ID NO: 76. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 77. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 78. In some embodiments the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 80% sequence identity to a sequence of SEQ ID NO: 79. In some embodiments the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 29. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 81. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 82. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of SEQ ID NO: 1096.

[0464] In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 58. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 59. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 60. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 61. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 62. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 65. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 66. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 67. In some embodiments, the peptide:MHC complexWSGR Docket No.50401-795.601 comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 68. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 69. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 70. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 71. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 72. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 75. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 76. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 77. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 78. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 79. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 29. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 81. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 82. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence having at least 90% sequence identity to a sequence of SEQ ID NO: 1096.

[0465] In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 58. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 59. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 60. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 61. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 62. In some embodiments the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 65. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 66. In someWSGR Docket No.50401-795.601 embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 67. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 68. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 69. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 70. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 71. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 72. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 75. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 76. In some embodiments the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 77. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 78. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 79. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 29. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 81. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 82. In some embodiments, the peptide:MHC complex comprises the RAS epitope sequence having a sequence according to SEQ ID NO: 1096.

[0466] Also provided herein is a cell comprising the recombinant nucleic acids presented herein. In some embodiments, the cell is an immune cell. In some embodiments, the cell is a myeloid lineage cell. In some embodiments, the cell is a lymphocyte. In some embodiments, the cell is a B cell. In some embodiments, the cell is a T cell. In some cases, upon binding of the TCR to the peptide:MHC complex, the cell produces a proinflammatory cytokine. In some cases, the proinflammatory cytokine is IFN-γ. In some cases, the proinflammatory cytokine is TNF-α. In some cases, the proinflammatory cytokine is IL-12. In some cases, the proinflammatory cytokine is IL-6. In some cases, the proinflammatory cytokine is IL-17. In some embodiments, the proinflammatory cytokine is a chemokine. In some cases, upon binding of the TCR to the peptide:MHC complex, cell division is increased. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 2% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. InWSGR Docket No.50401-795.601 some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 5% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 10% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 15% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 25% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 50% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 100% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 150% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 200% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex. In some embodiments, upon binding of the TCR to the peptide:MHC complex, cytotoxicity of the cell against target cell is increased by 500% or more compared to an otherwise identical cell not having a TCR specific for the peptide:MHC complex.

[0467] Also provided herein is a recombinant nucleic acid encoding a TCR comprising a TCR beta chain construct. In some embodiments, the recombinant nucleic acid encoding a TCR comprises a TCR alpha chain construct. In some embodiments, the beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the beta chain CDR3 comprises a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the beta chain CDR3 comprises an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct comprises a variable region comprising a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to identity to an amino acid sequence set forth in SEQ ID NO: 52 or SEQ ID NO: 53. In some embodiments, the TCR beta chain construct comprises a variable region comprising a sequence having at least 80% sequence identity toWSGR Docket No.50401-795.601 an amino acid sequence set forth in SEQ ID NO: 52 or SEQ ID NO: 53. In some embodiments, the TCR beta chain construct comprises a variable region comprising an amino acid sequence set forth in SEQ ID NO: 52 or SEQ ID NO: 53. In some embodiments, the TCR beta chain construct comprises a complementarity determining region 1 (CDR1) having an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to an amino acid sequence set forth in SEQ ID NO: 55 and a complementarity determining region 2 (CDR2) having an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to an amino acid sequence set forth in SEQ ID NO: 56. In some embodiments, the TCR beta chain construct comprises a complementarity determining region 1 (CDR1) having an amino acid sequence set forth in SEQ ID NO: 55 and a complementarity determining region 2 (CDR2) having an amino acid set forth in SEQ ID NO: 56. In some embodiments, the TCR alpha chain construct comprises a CDR1, a CDR2, and a CDR3. In some embodiments, the CDR1 comprises an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence set forth in SEQ ID NO: 46, the CDR2 comprises an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to identity toa sequence set forth in SEQ ID NO: 47, and the CDR3 comprises an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence set forth in SEQ ID NO: 48. In some embodiments, the CDR1 comprises an amino acid sequence set forth in SEQ ID NO: 46, the CDR2 comprises an amino acid sequence set forth in SEQ ID NO: 47, and the CDR3 comprises an amino acid sequence set forth in SEQ ID NO: 48. In some embodiments, the TCR alpha chain construct comprises a variable region comprising a sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to identity to an amino acid sequence set forth in SEQ ID NO: 43 or SEQ ID NO: 44. In some embodiments, the TCR alpha chain construct comprises a variable region comprising a sequence having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NO: 43 or SEQ ID NO: 44. In some embodiments, the TCR alpha chain construct comprises a variable region comprising an amino acid sequence set forth in SEQ ID NO: 43 or SEQ ID NO: 44. In some embodiments, the TCR comprises a beta chain having an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to SEQ ID NO: 49 or SEQ ID NO: 51 and an alpha chain having an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to SEQ ID NO: 40 or SEQ ID NO: 42. In some embodiments, the TCR comprises a beta chain having an amino acidWSGR Docket No.50401-795.601 sequence that is at least 80% identical to SEQ ID NO: 49 or SEQ ID NO: 51 and an alpha chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 40 or SEQ ID NO: 42. In some embodiments, the TCR comprises a beta chain having an amino acid sequence set forth in SEQ ID NO: 49 or SEQ ID NO: 51 and an alpha chain having an amino acid sequence set forth in SEQ ID NO: 40 or SEQ ID NO: 42. Methods of Treatment

[0468] The methods of the disclosure can be used to treat any type of cancer known in the art. Non- limiting examples of cancers to be treated by the methods of the present disclosure can include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), pancreatic adenocarcinoma, breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer), cutaneous melanoma, synovial sarcoma, myxoid and round cell liposarcoma, osteosarcoma, and neuroblastoma ,esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other neoplastic malignancies.

[0469] Additionally, the disease or condition provided herein includes refractory or recurrent malignancies whose growth may be inhibited using the methods of treatment of the present disclosure. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcomata, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, melanoma and renal cell carcinoma.

[0470] Specific examples of cancers that can be prevented and / or treated in accordance with present disclosure include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplastic syndrome, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin’s disease, non-Hodgkin’s disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom’s macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma,WSGR Docket No.50401-795.601 cholesteatoma-induced bone osteosarcoma, Paget’s disease of bone, osteosarcoma, chondrosarcoma, Ewing’s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangio sarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget’s disease (including juvenile Paget’s disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytoma and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing’s disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; colorectal cancer, colon carcinoma; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, androgen-independent prostate cancer, androgen-WSGR Docket No.50401-795.601 dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acrallentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and / or uterus); renal carcinoma; Wilms’ tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas. Cancers include, but are not limited to, B cell cancer, e.g., multiple myeloma, Waldenstrom’s macroglobulinemia, the heavy chain diseases, such as, for example, alpha chain disease, gamma chain disease, and mu chain disease, benign monoclonal gammopathy, and immunocytic amyloidosis, melanomas, breast cancer, lung cancer, bronchus cancer, colorectal cancer, prostate cancer (e.g., metastatic, hormone refractory prostate cancer), pancreatic cancer, stomach cancer, ovarian cancer, urinary bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, cancer of the oral cavity or pharynx, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small bowel or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, cancer of hematological tissues, and the like. Other non-limiting examples of types of cancers applicable to the methods encompassed by the present disclosure include human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, liver cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, bone cancer, brain tumor, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, e.g., acuteWSGR Docket No.50401-795.601 lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin’s disease and non- Hodgkin’s disease), multiple myeloma, Waldenstrom’s macroglobulinemia, and heavy chain disease. In some embodiments, the cancer whose phenotype is determined by the method of the present disclosure is an epithelial cancer such as, but not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer, gynecologic cancers, renal cancer, laryngeal cancer, lung cancer, oral cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer. In other embodiments, the cancer is breast cancer, prostate cancer, lung cancer, or colon cancer. In still other embodiments, the epithelial cancer is non-small-cell lung cancer, nonpapillary renal cell carcinoma, cervical carcinoma, ovarian carcinoma (e.g., serous ovarian carcinoma), or breast carcinoma. The epithelial cancers may be characterized in various other ways including, but not limited to, serous, endometrioid, mucinous, clear cell, brenner, or undifferentiated. In some embodiments, the present disclosure is used in the treatment, diagnosis, and / or prognosis of lymphoma or its subtypes, including, but not limited to, mantle cell lymphoma. Lymphoproliferative disorders are also considered to be proliferative diseases.

[0471] The present disclosure provides a method of treating a subject with a disease or condition. The disease or condition can comprise a cancer. The method can comprise administering to the subject a therapy comprising a multiepitopic polypeptide or a recombinant nucleic acid encoding the multiepitopic polypeptide. The multiepitopic polypeptide can comprise a RAS polypeptide. The RAS polypeptide may not be a full-length RAS polypeptide. In some embodiments, each sequence of the multiepitopic polypeptide can be a different RAS epitope sequence. In some embodiments, the antigen presenting cells (APCs) of the subject administered the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide can present a RAS epitope sequence as a peptide:MHC complex. In some embodiments, the APCs of the subject present more of a RAS epitope sequence compared to the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide. In some embodiments, the APCs of the subject express more peptide:MHC complexes comprising the RAS epitope sequence compared to the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide. In some embodiments, the APCs of the subject express more of the RAS epitope sequence compared to the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide. In some embodiments, the full-length RAS polypeptide is a full-length KRAS, NRAS or HRAS polypeptide.

[0472] In some embodiments, the therapy comprises a cell comprising the multiepitopic polypeptide or the recombinant nucleic acid encoding the multiepitopic polypeptide. In some embodiments, theWSGR Docket No.50401-795.601 multiepitopic polypeptide comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence. In some embodiments, the first RAS epitope sequence and the second RAS epitope sequence are different. In some embodiments, the presentation of the first and / or second RAS epitope sequence as a peptide:MHC complex by APCs of the subject administered the therapy is higher than the presentation of the first and / or second RAS epitope sequence as the peptide:MHC complex by the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide. In some embodiments, the full-length RAS polypeptide is a full-length KRAS, NRAS or HRAS polypeptide. In some embodiments, the first RAS amino acid sequence is a first KRAS, NRAS or HRAS amino acid sequence. In some embodiments, the second RAS amino acid sequence is a second KRAS, NRAS or HRAS amino acid sequence.

[0473] In some cases, the APCs of the subject administered with the multiepitopic polypeptide having different RAS epitopes can present more (e.g., at least 1.1 times, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 120 times, 150 times, 200 times or more) of a RAS epitope sequence compared to the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide. Presentation can be measured by mass spectrometry detecting RAS -specific MHC molecules following lysis and protein extraction of APCs. Presentation can also be measured by mass spectrometry detecting components of the RAS epitope sequence.

[0474] In some cases, the APCs having (e.g., transfected or otherwise delivered with) the multiepitopic polypeptide having different RAS epitopes can present more (e.g., at least 1.1 times, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 120 times, 150 times, 200 times or more) of a RAS epitope sequence compared to the APCs having the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide. Presentation can be measured by mass spectrometry detecting RAS -specific MHC molecules following lysis and protein extraction of APCs. Presentation...

Claims

WSGR Docket No.50401-795.601 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a subject with a disease or condition comprising administering to the subject a therapy comprising (i) a multiepitopic polypeptide, (ii) a recombinant nucleic acid encoding the multiepitopic polypeptide, or (iii) a cell comprising the multiepitopic polypeptide or the recombinant nucleic acid encoding the multiepitopic polypeptide, wherein the multiepitopic polypeptide does not comprise a full-length RAS polypeptide and comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence, wherein the first RAS epitope sequence and the second RAS epitope sequence are different, and wherein presentation of the first and / or second RAS epitope sequence as a peptide:MHC complex by antigen presenting cells (APCs) of the subject administered the therapy is higher than the presentation of the first and / or second RAS epitope sequence as the peptide:MHC complex by the APCs of a subject administered the full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide.

2. A method of treating a subject with a disease or condition comprising administering to the subject a therapy comprising (i) a multiepitopic polypeptide, (ii) a recombinant nucleic acid encoding the multiepitopic polypeptide, or (iii) a cell comprising the multiepitopic polypeptide or the recombinant nucleic acid encoding the multiepitopic polypeptide, wherein the multiepitopic polypeptide does not comprise a full-length RAS polypeptide and comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence, wherein the first RAS epitope sequence and the second RAS epitope sequence are different, and wherein the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker.

3. The method of claim 1 or 2, wherein the full-length RAS polypeptide is a full-length KRAS, NRAS or HRAS polypeptide, wherein the first RAS amino acid sequence is a first KRAS, NRAS or HRAS amino acid sequence, and wherein the second RAS amino acid sequence is a second KRAS, NRAS or HRAS amino acid sequence.

4. The method of any one of claims 1-3, further comprising administering the subject a T-cell receptor (TCR), a recombinant nucleic acid encoding the TCR or a cell comprising the TCR or the recombinant nucleic acid encoding the TCR.

5. The method of any one of claims 1-4, wherein the first RAS epitope sequence and the second RAS epitope sequence is separated by a linker.WSGR Docket No.50401-795.601 6. The method of any one of claims 1-5, wherein the first RAS amino acid sequence is the first epitope sequence and / or the second RAS amino acid sequence is the second epitope sequence.

7. The method of any one of claims 1-4, wherein the first RAS amino acid sequence comprises a first RAS mutation, and / or the second RAS amino acid sequence comprises a second RAS mutation different from the first RAS mutation.

8. The method of claim 7, wherein the first RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

9. The method of claim 7 or 8, wherein the second RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

10. The method of any one of claims 7-9, wherein the first RAS amino acid sequence is processed into one or more epitopes comprising the first RAS mutation within a cell.

11. The method of any one of claims 7-9, wherein the first RAS mutation is G12V, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72.

12. The method of any one of claims 7-9, wherein the first RAS mutation is G12D, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 28, 75-79.

13. The method of any one of claims 7-9, wherein the first RAS mutation is G12C, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096.

14. The method of any one of claims 1-13, wherein the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 7 to 12 consecutive amino acids from the full-length RAS polypeptide.

15. The method of any one of claims 1-13, wherein the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 13 to 25 consecutive amino acids from the full-length RAS polypeptide.

16. The method of any one of claims 1 and 3-15, wherein the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker.

17. The method of any one of claims 1-16, wherein the first RAS amino acid sequence comprises the first RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the first RAS epitope sequence from the full-length RAS polypeptide.

18. The method of any one of claims 1-17, wherein the second RAS amino acid sequence comprises the second RAS epitope sequence and one or more residues flanking the N- terminus or the C-terminus of the second RAS epitope sequence from the full-length RAS polypeptide.WSGR Docket No.50401-795.601 19. The method of any one of claims 1-18, wherein the multiepitopic polypeptide does not comprise more than 12 or more consecutive amino acids from the full-length RAS polypeptide, or the multiepitopic polypeptide does not comprise more than 25 or more consecutive amino acids from the full-length RAS polypeptide.

20. The method of any one of claims 4-19, wherein the TCR recognizes and binds to a peptide:MHC complex, the peptide:MHC complex comprising (i) the first or the second RAS epitope sequence, and (ii) a human MHC encoded by an HLA allele.

21. The method of any one of claims 1-20, wherein the multiepitopic polypeptide is a RAS polypeptide comprising the first RAS epitope sequence and the second RAS epitope sequence.

22. The method of any one of claims 2-21, wherein the linker is a cleavable linker.

23. A method of treating a subject with a disease or condition comprising administering to the subject (a) a RAS polypeptide, (b) a recombinant nucleic acid encoding the RAS polypeptide, or (c) a cell comprising the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide, wherein the RAS polypeptide comprises a RAS epitope sequence, wherein the subject has been previously administered a T-cell receptor (TCR), a recombinant nucleic acid encoding the TCR, or a cell comprising the TCR or the recombinant nucleic acid encoding the TCR, wherein the TCR recognizes and binds to a peptide:MHC complex, the peptide:MHC complex comprising (i) the RAS epitope sequence, and (ii) a human MHC encoded by an HLA allele.

24. A method of treating a subject with a disease or condition comprising administering to the subject a T-cell receptor (TCR), a recombinant nucleic acid encoding the TCR or a cell comprising the TCR or the recombinant nucleic acid encoding the TCR, wherein the TCR recognizes and binds to a peptide:MHC complex, the peptide:MHC complex comprising (i) a RAS epitope sequence, and (ii) a human MHC encoded by an HLA allele, wherein the subject has been previously administered (a) a RAS polypeptide, (b) a recombinant nucleic acid encoding the RAS polypeptide, or (c) a cell comprising the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide, wherein the RAS polypeptide comprises the RAS epitope sequence.

25. A method of treating a subject with a disease or condition comprising, (a) administering to the subject (i) a RAS polypeptide, (ii) a recombinant nucleic acid encoding the RAS polypeptide, or (iii) a cell comprising the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide, wherein the RAS polypeptide comprises a RAS epitope sequence; andWSGR Docket No.50401-795.601 (b) administering to the subject a TCR, a recombinant nucleic acid encoding the TCR or a cell comprising the TCR or the recombinant nucleic acid encoding the TCR, wherein the TCR recognizes and binds to a peptide:MHC complex, the peptide:MHC complex comprising (i) the RAS peptide sequence, and (ii) a human MHC encoded by an HLA allele.

26. The method of claim 25, wherein administering in (a) is performed concurrently with administering in (b).

27. The method of claim 25, wherein administering in (a) is prior to administering in (b).

28. The method of claim 25, wherein administering in (a) is subsequent to administering in (b).

29. The method of any one of claims 23, 25 and 28, wherein the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide is administered at least 1 day, 2 days, 5 days, 10 days, 20 days, 30 days, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years or more after the subject has been administered the TCR or the recombinant nucleic acid encoding the TCR.

30. The method of any one of claims 24, 25 and 27, wherein the TCR or the recombinant nucleic acid encoding the TCR is administered at least 1 day, 2 days, 5 days, 10 days, 20 days, 30 days, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years or more after the subject has been administered the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide.

31. The method of any one of claims 4-30, wherein the cell is an immune cell.

32. The method of any one of claims 4-31, wherein the T-cell receptor (TCR) or the recombinant nucleic acid encoding the TCR is expressed by an immune cell.

33. The method of any one of claims 4-30, wherein the TCR is a soluble TCR.

34. The method of any one of claims 4-33, further comprising administering two or more different TCRs or recombinant nucleic acids encoding the two or more different TCRs, or cells comprising the two or more different TCRs or the recombinant nucleic acids encoding the two or more different TCRs and wherein the two or more different TCRs comprise a first TCR and a second TCR.

35. The method of claim 34, wherein the two or more different TCRs are expressed on surface of two different immune cells.

36. The method of claim 34 or 35, wherein the first TCR and the second TCR bind to different peptide:MHC complexes, each peptide:MHC complex comprising (i) an epitope sequence and (ii) a human MHC encoded by an HLA allele.WSGR Docket No.50401-795.601 37. The method of any one of claims 34-36, wherein the two or more different TCRs or recombinant nucleic acids encoding the two or more different TCRs are administered separately or co-administered in a same mixture.

38. The method of any one of claims 34-37, wherein the first TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12V mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA- A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, and the second TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12D mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA- A*68:

01.

39. The method of any one of claims 34-37, wherein the first TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12V mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA- A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, and the second TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12C mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:

03.

40. The method of any one of claims 34-37, wherein the first TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12D mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA- C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA-A*68:01, and the second TCR binds to a peptide:MHC complex comprising an epitope sequence having a G12C mutation and an MHC encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:

03.

41. The method of any one of claims 34-37, wherein the first TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72 and an MHC encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05 and the second TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 28, 75-79 and an MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-WSGR Docket No.50401-795.601 C*08:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA-A*68:01; the first TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72 and an MHC encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA- A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01 and, HLA-A*03 and the second TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096 and an MHC encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03; or the first TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 28, 75-79 and an MHC encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, and HLA-A*68:01 and the second TCR binds to a peptide:MHC complex comprising an epitope sequence selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096 and an MHC encoded by an HLA allele selected from the group consisting HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA- A*68:01, and HLA-C*03:

03.

42. The method of any one of claims 23-38, wherein the RAS polypeptide does not comprise a full-length RAS protein sequence.

43. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NOs: 58 or 59.

44. The method of claim 43, wherein the HLA allele is selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*03:02, HLA-A*03:05, HLA- B*40:01, and HLA-A*68:

01.

45. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NO:

60.

46. The method of claim 40, wherein the HLA allele is HLA-C*01:

02.

47. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NOs: 61 or 62.

48. The method of claim 47, wherein the HLA allele is HLA-C*03:03, or HLA-C*03:

04.

49. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NOs: 58 or 59.

50. The method of claim 49, wherein the MHC allele is HLA-A*11:

01.

51. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 65-71.WSGR Docket No.50401-795.601 52. The method of claim 51, wherein the MHC allele is HLA-DRB1*07:

01.

53. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 58 or 72.

54. The method of claim 53, wherein the MHC allele is selected from the group consisting of HLA-A*03:01, HLA-A*03:02, and HLA-A*03:

05.

55. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NO:

75.

56. The method of claim 55, wherein the MHC allele is selected from the group consisting of HLA-B*07:02, HLA-C*08:02, HLA-C*03:04, and HLA-C*05:

01.

57. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NO:

76.

58. The method of claim 57, wherein the MHC allele is selected from the group consisting of HLA-A*3:01, HLA-A*11:01, and HLA-A*68:

01.

59. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NO:

77.

60. The method of claim 59, wherein the MHC allele is HLA-A*11:

01.

61. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NOs: 78 or 79.

62. The method of claim 61, wherein the MHC allele is HLA-C*08:

02.

63. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NO:

29.

64. The method of claim 63, wherein the MHC allele is HLA-DRB1*11:

01.

65. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NO: 81 or 1096.

66. The method of claim 65, wherein the MHC allele is selected from the group consisting of HLA-A*3:01, HLA-A*11:01, and HLA-A*68:

01.

67. The method of any one of claims 23-42, wherein the RAS epitope sequence comprises a sequence of SEQ ID NO:

82.

68. The method of claim 67, wherein the MHC allele is HLA-C*03:

03.

69. The method of any one of claims 21-68, wherein the RAS polypeptide is a multiepitopic polypeptide, and wherein the multiepitopic polypeptide does not comprise a full-length RAS polypeptide and comprises two or more different RAS epitope sequences.

70. The method of claim 69, wherein the multiepitopic polypeptide comprises at least 3, 4, 5, or more different RAS epitope sequences.WSGR Docket No.50401-795.601 71. The method of claim 69 or 70, wherein the two or more different RAS epitope sequences are separated by linker sequences.

72. The method of any one of claims 69-71, wherein antigen presenting cells (APCs) of the subject administered the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide comprising the multiepitopic polypeptide present more of a RAS epitope sequence as a peptide:MHC complex compared to the APCs of a subject administered a full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide.

73. The method of any one of claims 69-72, wherein T cells of the subject administered the multiepitopic polypeptide or a recombinant nucleic acid encoding the multiepitopic polypeptide exhibit increased expansion compared to T cells of a subject administered a full-length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide.

74. The method of any one of claims 69-73, wherein the multiepitopic polypeptide comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence, and wherein the first RAS epitope sequence and the second RAS epitope sequence are different or wherein the first RAS amino acid sequence and the second RAS amino acid sequence comprise different RAS mutations.

75. The method of claim 74, wherein the first RAS epitope sequence and the second RAS epitope sequence is separated by a linker.

76. The method of claim 74 or 75, wherein the first amino acid sequence is the first epitope sequence and / or the second amino acid sequence is the second epitope sequence.

77. The method of any one of claims 74-76, wherein the first amino acid sequence consists of the first epitope sequence, and / or the second amino acid sequence consists of the second epitope sequence.

78. The method of any one of claims 74-77, wherein the first RAS amino acid sequence comprises a first RAS mutation, and / or the second RAS amino acid sequence comprises a second RAS mutation different from the first RAS mutation.

79. The method of claim 78, wherein the first RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

80. The method of claim 78 or 79, wherein the second RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

81. The method of any one of claims 78-80, wherein the first RAS amino acid sequence is processed into one or more epitopes comprising the first RAS mutation within a cell.WSGR Docket No.50401-795.601 82. The method of any one of claims 78-80, wherein the first RAS mutation is G12V, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72.

83. The method of any one of claims 78-80, wherein the first RAS mutation is G12D, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 28, 75-79.

84. The method of any one of claims 78-80, wherein the first RAS mutation is G12C, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096.

85. The method of any one of claims 74-84, wherein the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 7 to 12 consecutive amino acids from the full-length RAS polypeptide.

86. The method of any one of claims 74-84, wherein the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 13 to 25 consecutive amino acids from the full-length RAS polypeptide.

87. The method of any one of claims 74-86, wherein the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker.

88. The method of any one of claims 74, 75 and 85-87, wherein the first amino acid sequence comprises the first RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the first RAS epitope sequence from the full-length RAS polypeptide.

89. The method of any one of claims 74, 75 and 85-88, wherein the second amino acid sequence comprises the second RAS epitope sequence and one or more residues flanking the N- terminus or the C-terminus of the second RAS epitope sequence from the full-length RAS polypeptide.

90. The method of any one of claims 69-89, wherein the multiepitopic polypeptide does not comprise more than 12 or more consecutive amino acids from the full-length RAS polypeptide, or the multiepitopic polypeptide does not comprise more than 25 or more consecutive amino acids from the full-length RAS polypeptide.

91. The method of any one of claims 74-90, wherein the first RAS epitope sequence and the second RAS epitope sequence are presentable by different HLA alleles, are presented by different HLA alleles, bind to different HLA alleles, are predicted to bind to different HLA alleles, or are predicted to be presented by different HLA alleles.

92. The method of any one of claims 74-91, wherein a first RAS epitope sequence (i) binds to or is predicted to bind to a first HLA allele with a KD of less than 100 nM and (ii) to binds to or is predicted to bind to a second HLA allele with a KD of more than 500 nM.WSGR Docket No.50401-795.601 93. The method of any one of claims 74-92, wherein the first amino acid sequence is operably linked to the second amino acid sequence via a linker.

94. The method of claim 93, wherein the linker is a cleavable linker.

95. The method of claim 93 or 94, wherein the linker comprises a sequence of SEQ ID NO:

31.

96. The method of any one of claims 69-95, wherein the multiepitopic polypeptide comprises a first amino acid sequence comprising a first RAS epitope sequence, operably linked to a second amino acid sequence comprising a second RAS epitope sequence, operably linked to a third amino acid sequence comprising a third RAS epitope sequence.

97. The method of claim 96, wherein the first RAS epitope sequence, the second RAS epitope sequence, and / or the third RAS epitope sequence comprises a RAS mutation selected from the group consisting of G12V, G12D, and G12C, and wherein the first RAS epitope sequence, the second RAS epitope sequence, and the third RAS epitope sequence comprise different RAS mutations.

98. The method of claim 97, wherein the first RAS epitope sequence comprises a G12V mutation.

99. The method of claim 97 or 98,wherein the second RAS epitope sequence comprises a G12D mutation.

100. The method of any one of claims 97-99, wherein the third RAS epitope sequence comprises a G12C mutation.

101. The method of any one of claims 96-100, wherein (i) the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA- A*03:02, and HLA-A*03:05, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA- A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA- DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA- A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01,WSGR Docket No.50401-795.601 HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, (ii) the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA- C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA- A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA- C*08:02, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA- A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, and (iii) the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA- A*68:01, and HLA-C*03:03, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:

03.

102. The method of any one of claims 69-101, wherein the subject does not express an HLA allele that recognizes each RAS epitope sequence of the multiepitopic polypeptide.

103. The method of any one of claims 69-102, wherein the subject only expresses HLA alleles that recognize a subset of RAS epitope sequences of the multiepitopic polypeptide.

104. The method of any one of claims 24-101, wherein the RAS polypeptide comprises one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

105. The method of claim 104, wherein the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

106. The method of claim 104, wherein the RAS polypeptide comprises two, three, four, or five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.WSGR Docket No.50401-795.601 107. The method of claim 104, wherein the RAS polypeptide comprises two, three, four, or five copies of each sequence of SEQ ID NOs: 27-29.

108. The method of claim 104, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 27, operably linked to a sequence of SEQ ID NO: 29, and operably linked to a sequence of SEQ ID NO:

28.

109. The method of claim 108, wherein the sequence of SEQ ID NO: 27 is operably linked to the sequence of SEQ ID NOs: 29 via a linker, and the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 28 via a linker.

110. The method of claim 109, wherein the linker is a cleavable linker.

111. The method of claim 110, wherein the linker comprises a sequence of SEQ ID NO:

31.

112. The method of claim 104, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NOs: 29, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO:

27.

113. The method of claim 112, wherein the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 28 via a linker, and the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 27 via a linker.

114. The method of claim 113, wherein the linker is a cleavable linker.

115. The method of claim 114, wherein the linker comprises a sequence of SEQ ID NO:

31.

116. The method of claim 104, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 28, operably linked to a sequence of SEQ ID NO: 27, and operably linked to a sequence of SEQ ID NO:

29.

117. The method of claim 116, wherein the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 27 via a linker, and the sequence of SEQ ID NO: 27 is operably linked to a sequence of SEQ ID NO: 29 via a linker.

118. The method of claim 117, wherein the linker is a cleavable linker.

119. The method of claim 118, wherein the linker comprises a sequence of SEQ ID NO:

31.

120. The method of claim 104, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 27, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO:

29.

121. The method of claim 120, wherein the sequence of SEQ ID NO: 27 is operably linked to the sequence of SEQ ID NO: 28 via a linker, and the sequence of SEQ ID NO: 28 is operably linked to a sequence of SEQ ID NO: 29 via a linker.

122. The method of claim 121, wherein the linker is a cleavable linker.

123. The method of claim 122, wherein the linker comprises a sequence of SEQ ID NO: 31.WSGR Docket No.50401-795.601 124. The method of claim 104, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 28, operably linked to a sequence of SEQ ID NO: 29, and operably linked to a sequence of SEQ ID NO:

27.

125. The method of claim 124, wherein the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 29 via a linker, and the sequence of SEQ ID NO: 29 is operably linked to a sequence of SEQ ID NO: 27 via a linker.

126. The method of claim 125, wherein the linker is a cleavable linker.

127. The method of claim 126, wherein the linker comprises a sequence of SEQ ID NO:

31.

128. The method of claim 104, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 29, operably linked to a sequence of SEQ ID NO: 27, and operably linked to a sequence of SEQ ID NO:

28.

129. The method of claim 128, wherein the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 27 via a linker, and the sequence of SEQ ID NO: 27 is operably linked to a sequence of SEQ ID NO: 28 via a linker.

130. The method of claim 129, wherein the linker is a cleavable linker.

131. The method of claim 130, wherein the linker comprises a sequence of SEQ ID NO:

31.

132. The method of any one of claims 21-119, wherein the RAS polypeptide comprises at least two copies of a multiepitopic polypeptide, and wherein each copy comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 29, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO:

27.

133. The method of claim 132, wherein the RAS polypeptide comprises three copies of the multiepitopic polypeptide.

134. The method of claim 132, wherein the RAS polypeptide comprises five copies of the multiepitopic polypeptide.

135. The method of any one of claims 23-134, wherein the RAS polypeptide further comprises a secretory domain (Sec) sequence at the N terminus of the multiepitopic polypeptide.

136. The method of claim 135, wherein the Sec sequence comprises a sequence of SEQ ID NO:

32.

137. The method of claim 135 or 136, wherein the Sec sequence is operably linked to the multiepitopic polypeptide via a linker.

138. The method of claim 137, wherein the linker comprises a sequence of SEQ ID NO: 30 or 31.

139. The method of any one of claims 23-138, wherein the RAS polypeptide further comprises an MHC class I trafficking domain (MITD) sequence at the C terminus of the multiepitopic polypeptide.WSGR Docket No.50401-795.601 140. The method of claim 139, wherein the MITD sequence comprises a sequence of SEQ ID NO:

33.

141. The method of claim 139 or 140, wherein the multiepitopic polypeptide is operably linked to the MITD sequence via a linker.

142. The method of claim 141, wherein the linker comprises a sequence of SEQ ID NO: 30 or 112.

143. The method of any one of claims 23-142, wherein the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO:

25.

144. The method of any one of claims 23-142, wherein the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO:

26.

145. The method of any one of claims 23-142, wherein the RAS polypeptide comprises a sequence having at least 80% sequence identity to a sequence of SEQ ID NO:

113.

146. The method of any one of claims 23-145, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

147. The method of claim 146, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

148. The method of claim 146, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises two, three, four, or five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104- 106, 108-110.

149. The method of claim 146, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises two, three, four, or five copies of each sequence of SEQ ID NOs: 14- 23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

150. The method of claim 146, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17- 19, 86, 93, 97, 101, 105, and 109.

151. The method of claim 150, wherein the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88,WSGR Docket No.50401-795.601 94, 98, 102, 106, and 110 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109via a linker sequence.

152. The method of claim 151, wherein the linker sequence encodes a cleavable linker.

153. The method of claim 152, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13, 85, 87, and 89.

154. The method of claim 146, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14- 16, 84, 92, 96, 100, 104, and 108.

155. The method of claim 154, wherein the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 via a linker sequence.

156. The method of claim 155, wherein the linker sequence encodes a cleavable linker.

157. The method of claim 156, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13, 85, 87, and 89.

158. The method of claim 146, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20- 23, 88, 94, 98, 102, 106, and 110.

159. The method of claim 158, wherein the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 is operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 via a linker sequence.

160. The method of claim 159, wherein the linker sequence is a cleavable linker.

161. The method of claim 160, wherein the linker sequence comprises a sequence of selected from the group consisting of SEQ ID NOs: 5, 6, 8-13, 85, 87, and 89.WSGR Docket No.50401-795.601 162. The method of claim 146, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises at least two copies of a string of sequences, and wherein each string of sequences comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108.

163. The method of claim 162, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of the string of sequences.

164. The method of claim 162, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of the string of sequences.

165. The method of any one of claims 146-164, wherein the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding a secretory (Sec) sequence at the 5’end of the string of sequences.

166. The method of claim 165, wherein the sequence encoding the Sec sequence comprises a sequence of SEQ ID NO:

3.

167. The method of claim 165 or 166, wherein the sequence encoding the Sec sequence is operably linked to the string of sequences via a linker sequence.

168. The method of any one of claims 165-167, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

169. The method of any one of claims 146-168, wherein the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding an MITD sequence at the 3’ end of the string of sequences.

170. The method of claim 169, wherein the sequence encoding the MITD domain comprises a sequence of SEQ ID NO: 24 or 90.

171. The method of claim 169 or 170, wherein the string of sequences is operably linked to the sequence encoding the MITD sequence via a linker sequence.

172. The method of any one of claims 169-171, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, and 89.

173. The method of any one of claims 146-172, wherein the recombinant nucleic acid is codon- optimized.

174. The method of any one of claims 146-173, wherein the recombinant nucleic acid is an RNA.

175. The method of any one of claims 146-174, wherein the recombinant nucleic acid comprises a sequence having at least 60% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 2, 91, 95, 99, 103, 107, 111.WSGR Docket No.50401-795.601 176. The method of any one of claims 173-175, wherein the subject expresses more of the RAS epitope when administered with the codon-optimized recombinant nucleic acid than administered with wild-type recombinant nucleic acid.

177. The method of any one of claims 20-176, wherein the TCR comprises a TCR beta chain construct and a TCR alpha chain construct, wherein the TCR beta chain construct comprises a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

57.

178. The method of claim 177, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence with at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NO: 52 or SEQ ID NO:

53.

179. The method of claim 177 or 178, wherein the TCR beta chain construct comprises a complementarity determining region 1 (CDR1) having an amino acid sequence set forth in SEQ ID NO: 55 and a complementarity determining region 2 (CDR2) having an amino acid sequence set forth in SEQ ID NO:

56.

180. The method of any one of claims 177-179, wherein the TCR alpha chain construct comprises a CDR1, a CDR2, and a CDR3, wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 46, the CDR2 has an amino acid sequence set forth in SEQ ID NO: 47, and the CDR3 has an amino acid sequence set forth in SEQ ID NO:

48.

181. The method of any one of claims 177-180, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NO: 43 or SEQ ID NO:

44.

182. The method of any one of claims 177-181, wherein the TCR comprises: (a) a beta chain having an amino acid sequence set forth in SEQ ID NO: 49 or SEQ ID NO: 51, or an amino acid sequence that is at least 80% identical to SEQ ID NO: 49 or SEQ ID NO: 51, and (b) an alpha chain having an amino acid sequence set forth in SEQ ID NO: 40 or SEQ ID NO: 42, or an amino acid sequence that is at least 80% identical to SEQ ID NO: 40 or SEQ ID NO:

42.

183. The method of any one of claims 20-176, wherein the TCR is selected from the TCRs presented in Tables 8A-8D.

184. The method of any one of claims 32-183, wherein binding of the TCR to the peptide:MHC complex results in production of a cytokine by the immune cell.

185. The method of claim 184, wherein the cytokine is IFN-γ, TNF-α, IL-2, IL-18, or any combination thereof.

186. A recombinant nucleic acid encoding a RAS polypeptide comprising a multiepitopic polypeptide, wherein the multiepitopic polypeptide does not comprise a full-length RASWSGR Docket No.50401-795.601 polypeptide and comprises a first RAS amino acid sequence comprising a first RAS epitope sequence and a second RAS amino acid sequence comprising a second RAS epitope sequence, wherein the first RAS epitope sequence and the second RAS epitope sequence are different, and wherein the first RAS amino acid sequence and the second RAS amino acid sequence are linked via a linker.

187. The recombinant nucleic acid of claim 186, wherein presentation of the first and / or second RAS epitope sequence as a peptide:MHC complex by antigen presenting cells (APCs) of the subject administered the RAS polypeptide or the recombinant nucleic acid encoding the RAS polypeptide is higher than the presentation of the first and / or second RAS epitope sequence as the peptide:MHC complex by the APCs of a subject administered the full- length RAS polypeptide or a recombinant nucleic acid encoding the full-length RAS polypeptide.

188. The recombinant nucleic acid of claim 186 or 187, wherein the first RAS amino acid sequence is the first epitope sequence and / or the second RAS amino acid sequence is the second epitope sequence.

189. The recombinant nucleic acid of any one of claims 186-188, wherein the first RAS amino acid sequence consists of the first epitope sequence, and / or the second RAS amino acid sequence consists of the second epitope sequence.

190. The recombinant nucleic acid of any one of claims 186-189, wherein the first RAS amino acid sequence comprises a first RAS mutation, and / or the second RAS amino acid sequence comprises a second RAS mutation different from the first RAS mutation.

191. The recombinant nucleic acid of claim 190, wherein the first RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

192. The recombinant nucleic acid of claim 190 or 191, wherein the second RAS mutation is selected from the group consisting of G12V, G12D, and G12C.

193. The recombinant nucleic acid of any one of claims 190-192, wherein the first RAS amino acid sequence is processed into one or more epitopes comprising the first RAS mutation within a cell.

194. The recombinant nucleic acid of any one of claims 190-193, wherein the first RAS mutation is G12V, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 27, 58-62 and 65-72.

195. The recombinant nucleic acid of any one of claims 190-193, wherein the first RAS mutation is G12D, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 28, 75-79.WSGR Docket No.50401-795.601 196. The recombinant nucleic acid of any one of claims 190-193, wherein the first RAS mutation is G12C, and wherein the one or more epitopes are selected from the group consisting of SEQ ID NOs: 29, 81, 82, and 1096.

197. The recombinant nucleic acid of any one of claims 186-196, wherein the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 7 to 12 consecutive amino acids from the full-length RAS polypeptide.

198. The recombinant nucleic acid of any one of claims 186-189, wherein the first RAS epitope sequence and / or the second RAS epitope sequence consists of from 13 to 25 consecutive amino acids from the full-length RAS polypeptide.

199. The recombinant nucleic acid of any one of claims 186-198, wherein the first RAS amino acid sequence and the second RAS amino acid sequence is separated by a linker.

200. The recombinant nucleic acid of any one of claims 186, 187 and 197-199, wherein the first RAS amino acid sequence comprises the first RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the first RAS epitope sequence from the full-length RAS polypeptide.

201. The recombinant nucleic acid of any one of claims 186, 187 and 197-200, wherein the second RAS amino acid sequence comprises the second RAS epitope sequence and one or more residues flanking the N-terminus or the C-terminus of the second RAS epitope sequence from the full-length RAS polypeptide.

202. The recombinant nucleic acid of any one of claims 186-201, wherein the multiepitopic polypeptide does not comprise more than 12 or more consecutive amino acids from the full- length RAS polypeptide, or the multiepitopic polypeptide does not comprise more than 25 or more consecutive amino acids from the full-length RAS polypeptide.

203. The recombinant nucleic acid of any one of claims 186-202, wherein the RAS polypeptide further comprises a Secretory (Sec) sequence at the N terminus of the multiepitopic polypeptide.

204. The recombinant nucleic acid of claim 203, wherein the Sec sequence comprises a sequence of SEQ ID NO:

32.

205. The recombinant nucleic acid of any one of claims 186-204, wherein the Sec sequence is operably linked to the multiepitopic polypeptide via a linker.

206. The recombinant nucleic acid of claim 205, wherein the linker comprises a sequence of SEQ ID NO: 30 or 31.

207. The recombinant nucleic acid of any one of claims 186-206, wherein the RAS polypeptide further comprises an MHC class I trafficking signal (MITD) sequence at the C terminus of the multiepitopic polypeptide.WSGR Docket No.50401-795.601 208. The recombinant nucleic acid of claim 207, wherein the MITD sequence comprises a sequence of SEQ ID NO:

33.

209. The recombinant nucleic acid of claim 207, wherein the multiepitopic polypeptide is operably linked to the MITD sequence via a linker.

210. The recombinant nucleic acid of claim 209, wherein the linker comprises a sequence of SEQ ID NO: 30 or 112.

211. The recombinant nucleic acid of any one of claims 186-210, wherein the multiepitopic polypeptide comprises at least 3, 4, 5, or more different RAS epitope sequences.

212. The recombinant nucleic acid of any one of claims 186-211, wherein the first RAS epitope sequence and the second RAS epitope sequence are presentable by different HLA alleles, are presented by different HLA alleles, bind to different HLA alleles, are predicted to bind to different HLA alleles, or are predicted to be presented by different HLA alleles.

213. The recombinant nucleic acid of any one of claims 186-212, wherein a first RAS epitope sequence (i) binds to or is predicted to bind to a first HLA allele with a KD of less than 100 nM and (ii) to binds to or is predicted to bind to a second HLA allele with a KD of more than 500 nM.

214. The recombinant nucleic acid of any one of claims 186-213, wherein the linker comprises a sequence of SEQ ID NO: 31 or 112.

215. The recombinant nucleic acid of claim 211, wherein the multiepitopic polypeptide comprises a first amino acid sequence comprising a first RAS epitope sequence, operably linked to a second amino acid sequence comprising a second RAS epitope sequence, operably linked to a third amino acid sequence comprising a third RAS epitope sequence.

216. The recombinant nucleic acid of claim 215, wherein (i) the first RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA- A*03:02, and HLA-A*03:05, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA- A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA- DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA- A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03,WSGR Docket No.50401-795.601 HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-A*11:01, HLA-A*03:01, HLA-A*30:01, HLA-A*68:01, HLA-B*40:01, HLA-C*01:02, HLA-C*03:03, HLA-C*03:04, HLA-DRB1*07:01, HLA-A*03:02, and HLA-A*03:05, (ii) the second RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA- C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02,binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA- A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA-A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA- C*08:02, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-B*07:02, HLA-C*03:04, HLA-C*05:01, HLA- A*-3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*08:02, and (iii) the third RAS epitope sequence is presentable by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, is presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, binds to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:03, is predicted to bind to an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA- A*68:01, and HLA-C*03:03, or is predicted to be presented by an MHC molecule encoded by an HLA allele selected from the group consisting of HLA-DRB1*11:01, HLA-A*3:01, HLA-A*11:01, HLA-A*68:01, and HLA-C*03:

03.

217. The recombinant nucleic acid of any one of claims 186-215, wherein the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2])x- CT seq, where x is an integer from 1 to 10.

218. The recombinant nucleic acid of any one of claims 186-215, wherein the multiepitopic polypeptide comprises the formula NT seq – ([Antigen1]-cleavable linker1-[Antigen2]- cleavable linker2-[Antigen3])x-CT seq, where x is an integer from 1 to 10.WSGR Docket No.50401-795.601 219. The recombinant nucleic acid of claim 217 or 218, wherein the NT seq comprises a Secretory (Sec) sequence and a N-terminal linker sequence.

220. The recombinant nucleic acid of any one of claims 217-219, wherein the CT seq comprises a C-terminal linker and a MITD sequence.

221. The recombinant nucleic acid of any one of claims 217-220, wherein the Antigen1, Antigen2, or Antigen3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 27-29.

222. The recombinant nucleic acid of any one of claims 217-221, wherein the cleavable linker1 or cleavable linker2 is selected from the group consisting of SEQ ID NOs: 30, 31, and 112.

223. The recombinant nucleic acid of any one of claims 219-222, wherein the N-terminal linker sequence or the C-terminal linker sequence is selected from the group consisting of SEQ ID NOs: 30, 31, and 112.

224. The recombinant nucleic acid of any one of claims 186-214, wherein the RAS polypeptide comprises one or more sequences selected from the group consisting of SEQ ID NOs: 27- 29.

225. The recombinant nucleic acid of claim 224, wherein the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

226. The recombinant nucleic acid of claim 224, wherein the RAS polypeptide comprises two, three, four, or five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 27-29.

227. The recombinant nucleic acid of claim 224, wherein the RAS polypeptide comprises two, three, four, or five copies of each sequence of SEQ ID NOs: 27-29.

228. The recombinant nucleic acid of claim 224, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 27, operably linked to a sequence of SEQ ID NO: 29, and operably linked to a sequence of SEQ ID NO:

28.

229. The recombinant nucleic acid of claim 228, wherein the sequence of SEQ ID NO: 27 is operably linked to the sequence of SEQ ID NO: 29 via a linker, and the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 28 via a linker.

230. The recombinant nucleic acid of claim 229, wherein the linker is a cleavable linker.

231. The recombinant nucleic acid of claim 230, wherein the linker comprises a sequence of SEQ ID NO:

31.

232. The recombinant nucleic acid of claim 224, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 29, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO: 27.WSGR Docket No.50401-795.601 233. The recombinant nucleic acid of claim 232, wherein the sequence of SEQ ID NO: 29 is operably linked to the sequence of SEQ ID NO: 28 via a linker, and the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 27 via a linker.

234. The recombinant nucleic acid of claim 233, wherein the linker is a cleavable linker.

235. The recombinant nucleic acid of claim 234, wherein the linker comprises a sequence of SEQ ID NO:

31.

236. The recombinant nucleic acid of claim 224, wherein the RAS polypeptide comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 28, operably linked to a sequence of SEQ ID NO: 27, and operably linked to a sequence of SEQ ID NO:

29.

237. The recombinant nucleic acid of claim 236, wherein the sequence of SEQ ID NO: 28 is operably linked to the sequence of SEQ ID NO: 27 via a linker, and the sequence of SEQ ID NO: 27 is operably linked to a sequence of SEQ ID NO: 29 via a linker.

238. The recombinant nucleic acid of claim 237, wherein the linker is a cleavable linker.

239. The recombinant nucleic acid of claim 238, wherein the linker comprises a sequence of SEQ ID NO:

31.

240. The recombinant nucleic acid of claim 224, wherein the RAS polypeptide comprises at least two copies of a multiepitopic polypeptide, and wherein each copy comprises, from N terminus to C terminus, a sequence of SEQ ID NO: 29, operably linked to a sequence of SEQ ID NO: 28, and operably linked to a sequence of SEQ ID NO:

27.

241. The recombinant nucleic acid of claim 240, wherein the RAS polypeptide comprises three copies of the multiepitopic polypeptide.

242. The recombinant nucleic acid of claim 240, wherein the RAS polypeptide comprises five copies of the multiepitopic polypeptide.

243. The recombinant nucleic acid of any one of claims 186-214, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.

244. The recombinant nucleic acid of any one of claims 186-214, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises one or more copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96- 98, 100-102, 104-106, 108-110.

245. The recombinant nucleic acid of any one of claims 186-214, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises two, three, four, or five copies of one or more sequences selected from the group consisting of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108-110.WSGR Docket No.50401-795.601 246. The recombinant nucleic acid of any one of claims 186-214, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises two, three, four, or five copies of each sequence of SEQ ID NOs: 14-23, 84, 86, 88, 92-94, 96-98, 100-102, 104-106, 108- 110.

247. The recombinant nucleic acid of any one of claims 186-214, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109.

248. The recombinant nucleic acid of claim 247, wherein the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence.

249. The recombinant nucleic acid of claim 248, wherein the linker sequence encodes a cleavable linker.

250. The recombinant nucleic acid of claim 249, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13, 85, 87, and 89.

251. The recombinant nucleic acid of any one of claims 186-214, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108.

252. The recombinant nucleic acid of claim 251, wherein the sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108 via a linker sequence.WSGR Docket No.50401-795.601 253. The recombinant nucleic acid of claim 252, wherein the linker sequence encodes a cleavable linker.

254. The recombinant nucleic acid of claim 253, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13, 85, 87, and 89.

255. The recombinant nucleic acid of any one of claims 186-214 wherein the recombinant nucleic acid encoding the RAS polypeptide comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110.

256. The recombinant nucleic acid of claim 255, wherein the sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109 is operably linked to the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108via a linker sequence, and the sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108is operably linked to a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110 via a linker sequence.

257. The recombinant nucleic acid of claim 256, wherein the linker sequence is a cleavable linker.

258. The recombinant nucleic acid of claim 257, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 5, 6, 8-13, 85, 87, and 89.

259. The recombinant nucleic acid of any one of claims 186-214, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises at least two copies of a string of sequences, and wherein each string of sequences comprises, from 5’ end to 3’ end, a sequence selected from the group consisting of SEQ ID NOs: 20-23, 88, 94, 98, 102, 106, and 110, operably linked to a sequence selected from the group consisting of SEQ ID NOs: 17-19, 86, 93, 97, 101, 105, and 109, and operably linked to a sequence selected from the group consisting of SEQ ID NOs: 14-16, 84, 92, 96, 100, 104, and 108.

260. The recombinant nucleic acid of claim 259, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises three copies of the string of sequences.

261. The recombinant nucleic acid of claim 259, wherein the recombinant nucleic acid encoding the RAS polypeptide comprises five copies of the string of sequences.

262. The recombinant nucleic acid of any one of claims 186-261, wherein the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding a Sec sequence at the 5’ end of the string of sequences.WSGR Docket No.50401-795.601 263. The recombinant nucleic acid of claim 262, wherein the sequence encoding the Sec sequence comprises a sequence of SEQ ID NO:

3.

264. The recombinant nucleic acid of claim 263, wherein the sequence encoding the Sec sequence is operably linked to the string of sequences via a linker sequence.

265. The recombinant nucleic acid of claim 264, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

266. The recombinant nucleic acid of any one of claims 186-265, wherein the recombinant nucleic acid encoding the RAS polypeptide further comprises a sequence encoding an MITD sequence at the 3’ end of the string of sequences.

267. The recombinant nucleic acid of claim 266, wherein the sequence encoding the MITD sequence comprises a sequence of SEQ ID NO: 24 or 90.

268. The recombinant nucleic acid of claim 266, wherein the string of sequences is operably linked to the sequence encoding the MITD sequence via a linker sequence.

269. The recombinant nucleic acid of claim 268, wherein the linker sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 7, 83, and 89.

270. A recombinant nucleic acid having at least 60% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 2, 91, 95, 99, 103, 107, 111.

271. A recombinant nucleic acid having at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1, 2, 91, 95, 99, 103, 107, 111.

272. A polypeptide encoded by the recombinant nucleic acid of any one of claims 186-271.

273. A pharmaceutical composition comprising the recombinant nucleic acid of any one of claims 186-271 or the polypeptide of claim 272, and a pharmaceutically acceptable carrier.

274. The recombinant nucleic acid of any one of claims 186-271, the polypeptide of claim 272, or the pharmaceutical composition of claim 273 for use in therapy.

275. Use of the recombinant nucleic acid of any one of claims 186-271, the polypeptide of claim 272, or the pharmaceutical composition of claim 273, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

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