A method for inducing neoepitope-specific T cells using PD-1 axis-binding antagonists and RNA vaccines.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- GENENTECH INC
- Filing Date
- 2026-03-02
- Publication Date
- 2026-06-23
Smart Images
Figure 2026102654000001_ABST
Abstract
Claims
1. A method for inducing neoepitope-specific CD8+ T cells in an individual having a tumor, comprising administering an effective amount of an RNA vaccine to the individual, wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and wherein about 1% to about 6% of the CD8+ T cells in a peripheral blood sample obtained from the individual after administration of the RNA vaccine are neoepitope-specific CD8+ T cells specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
2. The method according to claim 1, wherein the peripheral blood sample comprises about 5% or about 6% CD8+ T cells specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
3. The method according to claim 1 or 2, wherein the neoepitope-specific CD8+ T cells are detected in the peripheral blood sample by ex vivo ELISPOT or MHC multimer analysis.
4. The method according to any one of claims 1 to 3, wherein administration of the RNA vaccine to the individual results in induction of neoepitope-specific CD4+ T cells in the peripheral blood of the individual compared to before administration of the RNA vaccine, and the neoepitope-specific CD4+ T cells are specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
5. The method according to claim 4, wherein the neoepitope-specific CD4+ T cells are detected in a peripheral blood sample obtained from the individual by ex vivo ELISPOT analysis.
6. The method according to any one of claims 1 to 5, wherein administration of the RNA vaccine to multiple individuals results in the induction of neoepitope-specific CD4+ or CD8+ T cells in the peripheral blood of at least about 70% of the multiple individuals compared to before administration of the RNA vaccine, the neoepitope-specific CD4+ or CD8+ T cells are specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine, and the induction of neoepitope-specific CD4+ or CD8+ T cells is evaluated by ex vivo ELISPOT or MHC multimer analysis.
7. The method according to any one of claims 1 to 6, wherein administration of the RNA vaccine to the individual results in an increase in the level of one or more inflammatory cytokines in the peripheral blood of the individual compared to the level of one or more inflammatory cytokines before administration of the RNA vaccine.
8. The method according to claim 7, wherein the elevated level of one or more inflammatory cytokines is present in the peripheral blood of the individual about 4 to 6 hours after administration of the RNA vaccine.
9. The method according to claim 7 or claim 8, wherein the one or more inflammatory cytokines are selected from the group consisting of IFNγ, IFNα, IL-12, and IL-6.
10. A method for inducing the transport of neoepitope-specific CD8+ T cells to a tumor in an individual, comprising administering an effective amount of an RNA vaccine to the individual, wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and the neoepitope-specific CD8+ T cells transported to the tumor after administration of the RNA vaccine are specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
11. The method according to any one of claims 1 to 10, wherein the neoepitope-specific CD8+ T cells have a memory phenotype.
12. The neoepitope-specific CD8+ T cells having a memory phenotype are effector memory T cells (T ｅｍ The method according to claim 11.
13. The aforementioned effector memory T cells (T ｅｍ The method according to claim 12, wherein ) is CD45RO positive and CCR7 negative.
14. The method according to any one of claims 1 to 13, wherein the neoepitope-specific CD8+ T cells are PD-1+.
15. The method according to any one of claims 1 to 14, wherein the individual has a tumor with a low to moderate mutational burden.
16. The method according to any one of claims 1 to 15, wherein the individual has a low tumor load.
17. The method according to any one of claims 1 to 16, wherein the tumor has low or negative PD-L1 expression.
18. The method according to claim 17, wherein less than 5% of the tumor cells in the sample obtained from the tumor express PD-L1.
19. The method according to claim 17, wherein less than 5% of the immune cells in the sample obtained from the tumor express PD-L1.
20. The method according to claim 18 or claim 19, wherein the percentage of tumor cells or immune cells expressing PD-L1 in a sample obtained from the tumor is determined by immunohistochemistry.
21. The method according to any one of claims 1 to 20, wherein the administration of the RNA vaccine results in a complete response (CR) or a partial response (PR) in the individual.
22. The method according to any one of claims 1 to 21, wherein the individual has a locally progressive or metastatic solid tumor, or has one or more metastatic recurrences.
23. The method according to any one of claims 1 to 22, wherein the tumor is a non-small cell lung cancer (NSCLC) tumor, a bladder tumor, a kidney tumor, a head and neck tumor, a sarcoma tumor, a breast tumor, a melanoma tumor, a prostate tumor, an ovarian tumor, a stomach tumor, a liver tumor, a urothelial tumor, a colon tumor, a kidney tumor, a cervical tumor, a Merkel cell carcinoma (MCC) tumor, an endometrial tumor, a soft tissue sarcoma tumor, an esophageal tumor, a gastroesophageal junction tumor, an osteosarcoma tumor, a thyroid tumor, or a colorectal tumor.
24. The method according to claim 23, wherein the breast tumor is a triple-negative breast cancer (TNBC) tumor.
25. The method according to claim 23, wherein the tumor is a urothelial tumor, and administration of the RNA vaccine to multiple individuals results in an objective response in at least about 10% of the multiple individuals.
26. The method according to claim 23, wherein the tumor is a renal tumor, and administration of the RNA vaccine to multiple individuals results in an objective response in at least about 22% of the multiple individuals.
27. The method according to claim 23, wherein the tumor is a melanoma tumor, and administration of the RNA vaccine to multiple individuals results in an objective response in at least about 30% of the multiple individuals.
28. The method according to claim 24, wherein the tumor is a TNBC tumor, and administration of the RNA vaccine to multiple individuals results in an objective response in at least about 4% of the multiple individuals.
29. The method according to claim 23, wherein the tumor is an NSCLC tumor, and administration of an RNA vaccine to multiple individuals results in an objective response in at least about 10% of the multiple individuals.
30. The method according to any one of claims 1 to 29, wherein, prior to the administration of the RNA vaccine, the individual has been treated with one or more cancer treatments or three to five cancer treatments.
31. The method according to any one of claims 1 to 29, wherein, prior to the administration of the RNA vaccine, the individual has been treated with approximately 1 to 17 or approximately 1 to 9 pre-treatments for systemic cancer.
32. The method according to any one of claims 1 to 31, wherein the individual is treated with checkpoint inhibitor therapy before administration of the RNA vaccine.
33. The method according to any one of claims 1 to 31, wherein the individual has not been treated with checkpoint inhibitor therapy prior to the administration of the RNA vaccine.
34. The method according to any one of claims 1 to 33, wherein the RNA vaccine comprises one or more polynucleotides encoding 10 to 20 neoepitopes resulting from cancer-specific somatic mutations present in the tumor specimen.
35. The method according to any one of claims 1 to 34, wherein the RNA vaccine is formulated into lipoplex nanoparticles or liposomes.
36. The method according to claim 35, wherein the lipoplex nanoparticles or liposomes include one or more lipids that form a multilayer structure that encapsulates the RNA of the RNA vaccine.
37. The method according to claim 36, wherein the one or more lipids comprise at least one cationic lipid and at least one helper lipid.
38. The method according to claim 36, wherein the one or more lipids include (R)-N,N,N-trimethyl-2,3-dioleyloxy-1-propaneaminium chloride (DOTMA) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE).
39. The liposome according to claim 38, wherein the total charge ratio of positive charge to negative charge of the liposome is 1.3:2 (0.65) at physiological pH.
40. The method according to any one of claims 1 to 39, wherein the RNA vaccine is administered to the individual in a dose of approximately 15 μg, approximately 25 μg, approximately 38 μg, approximately 50 μg, approximately 75 μg, or approximately 100 μg.
41. The method according to any one of claims 1 to 40, wherein the RNA vaccine is administered intravenously to the individual.
42. The method according to any one of claims 1 to 41, wherein the RNA vaccine is administered to the individual at intervals of seven days or one week.
43. The method according to any one of claims 1 to 41, wherein the RNA vaccine is administered to the individual at intervals of 14 days or 2 weeks.
44. The method according to claim 42 or 43, wherein the RNA vaccine is administered to the individual for 12 weeks or 84 days.
45. The method according to any one of claims 1 to 41, wherein the RNA vaccine is administered to the individual in a 21-day cycle, and the RNA vaccine is administered to the individual on days 1, 8 and 15 of cycle 1; days 1, 8 and 15 of cycle 2; days 1 and 15 of cycle 3; and day 1 of cycle 7.
46. The method according to claim 45, further comprising administering the RNA vaccine on day 1 of cycle 13 and every 24 weeks or 168 days thereafter.
47. The method according to claim 46, wherein the administration of the RNA vaccine is continued until the progression of the disease occurs in the individual.
48. The method according to any one of claims 1 to 41, wherein the RNA vaccine is administered to the individual during the induction stage and the maintenance stage thereafter, the RNA vaccine is administered to the individual during the induction stage at intervals of one or two weeks, and the RNA vaccine is administered to the individual during the maintenance stage at intervals of 24 weeks.
49. The method according to any one of claims 1 to 41, wherein the RNA vaccine is administered to the individual during the induction stage and the maintenance stage thereafter, the RNA vaccine is administered to the individual during the induction stage at intervals of 7 or 14 days, and the RNA vaccine is administered to the individual during the maintenance stage at intervals of 168 days.
50. The RNA vaccine is administered to the individual during the induction phase and the maintenance phase following the induction phase, and the RNA vaccine is administered to the individual in 21-day cycles; During the induction stage, the RNA vaccine is administered to the individual on days 1, 8 and 15 of cycle 1; days 1, 8 and 15 of cycle 2; days 1 and 15 of cycle 3; and day 1 of cycle 7; and The method according to any one of claims 1 to 41, wherein during the maintenance phase, the RNA vaccine is administered to the individual once on day 1 of cycle 13 and once every 24 weeks or 168 days thereafter.
51. The method according to claim 48 or claim 49, wherein the induction step comprises up to nine administrations of the RNA vaccine.
52. The method according to any one of claims 48 to 51, wherein the maintenance step is continued until the progression of the disease occurs in the individual.
53. The RNA vaccine, in the 5'→3' direction, (1) 5' cap; (2) 5' Untranslated region (UTR); (3) Polynucleotide sequences encoding secretory signal peptides; (4) Polynucleotide sequences encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in the tumor specimen; (5) Polynucleotide sequences encoding at least a portion of the transmembrane domain and cytoplasmic domain of a major histocompatibility complex (MHC) molecule; (6) 3'UTR, (a) the 3' untranslated region or fragment of the amino-terminal enhancer of Split(AES) mRNA; and (b) Non-coding RNA or fragments of mitochondrial-encoded 12S RNA 3'UTR; and (7) Poly(A) array The method according to any one of claims 1 to 52, comprising an RNA molecule containing the following.
54. The method according to claim 53, wherein the RNA molecule further comprises a polynucleotide sequence encoding an amino acid linker, the polynucleotide sequence encoding the amino acid linker and the first epitope of the one or more neoepitopes form a first linker-neoepitope module, and the polynucleotide sequence forming the first linker-neoepitope module is located in the 5'→3' direction between the polynucleotide sequence encoding the secretory signal peptide and the polynucleotide sequence encoding at least a portion of the transmembrane domain and the cytoplasmic domain of the MHC molecule.
55. The method according to claim 54, wherein the amino acid linker comprises the sequence GGGGGGGGGG (SEQ ID NO: 39).
56. The method according to claim 54, wherein the polynucleotide sequence encoding the amino acid linker includes the sequence GGGCCUCUGGGAGGGAGGGCGCGCGGGAGGC (SEQ ID NO: 37).
57. The method according to any one of claims 54 to 56, wherein the RNA molecule further comprises at least one second linker-epitope module in the 5'→3' direction, the at least one second linker-epitope module comprising a polynucleotide sequence encoding an amino acid linker and a polynucleotide sequence encoding a neoepitope, the polynucleotide sequence forming the second linker-neoepitope module being located in the 5'→3' direction between the polynucleotide sequence encoding the neoepitope of the first linker-neoepitope module and the polynucleotide sequence encoding at least a portion of the transmembrane domain and the cytoplasmic domain of the MHC molecule, and the neoepitope of the first linker-epitope module being different from the neoepitope of the second linker-epitope module.
58. The method according to claim 57, wherein the RNA molecule comprises five linker-epitope modules, each of which encodes a different neoepitope.
59. The method according to claim 57, wherein the RNA molecule comprises 10 linker-epitope modules, each of which encodes a different neoepitope.
60. The method according to claim 57, wherein the RNA molecule comprises 20 linker-epitope modules, each of which encodes a different neoepitope.
61. The RNA molecule according to any one of claims 53 to 60, further comprising a second polynucleotide sequence encoding an amino acid linker, wherein the second polynucleotide sequence encoding the amino acid linker is located in the 3' direction between a polynucleotide sequence encoding the most distal neoepitope and the polynucleotide sequence encoding at least a portion of the transmembrane domain and the cytoplasmic domain of the MHC molecule.
62. The aforementioned 5' cap has the following structure: The method according to any one of claims 53 to 61, comprising the D1 diastereomer.
63. The method according to any one of claims 53 to 62, wherein the 5'UTR includes the sequence UUCUUCUGUGUCCCCACAGAACUCCAGAGAGAACCCCGCCCACC (Sequence ID 23).
64. The method according to any one of claims 53 to 62, wherein the 5'UTR includes the sequence GGCGAACUALAGUAUUCUUCUGUGUCCCCCACAGACUCAGAGACCCGCCCACC (Sequence ID 21).
65. The method according to any one of claims 53 to 64, wherein the secretory signal peptide comprises the amino acid sequence MRVMAPPRTLILLLSGALALTETWAGS (SEQ ID NO: 27).
66. The method according to any one of claims 53 to 64, wherein the polynucleotide sequence encoding the secretory signal peptide includes the sequence AUGAGAGUGAAUGGCCCCCCCAGAACCUCUGCUGUGUCUGGGCGCCCCUUGGCUCACAGAGACAUGGGCCGGAAGACAGC (SEQ ID NO: 25).
67. The method according to any one of claims 53 to 66, wherein at least a portion of the transmembrane domain and the cytoplasmic domain of the MHC molecule comprises the amino acid sequence IVGIVAGLAVLAVVVIGAVVATVMCRRRKSSGGKGGSYSQAASSDSAQGSDVSLTA (SEQ ID NO: 30).
68. The method according to any one of claims 53 to 66, wherein the polynucleotide sequence encoding at least a portion of the transmembrane domain and the cytopathic domain of the MHC molecule includes the sequence AUCGUGGGAAUUGUGGCAGGGAACUGUGCUGGCCGUGGCCAUUCGGGAGCCCGUGGCUACCGUGAAUGUGGCAGAGACGGAAGUCCAAGUCUCCAAGUCUCCAAGUCUCCAAGUCUCGAAUAGUCCCCAAGUCCAAGUCUCCAAGUCUCGAAUAGUCCCCAAGUCUCCAAGUCUCCAAGUCUCGAAUAGUCCCCAAGUCUCCAAGUCUCCAAGUCUCCAAGUCUCCAAGUCUCCAAGUCUCCAAGUCUCCAAGUC (Sequence ID 28).
69. The method according to any one of claims 53 to 68, wherein the 3' untranslated region of the AES mRNA includes the sequence CUGGUACUGCAAUGCCAACGCCAAUGCCUAGCUGCCCCUUUUCCCGCGUGCGUACCCCGAGUCUUCCCCCCCGAGCUCUCGGGUUCCCCAAGGUAUGCCCCCACCUCCACCUGCUCUCUCUCUGCUAGUUCCCAGACACUCUCCC (Sequence ID 33).
70. The method according to any one of claims 53 to 69, wherein the non-coding RNA of the 12S RNA encoded in the dimethyl mitho includes the sequence CAAGCAACGCCAAGCAAUGCCAGCUCUCAAAAGCUUAGCCCUAGCCCCCCACGGGAAAAACAGCAGUGAAUUAACCUUUAGCAAUAACGAAAAAGCUAUAACCUAACCCCCAGGGUUGGUCAAUUUCGUGCCAAGCCCAACACCG (Sequence ID 35).
71. The 3'UTR has the sequence CUCGAGCUGGUACUGCAUGCACGCAAUGCUAGCUGCCCCUUUCCCGUCCUGGGGUACCCCGAGUCUCCCCGACCUCGGGU CCCAGGUAUGCUCCACCUCCACCUGCCCCACUCUCACCACCUGCUAGUUCCAGACACCUCCCCAAGCACGCAGCAAUGCAGCUCAAACG The method according to any one of claims 53 to 70, including CUUAGCCCUAGCCCAACACCCCCCACGGGGGAAAAACAGCAGUGAAUUAACCUUUAGCAAUAACGAAAAGUUUAACCUAUACCCCCACAGGGGUUGUCCAAUUUCGUGCCAAGCCCAACACCGAGAGACCUCGCUAGCCGCGUGCCU (Sequence ID 31).
72. The method according to any one of claims 53 to 71, wherein the poly(A) sequence comprises 120 adenine nucleotides.
73. The RNA vaccine, in the 5'→3' direction, Polynucleotide ENTER GGGCGAACUALAGUAUUCUCUCUGUCUCACAGACAUGGGCCCACAUGGGCCCCAGAAGAUGGGCCCCCCAGAAGAUGGGCCCCCCAGAAGAUGGGCCCCCCAGAAGAUGGGCGC(Sequence ID 19); Polynucleotide sequences encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in the tumor specimen; Polycryption AUCGUGGGAAUUGUGGCAAGGAGUGGCAAGUGCUGGCCGUGUGGGUGAAUUCGGCAAGCCGUGGCUACCGUGAAUGUGGCAGAAGGGGAAAAGUCCCCAAGGCGCCAAGCUACAGCCCAAGGCCCCA GCUCUGAUAGCGCCCAGGGCAGCGACGUGUCACUGACAGCCUAGUAACUCGAGCUGGUACUGCAUGC ACGCAAUGCUAGCUGCCCCUUUCCCGUCCUGGGGUACCCCGAGUCUCCCCGACCUCGGGUCCCAGGUA The method according to any one of claims 1 to 52, comprising an UL molecule containing UGCUCCCCACUCCCUCUCUCUCUCUCUCUCUCUCUCUCUCUCUCUCUCUCUCUCAUGCAGCUCUCUCAAAAAGCCUCUCAUGCCUCUCAAAAAGCCUCUCAUGCCUCAUGCCUCAUGCCUCACACCCCCCACGGGGGAAAAAGCAGUGAAUAACCCUUUUAGCAAUAAAAAGCCUCAUGCCUCAUGCCUCAUGCCUCAUGCCUCAUGCCUCAUGCCUCAUGCCUCAUGCCUCAUGCCUCUCAUGCCUCUCUCUCCUAGCCGCUCUCCU (SEQ ID NO: 20).
74. The method according to any one of claims 1 to 73, further comprising administering a PD-1 axis-coupled antagonist to the individual.
75. The method according to claim 74, wherein the PD-1 axially coupled antagonist is a PD-1 binding antagonist.
76. The method according to claim 75, wherein the PD-1 conjugated antagonist is an anti-PD-1 antibody.
77. The method according to claim 76, wherein the anti-PD-1 antibody is nivolumab or pembrolizumab.
78. The method according to claim 74, wherein the PD-1 axis-coupled antagonist is a PD-L1-coupled antagonist.
79. The method according to claim 78, wherein the PD-L1-binding antagonist is an anti-PD-L1 antibody.
80. The method according to claim 79, wherein the anti-PD-L1 antibody is avelumab or durvalumab.
81. The aforementioned anti-PD-L1 antibody, (a) A heavy chain variable region (VH) comprising HVR-H1 containing the amino acid sequence of GTFFSDSWIH (SEQ ID NO: 1), HVR-2 containing the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 2), and HVR-3 containing the amino acid RHWPGGGFDY (SEQ ID NO: 3), (b) The method according to claim 79, comprising a light chain variable region (VL) including HVR-L1 containing the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 4), HVR-L2 containing the amino acid sequence of SASFLYS (SEQ ID NO: 5), and HVR-L3 containing the amino acid sequence of QQYLYHPAT (SEQ ID NO: 6).
82. The anti-PD-L1 antibody contains a heavy chain variable region (V) including the amino acid sequence of SEQ ID NO:
7. Ｈ ) and the light chain variable region (V) containing the amino acid sequence of SEQ ID NO: 8 Ｌ The method according to claim 79, which includes the following:
83. The method according to claim 79, wherein the anti-PD-L1 antibody is atezolizumab.
84. The method according to any one of claims 74 to 83, wherein the PD-1 axis-coupled antagonist is administered intravenously to the individual.
85. The method according to any one of claims 79 to 84, wherein the anti-PD-L1 antibody is administered to the individual in a dose of approximately 1200 mg.
86. The method according to any one of claims 74 to 85, wherein the PD-1 axis-coupled antagonist is administered to the individual at intervals of 21 days or 3 weeks.
87. The method according to any one of claims 83 to 86, wherein the atezolizumab is administered to the individual in a 21-day cycle, and the atezolizumab is administered on day 1 of each of cycles 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
88. The method according to claim 87, further comprising administering atezolizumab on day 1 of cycle 13 and every three weeks or every 21 days thereafter.
89. The method according to claim 88, wherein the administration of atezolimab is continued until disease progression occurs in the individual.
90. The atezolimab is administered to the individual in a 21-day cycle during the induction phase and the maintenance phase following the induction phase. During the induction phase, atezolizumab is administered on day 1 of each of cycles 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and The method according to any one of claims 83 to 86, wherein during the maintenance phase following the induction phase, atezolimab is administered on day 1 of cycle 13 and thereafter every 3 weeks or 21 days.
91. The method according to claim 90, wherein the maintenance step is continued until the progression of the disease occurs in the individual.
92. The method according to any one of claims 1 to 91, wherein the individual is a human.
93. An RNA vaccine for use in a method for inducing neoepitope-specific CD8+ T cells in an individual having a tumor, wherein the method comprises administering an effective amount of the RNA vaccine to the individual, the RNA vaccine comprising one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and the RNA vaccine comprising about 1% to about 6% of CD8+ T cells in a peripheral blood sample obtained from the individual after administration of the RNA vaccine, being neoepitope-specific CD8+ T cells specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
94. An RNA vaccine for use in a method for inducing the transport of neoepitope-specific CD8+ T cells to a tumor in an individual, wherein the method comprises administering an effective amount of the RNA vaccine to the individual, the RNA vaccine comprising one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and the neoepitope-specific CD8+ T cells transported to the tumor after administration of the RNA vaccine are specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
95. The RNA vaccine for use according to claim 93 or claim 94, further comprising administering a PD-1 axis-binding antagonist to the individual.
96. A PD-1 axis-binding antagonist for use in a method for inducing neoepitope-specific CD8+ T cells in an individual having a tumor, wherein the method comprises administering an effective amount of the PD-1 axis-binding antagonist and an RNA vaccine to the individual, the RNA vaccine comprising one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and approximately 1% to approximately 6% of the CD8+ T cells in a peripheral blood sample obtained from the individual after administration of the PD-1 axis-binding antagonist and the RNA vaccine are neoepitope-specific CD8+ T cells specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
97. A PD-1 axis-binding antagonist for use in a method for inducing the transport of neoepitope-specific CD8+ T cells to a tumor in an individual, wherein the method comprises administering an effective amount of the PD-1 axis-binding antagonist and an RNA vaccine to the individual, the RNA vaccine comprising one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and the neoepitope-specific CD8+ T cells transported to the tumor after administration of the PD-1 axis-binding antagonist and the RNA vaccine are specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
98. A method for inducing neoepitope-specific CD8+ T cells in an individual having a tumor, comprising administering an effective amount of an RNA vaccine to the individual, wherein the RNA vaccine comprises one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and at least about 1% of the CD8+ T cells in a peripheral blood sample obtained from the individual after administration of the RNA vaccine are neoepitope-specific CD8+ T cells specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
99. An RNA vaccine for use in a method for inducing neoepitope-specific CD8+ T cells in an individual having a tumor, wherein the method comprises administering an effective amount of the RNA vaccine to the individual, the RNA vaccine comprising one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and at least about 1% of the CD8+ T cells in a peripheral blood sample obtained from the individual after administration of the RNA vaccine are neoepitope-specific CD8+ T cells specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.
100. A PD-1 axis-binding antagonist for use in a method for inducing neoepitope-specific CD8+ T cells in an individual having a tumor, wherein the method comprises administering an effective amount of the PD-1 axis-binding antagonist and an RNA vaccine to the individual, the RNA vaccine comprising one or more polynucleotides encoding one or more neoepitopes resulting from cancer-specific somatic mutations present in a tumor specimen obtained from the individual, and at least about 1% of the CD8+ T cells in a peripheral blood sample obtained from the individual after administration of the PD-1 axis-binding antagonist and the RNA vaccine are neoepitope-specific CD8+ T cells specific to at least one of the neoepitopes encoded by the one or more polynucleotides of the RNA vaccine.