Cells comprising non-HLA restricted t cell receptors

Abstract

The presently disclosed subject matter provides cells, compositions and methods for enhancing immune responses toward tumor antigens. It relates to cells comprising an antigen-recognizing receptor (e.g., a HIT receptor) and an inhibitory polynucleotide. These cells have improved activity and / or efficiency.

Description

[0001]072734.1771 PATENT CELLS COMPRISING NON-HLA RESTRICTED T CELL RECEPTORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63 / 668,511, filed July 8, 2024, the content of which is incorporated by reference in its entirety, and to which priority is claimed. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted herewith and is hereby incorporated by reference in its entirety. Said .xml copy, created on July 01, 2025, is named 0727341771, and is 512,687 bytes in size. INTRODUCTION The presently disclosed subject matter provides compositions and methods for targeting immune responses toward tumor antigen-bearing cells. It relates to compositions, e.g., modified immunoresponsive cells, comprising an antigen-recognizing receptor (e.g., a TCR-like fusion molecule (HIT receptor)) and an inhibitory polynucleotide that targets an endogenous TCR locus (e.g., TRAC, TRBC1, TRBC2, etc.), where the compositions mediate an immune response toward cells bearing the antigen. BACKGROUND OF THE INVENTION In the context of adoptive cell therapies, it has been shown that transgenes encoding chimeric receptors (e.g., CAR) can be efficiently integrated into the TRAC locus that encodes for the endogenous TCR α constant chain using an adeno-associated viral vector as the homology- directed repair template that dynamically control TCR expression levels in response to T-cell activation states. While this strategy allows to disrupt endogenous TCR expression and takes advantage of endogenous gene regulatory mechanisms, its applicability can be limited because of the high production and manufacturing costs as well as for safety reasons. Indeed, to date, all FDA-approved adoptive cell therapies use lentiviral or retroviral transduction to achieve transgene integration. Therefore, novel concepts to control TCR expression levels with reduced production and manufacturing costs are needed. SUMMARY OF THE INVENTION The presently disclosed subject matter provides compositions, e.g., modified immunoresponsive cells, comprising: (a) a polynucleotide encoding an antigen-recognizing receptor; and (b) an inhibitory polynucleotide targeting one or more genes. The presently disclosed subject matter further provides uses of these compositions in reducing tumor burden,ACTIVE 509948342.21 072734.1771 PATENT treating and / or preventing a neoplasm or a tumor, preventing and / or treating a pathogen infection, preventing and / or treating an autoimmune disease, and / or preventing and / or treating an infectious disease. In certain non-limiting embodiments, the presently disclosed subject matter provides a cell including: (a) a polynucleotide encoding an antigen-recognizing receptor, wherein the antigen- recognizing receptor is a HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and (b) an inhibitory polynucleotide targeting one or more endogenous genes. In certain embodiments, the inhibitory polynucleotide is positioned between a splice donor sequence and a splice acceptor sequence. In certain embodiments, the polynucleotide encoding the antigen-recognizing receptor and the inhibitory polynucleotide are operably linked. In certain embodiments, the polynucleotide encoding the antigen-recognizing receptor and the inhibitory polynucleotide are operably linked to a promoter. In certain embodiments, the cell comprises, from 5’ end to 3’ end, the promoter, the intron, and the polynucleotide encoding the antigen- recognizing receptor. In certain embodiments, the promoter is a constitutive promoter or an inducible promoter. In certain embodiments, the inhibitory polynucleotide includes one or more short hairpin RNA (shRNA), small interfering RNA (siRNA), double stranded RNA (dsRNA), antisense oligonucleotide, or a combination thereof. In certain embodiments, the inhibitory polynucleotide includes one or more shRNAs. In certain embodiments, the one or more genes are selected from TRAC, TRBC1, TRBC2, CD70, or a combination thereof. In certain embodiments, the one or more genes are TRAC, TRBC1, TRBC2, and CD70. In certain embodiments, the one or more genes are TRAC, TRBC1, and TRBC2. In certain embodiments, the inhibitory polynucleotide targeting TRAC includes the nucleotide sequence set forth in SEQ ID NO. 105, SEQ ID NO. 106, SEQ ID NO. 107, SEQ ID NO.108, SEQ ID NO.109, SEQ ID NO.110, SEQ ID NO.111, SEQ ID NO.112, SEQ ID NO. 113, SEQ ID NO. 114, SEQ ID NO. 115, or SEQ ID NO. 116. In certain embodiments, the inhibitory polynucleotide targeting TRAC includes the nucleotide sequence set forth in SEQ ID NO. 110. In certain embodiments, the inhibitory polynucleotide targeting TRAC includes the nucleotide sequence set forth in SEQ ID NO. 117, SEQ ID NO. 118, SEQ ID NO. 119, SEQ ID NO.120, SEQ ID NO.121, SEQ ID NO.122, SEQ ID NO.123, SEQ ID NO.124, SEQ ID NO. 125, SEQ ID NO. 126, SEQ ID NO. 127, or SEQ ID NO. 128. In certain embodiments, the inhibitory polynucleotide targeting TRAC includes the nucleotide sequence set forth in SEQ ID NO.122. In certain embodiments, the inhibitory polynucleotide targeting TRBC1 and TRBC2 includes the nucleotide sequence set forth in SEQ ID NO. 131, SEQ ID NO. 132, SEQ ID NO.ACTIVE 509948342.22 072734.1771 PATENT 133, SEQ ID NO. 134, SEQ ID NO. 135, or SEQ ID NO. 136. In certain embodiments, the inhibitory polynucleotide targeting TRBC1 and TRBC2 includes the nucleotide sequence set forth in SEQ ID NO.131. In certain embodiments, the inhibitory polynucleotide targeting TRBC1 and TRBC2 includes the nucleotide sequence set forth in SEQ ID NO. 137, SEQ ID NO. 138, SEQ ID NO. 139, SEQ ID NO. 140, SEQ ID NO. 141, or SEQ ID NO.142. In certain embodiments, the inhibitory polynucleotide targeting TRBC1 and TRBC2 includes the nucleotide sequence set forth in SEQ ID NO.137. In certain embodiments, the inhibitory polynucleotide targeting CD70 includes the nucleotide sequence set forth in SEQ ID NO. 144, SEQ ID NO. 145, SEQ ID NO. 146, SEQ ID NO. 147, or SEQ ID NO. 148. In certain embodiments, the inhibitory polynucleotide targeting CD70 includes the nucleotide sequence set forth in SEQ ID NO. 145. In certain embodiments, the inhibitory polynucleotide targeting CD70 includes the nucleotide sequence set forth in SEQ ID NO. 149, SEQ ID NO. 150, SEQ ID NO. 151, SEQ ID NO. 152, or SEQ ID NO. 153. In certain embodiments, the inhibitory polynucleotide targeting CD70 includes the nucleotide sequence set forth in SEQ ID NO.150. In certain embodiments, the inhibitory polynucleotide comprises a microRNA. In certain embodiments, the polynucleotide encoding the antigen-recognizing receptor and the inhibitory polynucleotide are integrated in a genome of the cell. In certain embodiments, the polynucleotide encoding the antigen-recognizing receptor and the inhibitory polynucleotide are not integrated in a TRAC locus and / or a TRBC locus. In certain embodiments, the polynucleotide encoding the antigen recognizing receptor and the inhibitory polynucleotide are operably linked. In certain embodiments, the antigen-recognizing receptor is a HIT receptor. In certain embodiments, the HIT receptor includes a first antigen-binding chain including an antigen-binding fragment of a heavy chain variable region (VH) of an antibody and a TRAC polypeptide and a second antigen-binding chain including an antigen-binding fragment of a light chain variable region (VL) of an antibody and a TRBC polypeptide, wherein the HIT receptor binds to an antigen in an HLA-independent manner. In certain embodiments, the HIT receptor includes a first antigen-binding chain including an antigen-binding fragment of a heavy chain variable region (VH) of an antibody and a TRBC polypeptide and a second antigen-binding chain including an antigen-binding fragment of a light chain variable region (VL) of an antibody and a TRAC polypeptide, wherein the HIT receptor binds to an antigen in an HLA-independent manner. In certain embodiments, the TRAC polypeptide includes an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to the amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 11; and the TRBC polypeptide includesACTIVE 509948342.23 072734.1771 PATENT an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 19. In certain embodiments, the TRAC polypeptide includes the amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 11; and the TRBC polypeptide includes the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 19. In certain embodiments, the TRAC polypeptide includes the amino acid sequence set forth in SEQ ID NO: 7; and the TRBC polypeptide includes the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the HIT receptor binds to an antigen with a dissociation constant (KD) of about 1 × 10-8M or less. In certain embodiments, the HIT receptor binds to the antigen with a dissociation constant (KD) of about 5 × 10-9M or less. In certain embodiments, the HIT receptor is capable of associating with a CD3ζ polypeptide. In certain embodiments, the HIT receptor, upon binding to an antigen, is capable of activating the CD3ζ polypeptide. In certain embodiments, the activation of the CD3ζ polypeptide is capable of activating the cell. In certain embodiments, the cell further comprises a polynucleotide encoding a chimeric antigen-recognizing receptor (CAR). In certain embodiments, the polynucleotide encoding the CAR is integrated in the genome of the cell. In certain embodiments, the polynucleotide encoding the CAR is not integrated in a TRAC locus and / or a TRBC locus. In certain embodiments, the polynucleotide encoding the HIT receptor, the inhibitory polynucleotide, and the polynucleotide encoding the CAR are operably linked. In certain embodiments, the CAR includes an extracellular antigen-binding domain that binds to a second antigen, and an intracellular signaling domain that is capable of delivering an activation signal to the cell. In certain embodiments, the intracellular signaling domain of the CAR includes a CD3ζ polypeptide. In certain embodiments, the CD3ζ polypeptide is a native CD3ζ polypeptide or a modified CD3ζ polypeptide. In certain embodiments, the modified CD3ζ polypeptide includes a native ITAM1, an ITAM2 variant consisting of two loss-of-function mutations, and an ITAM3 variant consisting of two loss-of-function mutations. In certain embodiments, the modified CD3ζ polypeptide includes the amino acid sequence set forth in SEQ ID NO: 169. In certain embodiments, the intracellular signaling domain of the CAR further includes at least one costimulatory signaling region. In certain embodiments, the at least one costimulatory signaling region includes at least an intracellular domain of a co-stimulatory molecule or a portion thereof. In certain embodiments, the costimulatory molecule is selected from the group consisting of CD28, 4-1BB, OX40, CD27, CD40, CD154, CD97, CD11a / CD18,ACTIVE 509948342.24 072734.1771 PATENT ICOS, DAP-10, CD2, CD150, CD226, and NKG2D. In certain embodiments, the CAR includes a transmembrane domain. In certain embodiments, the cell is a cell of the lymphoid lineage or a cell of the myeloid lineage. In certain embodiments, the cell of the lymphoid lineage is selected from the group consisting of a T cell, a B cell, a Natural Killer (NK) cell, and a dendritic cell. In certain embodiments, the cell is a T cell. In certain embodiments, the T cell is derived from an induced pluripotent stem cell. In certain embodiments, the T cell is a CD8+T cell. In certain embodiments, the CD8+ T cell is CD4 independent. In certain embodiments, the T cell is selected from the group consisting of a cytotoxic T lymphocyte (CTL), a γδ T cell, a tumor-infiltrating lymphocyte (TIL), a regulatory T cell, and a Natural Killer T (NKT) cell. In certain embodiments, the T cell is CD62L+, CD45RA+, or CD45RA+CD62L+. In certain embodiments, the HIT receptor and / or the CAR bind to a tumor antigen or a pathogen antigen. In certain embodiments, the tumor antigen is selected from the group consisting of CD19, CD70, IL1RAP, ABCG2, AChR, ACKR6, ADAMTS13, ADGRE2, ADGRE2 (EMR2), ADORA3, ADRA1D, AGER, ALS2, an antigen of a cytomegalovirus (CMV) infected cell (e.g. a cell surface antigen), ANO9, AQP2, ASIC3, ASPRV1, ATP6V0A4, B3GNT4, B7-H3, BCMA, BEST4, C3orf35, CADM3, CAIX, CAPN3, CCDC155, CCR1, CD10, CD117, CD123, CD133, CD135 (FLT3), CD138, CD20, CD22, CD244 (2B4), CD25, CD26 , CD30, CD300LF, CD312, CD32, CD321, CD33, CD34, CD36, CD38, CD41, CD44, CD44V6, CD47, CD49f, CD56, CD7, CD71, CD74, CD8, CD82, CD96, CD98, CD99, CDH13, CDHR1, CEA, CEACAM6, CHST3, CLEC12A, CLEC1A, CLL1, CNIH2, COL15A1, COLEC12, CPM, CR1, CX3CR1, CXCR4, CYP4F11, DAGLB, DARC, DFNB31, DGKI, EGF1R, EGFR-VIII, EGP-2, EGP-40, ELOVL6, EMB, EMC10, EMR2, ENG, EpCAM, EphA2, EPHA4, ERBB, ERBB2, Erb-B3, Erb-B4, E- selectin, EXOC3L4, EXTL3, FAM186B, FBP, FCGR1A, FCRL5, FKBP1B, FLRT1, folate receptor-α, FOLR2, FRMD5, GABRB2, GAS2, GD2, GD3, GDPD3, GNA14, GNAZ, GPC2, GPC3, GPR153, GPR56, GYPA, HEPHL1, HER-2, hERT, HILPDA, HLA-DR, HOOK1, hTERT, HTR2A, ICAM1, IGFBP3, IL10RB, IL20RB, IL23R, ILDR1, Interleukin-13 receptor subunit alpha-2 (IL-13Rα2), ITFG3, ITGA4, ITGA5, ITGA8, ITGAX, ITGB5, ITGB8, JAM3, KCND1, KCNJ5, KCNK13, KCNN4, KCNV2, KDR, KIF19, KIF26B, κ-light chain, L1CAM, LAX1, LEPR, Lewis Y (CD174), Lewis Y (LeY), LILRA2, LILRA6, LILRB2, LILRB3, LILRB4, LOXL4, LPAR2, LRRC37A3, LRRC8E, LRRN2, LRRTM2, LTB4R, MAGE-A1, MAGEA3, MANSC1, MART1,GP100, MBOAT1, MBOAT7, melanoma antigen family A, Mesothelin (MSLN), MFAP3L, MMP25, MRP1, MT-ND1, Mucin 1 (MUC1), Mucin 16 (MUC16), MYADM, MYADML2, NGFR, NKCS1, NKG2D ligands, NLGN3, NPAS2, NY- ESO-1, oncofetal antigen (h5T4), OTOA, P2RY13, p53, PDE3A, PEAR1, PIEZO1, PLXNA4,ACTIVE 509948342.25 072734.1771 PATENT PLXNC1, PNPLA3, PPFIA4, PPP2R5B, PRAME, PRAME, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), Proteinase3 (PR1), PSD2, PTPRJ, RDH16, receptor tyrosine-protein kinase Erb-B2, RHBDL3, RNF173, RNF183, ROR1, RYR2, SCIN, SCN11A, SCN2A, SCNN1D, SEC31B, SEMA4A, SH3PXD2A, SIGLEC6, SIGLEC11, SIRPB1, SLC16A6, SLC19A1, SLC22A5, SLC25A36, SLC25A41, SLC30A1, SLC34A3, SLC43A3, SLC44A1, SLC44A3, SLC45A3, SLC6A16, SLC6A6, SLC8A3, SLC9A1, SLCO2B1, SPAG17, STC1, STON2, SUN3, Survivin, SUSD2, SYNC, TACSTD2, TAS1R3, TEX29, TFR2, TIM-3 (HAVCR2), TLR2, TMEFF2, TMEM145, TMEM27, TMEM40, TMEM59L, TMEM89, TMPRSS5, TNFRSF14, TNFRSF1B, TRIM55, TSPEAR, TTYH3, tumor-associated glycoprotein 72 (TAG-72), Tyrosinase, vascular endothelial growth factor R2 (VEGF-R2), VLA- 4, Wilms tumor protein (WT-1), WNT4, WT1, and ZDHHC11. In certain embodiments, the HIT receptor binds to CD19 and includes a first antigen binding chain including a CDR1 including the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 48, and a second antigen binding chain including a CDR1 including the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 51. In certain embodiments, the CAR binds to CD22 and includes an extracellular antigen-binding domain including a VH including a CDR1 including amino acids having the sequence set forth in SEQ ID NO: 94, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 96; and a VL including a CDR1 including the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, the cell further comprises a polynucleotide encoding a chimeric co-stimulating receptor (CCR). In certain embodiments, the cell further comprises a polynucleotide encoding at least one exogenous costimulatory ligand. In certain embodiments, the cell further comprises a polynucleotide encoding a fusion polypeptide including: a) an extracellular domain and a transmembrane domain of a co- stimulatory ligand, and b) an intracellular domain of a first co-stimulatory molecule. In certain embodiments, the co-stimulatory ligand is selected from the group consisting of a tumor necrosis factor (TNF) family member, an immunoglobulin (Ig) superfamily member, and combinations thereof. In certain embodiments, the TNF family member is selected from the group consisting of 4-1BBL, OX40L, CD70, GITRL, CD40L, and combinations thereof. In certain embodiments, the Ig superfamily member is selected from the group consisting of CD80, CD86, ICOSLG, andACTIVE 509948342.26 072734.1771 PATENT combinations thereof. In certain embodiments, the co-stimulatory ligand is CD80. In certain embodiments, the first co-stimulatory molecule is selected from the group consisting of CD28, 4- 1BB, OX40, ICOS, DAP-10, CD27, CD40, NKG2D, CD2, and combinations thereof. In certain embodiments, the first co-stimulatory molecule is 4-1BB. In certain embodiments, the co- stimulatory ligand is CD80 and the first co-stimulatory molecule is 4-1BB. In certain embodiments, the fusion polypeptide includes the amino acid sequence set forth in SEQ ID NO: 185. In certain embodiments, the fusion polypeptide further includes an intracellular domain of a second co-stimulatory molecule. In certain embodiments, the second co-stimulatory molecule is selected from the group consisting of CD28, 4-1BB, OX40, ICOS, DAP-10, CD27, CD40, NKG2D, CD2, and combinations thereof. In certain embodiments, the second co-stimulatory molecule is CD28. In certain embodiments, the co-stimulatory ligand is CD80, the first co- stimulatory molecule is 4-1BB, and the second co-stimulatory molecule is CD28. In certain embodiments, the fusion polypeptide includes the amino acid sequence set forth in SEQ ID NO: 186. In certain embodiments, the cell is autologous or allogeneic. In certain non-limiting embodiments, the presently disclosed subject matter provides a cell comprising a polynucleotide encoding an antigen-recognizing receptor that binds a tumor antigen, wherein the antigen-recognizing receptor is an HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and an inhibitory polynucleotide targeting TRAC. In certain embodiments, the tumor antigen is selected from the group consisting of CD19, IL1RAP, ABCG2, AChR, ACKR6, ADAMTS13, ADGRE2, ADGRE2 (EMR2), ADORA3, ADRA1D, AGER, ALS2, an antigen of a cytomegalovirus (CMV) infected cell (e.g. a cell surface antigen), ANO9, AQP2, ASIC3, ASPRV1, ATP6V0A4, B3GNT4, B7-H3, BCMA, BEST4, C3orf35, CADM3, CAIX, CAPN3, CCDC155, CCR1, CD10, CD117, CD123, CD133, CD135 (FLT3), CD138, CD20, CD22, CD244 (2B4), CD25, CD26 , CD30, CD300LF, CD312, CD32, CD321, CD33, CD34, CD36, CD38, CD41, CD44, CD44V6, CD47, CD49f, CD56, CD7, CD71, CD74, CD8, CD82, CD96, CD98, CD99, CDH13, CDHR1, CEA, CEACAM6, CHST3, CLEC12A, CLEC1A, CLL1, CNIH2, COL15A1, COLEC12, CPM, CR1, CX3CR1, CXCR4, CYP4F11, DAGLB, DARC, DFNB31, DGKI, EGF1R, EGFR-VIII, EGP-2, EGP-40, ELOVL6, EMB, EMC10, EMR2, ENG, EpCAM, EphA2, EPHA4, ERBB, ERBB2, Erb-B3, Erb-B4, E-selectin, EXOC3L4, EXTL3, FAM186B, FBP, FCGR1A, FCRL5, FKBP1B, FLRT1, folate receptor-α, FOLR2, FRMD5, GABRB2, GAS2, GD2, GD3, GDPD3, GNA14, GNAZ, GPC2, GPC3, GPR153, GPR56, GYPA, HEPHL1, HER-2, hERT, HILPDA, HLA-DR, HOOK1, hTERT, HTR2A, ICAM1, IGFBP3, IL10RB, IL20RB, IL23R, ILDR1, Interleukin-13 receptor subunitACTIVE 509948342.27 072734.1771 PATENT alpha-2 (IL-13Rα2), ITFG3, ITGA4, ITGA5, ITGA8, ITGAX, ITGB5, ITGB8, JAM3, KCND1, KCNJ5, KCNK13, KCNN4, KCNV2, KDR, KIF19, KIF26B, κ-light chain, L1CAM, LAX1, LEPR, Lewis Y (CD174), Lewis Y (LeY), LILRA2, LILRA6, LILRB2, LILRB3, LILRB4, LOXL4, LPAR2, LRRC37A3, LRRC8E, LRRN2, LRRTM2, LTB4R, MAGE-A1, MAGEA3, MANSC1, MART1,GP100, MBOAT1, MBOAT7, melanoma antigen family A, Mesothelin (MSLN), MFAP3L, MMP25, MRP1, MT-ND1, Mucin 1 (MUC1), Mucin 16 (MUC16), MYADM, MYADML2, NGFR, NKCS1, NKG2D ligands, NLGN3, NPAS2, NY-ESO-1, oncofetal antigen (h5T4), OTOA, P2RY13, p53, PDE3A, PEAR1, PIEZO1, PLXNA4, PLXNC1, PNPLA3, PPFIA4, PPP2R5B, PRAME, PRAME, prostate stem cell antigen (PSCA), prostate- specific membrane antigen (PSMA), Proteinase3 (PR1), PSD2, PTPRJ, RDH16, receptor tyrosine-protein kinase Erb-B2, RHBDL3, RNF173, RNF183, ROR1, RYR2, SCIN, SCN11A, SCN2A, SCNN1D, SEC31B, SEMA4A, SH3PXD2A, SIGLEC6, SIGLEC11, SIRPB1, SLC16A6, SLC19A1, SLC22A5, SLC25A36, SLC25A41, SLC30A1, SLC34A3, SLC43A3, SLC44A1, SLC44A3, SLC45A3, SLC6A16, SLC6A6, SLC8A3, SLC9A1, SLCO2B1, SPAG17, STC1, STON2, SUN3, Survivin, SUSD2, SYNC, TACSTD2, TAS1R3, TEX29, TFR2, TIM-3 (HAVCR2), TLR2, TMEFF2, TMEM145, TMEM27, TMEM40, TMEM59L, TMEM89, TMPRSS5, TNFRSF14, TNFRSF1B, TRIM55, TSPEAR, TTYH3, tumor-associated glycoprotein 72 (TAG-72), Tyrosinase, vascular endothelial growth factor R2 (VEGF-R2), VLA- 4, Wilms tumor protein (WT-1), WNT4, WT1, and ZDHHC11. In certain non-limiting embodiments, the presently disclosed subject matter provides a cell comprising a polynucleotide encoding an antigen-recognizing receptor that binds CD70, wherein the antigen-recognizing receptor is an HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and an inhibitory polynucleotide targeting CD70. In certain embodiments, the HIT receptor comprises a first antigen binding chain comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66, and a second antigen binding chain comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 67, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 68, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 69. In certain non-limiting embodiments, the presently disclosed subject matter provides a cell comprising a polynucleotide encoding an antigen-recognizing receptor that binds CD70, wherein the antigen-recognizing receptor is an HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and an inhibitory polynucleotide targeting TRAC and CD70. In certain embodiments, the HIT receptor comprises a first antigen binding chain comprising aACTIVE 509948342.28 072734.1771 PATENT CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66, and a second antigen binding chain comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 67, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 68, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 69. In certain embodiments, the inhibitory polynucleotide targeting TRAC comprises the nucleotide sequence set forth in SEQ ID NO. 105, SEQ ID NO. 106, SEQ ID NO. 107, SEQ ID NO.108, SEQ ID NO.109, SEQ ID NO.110, SEQ ID NO.111, SEQ ID NO.112, SEQ ID NO. 113, SEQ ID NO.114, SEQ ID NO.115, SEQ ID NO.116, SEQ ID NO.117, SEQ ID NO.118, SEQ ID NO.119, SEQ ID NO.120, SEQ ID NO.121, SEQ ID NO.122, SEQ ID NO.123, SEQ ID NO. 124, SEQ ID NO. 125, SEQ ID NO. 126, SEQ ID NO. 127, or SEQ ID NO. 128. In certain embodiments, the inhibitory polynucleotide targeting CD70 comprises the nucleotide sequence set forth in SEQ ID NO. 144, SEQ ID NO. 145, SEQ ID NO. 146, SEQ ID NO. 147, SEQ ID NO. 148, SEQ ID NO. 149, SEQ ID NO. 150, SEQ ID NO. 151, SEQ ID NO. 152, or SEQ ID NO.153. The presently disclosed subject matter also provides a composition including the cell disclosed herein. In certain embodiments, the composition is a pharmaceutical composition further including a pharmaceutically acceptable excipient. Moreover, the presently disclosed subject matter provides a nucleic acid molecule including: (a) a polynucleotide encoding an antigen-recognizing receptor, wherein the antigen- recognizing receptor is a HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and (b) an intron including an inhibitory polynucleotide targeting one or more genes. In certain embodiments, the inhibitory polynucleotide is positioned between a splice donor sequence and a splice acceptor sequence of the intron. In certain embodiments, the polynucleotide encoding the antigen-recognizing receptor and the intron are operably linked to each other. In certain embodiments, the polynucleotide encoding the antigen-recognizing receptor and the inhibitory polynucleotide are operably linked to a promoter. In certain embodiments, the nucleic acid molecule includes, from 5' end to 3' end, the promoter, the intron, and the polynucleotide encoding a antigen-recognizing receptor . In certain embodiments, the promoter is a constitutive promoter or an inducible promoter. In certain embodiments, the antigen-recognizing receptor is a HIT receptor. In certain embodiments, the HIT receptor includes a first antigen-binding chain including an antigen-binding fragment of a heavy chain variable region (VH) of an antibody and a TRAC polypeptide and a second antigen-binding chain including an antigen-binding fragment of a light chain variableACTIVE 509948342.29 072734.1771 PATENT region (VL) of an antibody and a TRBC polypeptide, wherein the HIT receptor binds to an antigen in an HLA-independent manner. In certain embodiments, the HIT receptor includes a first antigen-binding chain including an antigen-binding fragment of a heavy chain variable region (VH) of an antibody and a TRBC polypeptide and a second antigen-binding chain including an antigen-binding fragment of a light chain variable region (VL) of an antibody and a TRAC polypeptide, wherein the HIT receptor binds to an antigen in an HLA-independent manner. In certain embodiments, the TRAC polypeptide includes the amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 11; and the TRBC polypeptide includes the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 19. In certain embodiments, the inhibitory polynucleotide includes one or more short hairpin RNA (shRNA), small interfering RNA (siRNA), double stranded RNA (dsRNA), antisense oligonucleotide, or a combination thereof. In certain embodiments, the inhibitory polynucleotide includes one or more shRNAs. In certain embodiments, the one or more genes are selected from TRAC, TRBC1, TRBC2, CD70, or a combination thereof. In certain embodiments, the inhibitory polynucleotide targeting TRAC includes the nucleotide sequence set forth in SEQ ID NO. 105, SEQ ID NO.106, SEQ ID NO.107, SEQ ID NO.108, SEQ ID NO.109, SEQ ID NO.110, SEQ ID NO. 111, SEQ ID NO. 112, SEQ ID NO. 113, SEQ ID NO. 114, SEQ ID NO. 115, SEQ ID NO.116, SEQ ID NO.117, SEQ ID NO.118, SEQ ID NO.119, SEQ ID NO.120, SEQ ID NO. 121, SEQ ID NO.122, SEQ ID NO.123, SEQ ID NO.124, SEQ ID NO.125, SEQ ID NO.126, SEQ ID NO. 127, or SEQ ID NO. 128. In certain embodiments, the inhibitory polynucleotide targeting TRBC1 and TRBC2 includes the nucleotide sequence set forth in SEQ ID NO.131, SEQ ID NO. 132, SEQ ID NO. 133, SEQ ID NO. 134, SEQ ID NO. 135, SEQ ID NO. 136, SEQ ID NO. 137, SEQ ID NO. 138, SEQ ID NO. 139, SEQ ID NO. 140, SEQ ID NO. 141, or SEQ ID NO. 142. In certain embodiments, the inhibitory polynucleotide targeting CD70 includes the nucleotide sequence set forth in SEQ ID NO. 144, SEQ ID NO. 145, SEQ ID NO. 146, SEQ ID NO.147, SEQ ID NO.148, SEQ ID NO.149, SEQ ID NO.150, SEQ ID NO.151, SEQ ID NO. 152, or SEQ ID NO. 153. In certain embodiments, the inhibitory polynucleotide includes a microRNA. In certain embodiments, the nucleic acid molecule further includes (a) a polynucleotide encoding a chimeric antigen-recognizing receptor (CAR); (b) a polynucleotide encoding a chimeric co-stimulating receptor (CCR); (c) a polynucleotide encoding at least one exogenous costimulatory ligand; and / or (d) a polynucleotide encoding a fusion polypeptide including an extracellular domain of a co-stimulatory ligand, a transmembrane domain of the co-stimulatory ligand, and an intracellular domain of a co-stimulatory molecule.ACTIVE 509948342.210 072734.1771 PATENT The presently disclosed subject matter further provides a vector or a lipid nanoparticle including the nucleic acid molecule disclosed herein. In certain embodiments, the vector is a lentiviral vector. In certain embodiments, the vector is a γ-retroviral vector. Additionally, the presently disclosed subject matter provides a composition or a cell including the nucleic acid molecule, the vector, or the lipid nanoparticle disclosed herein. In certain embodiments, the composition is a pharmaceutical composition further including a pharmaceutically acceptable excipient. Furthermore, the presently disclosed subject matter provides a method for producing a cell, the method including introducing into the cell the nucleic acid molecule, the vector, or the lipid nanoparticle disclosed herein. The presently disclosed subject matter also provides a cell produced by the methods disclosed herein. The presently disclosed subject matter provides a method of reducing tumor burden in a subject, preventing and / or treating a neoplasm or a tumor in a subject, preventing and / or treating a pathogen infection in a subject, preventing and / or treating an autoimmune disease in a subject, and / or preventing and / or treating an infectious disease in a subject. In certain embodiments, the method comprises administering to the subject an effective amount of the cells, the nucleic acid molecules, the vectors, the lipid nanoparticles, or the compositions disclosed herein. In certain embodiments, the method reduces the number of tumor cells, reduces tumor size, and / or eradicates the tumor in the subject. In certain embodiments, the neoplasm or tumor is cancer. In certain embodiments, the neoplasm or tumor is a solid tumor. In certain embodiments, the solid tumor is selected from the group consisting of melanoma, renal cell carcinoma, non-small-cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, lung neuroendocrine carcinoma, small-cell lung cancer, pancreatic cancer, breast cancer, astrocytoma, glioblastoma, laryngeal / pharyngeal carcinoma, EBV-associated nasopharyngeal carcinoma, and ovarian carcinoma. In certain embodiments, the neoplasm or tumor is a blood cancer. In certain embodiments, the neoplasm or tumor is a myeloid disorder, a B-cell malignancy, a leukemia, or a lymphoma. In certain embodiments, the myeloid disorder is selected from the group consisting of myelodysplastic syndromes, myeloproliferative neoplasms, chronic myelomonocytic leukemia, or acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, chronic myelocytic leukemia, and polycythemia vera. In certain embodiments, the myeloid disorder is acute myeloid leukemia (AML). In certain embodiments, the B-cell malignancy is selected from the group consisting of B cell non-Hodgkin lymphoma (NHL), B cell Hodgkin's lymphoma, B cell acute lymphocytic leukemia (ALL), B cell chronic lymphocytic leukemia (CLL), multipleACTIVE 509948342.211 072734.1771 PATENT myeloma (MM), CLL with Richter’s transformation, and CNS lymphoma. In certain embodiments, the B-cell malignancy is B cell acute lymphocytic leukemia. In certain embodiments, the leukemia is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), mixed-phenotype acute leukemia (MLL), hairy cell leukemia, B cell prolymphocytic leukemia, B-cell precursor acute lymphoblastic leukemia, and T-cell precursor acute lymphoblastic leukemia. In certain embodiments, the lymphoma is selected from the group consisting of Hodgkin’s lymphoma, non- Hodgkin’s lymphoma, B-cell non-Hodgkin’s lymphoma, T-cell non-Hodgkin’s lymphoma, and T-cell precursor acute lymphoblastic lymphoma. In certain embodiments, the subject has a relapse of the neoplasm or tumor. In certain embodiments, the subject received treatment which leads to residual tumor cells. Finally, the presently disclosed subject matter provides a kit comprising the cells, the nucleic acid molecules, the vectors, the lipid nanoparticles, or the compositions disclosed herein. In certain embodiments, the kit further comprises written instructions for reducing tumor burden, treating and / or preventing a neoplasm or a tumor, preventing and / or treating a pathogen infection, preventing and / or treating an autoimmune disease, and / or preventing and / or treating an infectious disease. BRIEF DESCRIPTION OF THE FIGURES The following Detailed Description, given by way of example, but not intended to limit the presently disclosed subject matter to specific embodiments described, may be understood in conjunction with the accompanying drawings. Figure 1 shows the strategy for prediction, screening, and identification of γRV knockdown of TRAC, TRBC, and CD70. Figure 2 shows strategy for selection of shTRBC candidates targeting homologous regions of TRBC1 and TRBC2. Sequence alignment of TRBC1 and TRBC2 open reading frames (ORFs) and mapping of shRNAs is shown. Highlighted shRNAs target 100% homologous regions of TRBC1 and TRBC2. Figures 3A-3D depict in vitro validation of predicted shRNAs in synthesized siRNA format. Figure 3A shows validation of siRNA targeting TRAC. Figure 3B shows validation of siRNA targeting TRBC. Figure 3C shows validation of siRNA targeting CD70. Figure 3D shows table summarizing validation results. SEQ ID Nos.144-153, 105-128, and 131-142 are depicted in Figures 3A-3D.ACTIVE 509948342.212 072734.1771 PATENT Figures 4A-4J depict schematics of different constructs and vectors described in the presently disclosed subject matter. Figure 4A shows the map of an SFG-gRV vector encoding a HIT receptor and including the shRNA sequences within its intron. Figure 4B shows the map of an unmodified vector. Figure 4C shows schematic of exemplary vectors including shRNAs positioned in intronic region. Figure 4D shows schematic of exemplary vectors including single shRNA insert. SEQ ID Nos. 236 and 268 are shown in Figure 4D. Figure 4E shows schematic of exemplary vectors including double shRNA insert (e.g., shTRAC#6 and shTRBC#1). SEQ ID Nos. 239 and 269 are shown in Figure 4E. Figure 4F shows schematic of exemplary vectors including triple shRNA insert (e.g., shTRAC#6, shTRBC#1, and shCD70#2). SEQ ID Nos. 251 and 270 are shown in Figure 4F. Figure 4G shows schematic of exemplary vectors including double shRNA insert (e.g., shTRAC#6 and shCD70#2) with insertions at positions 9259 and BgIII. Figure 4H shows schematic of exemplary vectors including double shRNA insert (e.g., shTRAC#6 and shCD70#2) with insertions at positions 9259 and BsrgI. SEQ ID Nos. 273-274 are shown in Figure 4H. Figures 4I-4K show representative vectors disclosed herein. Figure 4I shows the vector including the nucleotide sequence set forth in SEQ ID NO: 195. Figure 4J shows the vector including the nucleotide sequence set forth in SEQ ID NO: 196. Figure 4K shows the vector including the nucleotide sequence set forth in SEQ ID NO: 197. Figure 5 shows schematic of modification of HIT-TRBC to prevent shRNA transgene targeting. SEQ ID Nos.275-280 are shown. Figures 6A-6D depict shRNA targeting TRBC enhancing HIT receptor surface protein expression and killing properties in T cells. Figures 6A and 6B show HIT receptor surface expression in T cells. Figure 6C and 6D show CD19-HIT-mediated killing of Nalm6 B-ALL cell line. Figure 7 shows shRNA targeting TRAC improves HIT expression in primary unedited T cells. Figure 8 shows shRNA targeting TRAC enhances CD19-HIT-mediated killing of Nalm6 B-ALL cell line. Figure 9 shows shRNA targeting CD70 efficiently reduces CD70 surface protein expression in T cells. Figure 10 shows a summary of the different SFG-miRE-shRNA-HIT(+CAR) configurations described in the presently disclosed subject matter. Figures 11A and 11B depict HIT expression and CD3 expression in the presently disclosed cells. Figure 11A shows FACS analysis of T cells expressing CD19HIT, CD22CAR, and including shRNA-based TRAC knockdown. Figure 11B shows FACS analysis of CD3 levels in T cells expressing CD19HIT, CD22CAR, and including shRNA-based TRAC knockdown.ACTIVE 509948342.213 072734.1771 PATENT Figures 12A and 12B depict antileukemic effects of T cells expressing CD19HIT, CD22CAR, and including shRNA-based TRAC knockdown. Figure 12A shows in vitro cytotoxicity against Nalm6, using either Nalm6 expressing CD19 without CD22 (left) or using Nalm6 expressing CD22 without CD19 (right). Figure 12B shows in vivo tumor flux in an antigen-heterogenous (mixture of Nalm6 clones expressing either CD19 alone, CD22 alone or both) firefly-luciferase expressing Nalm6 B-ALL xenograft model. Figures 13A-13C depict HIT expression, CAR expression, and CD70 expression in T cells expressing HIT, CAR, and including shRNA-based TRAC and CD70 knockdown. HIT is targeting either CD19 (Figures 13A-13B) or CD70 (Figure 13C). CAR is targeting either CD22 (Figure 13A-13B) or CD312 (Figure 13C). Figures 13A and 13B show FACS analysis of CD70 using a single vector encoding shRNAs, HIT, and CAR. Figure 13C shows FACS analysis of the CD70HIT receptor and CD312CAR receptor, using a single vector encoding shRNAs, HIT, and CAR. Figure 14 shows in vitro efficacy of T cells expressing CD70HIT, CD312CAR, and including shRNA-based TRAC and CD70 knockdown in a MOLM13 AML model. Figure 14 shows in vitro cytotoxicity against MOLM13 AML cells, using either MOLM13 expressing both CD70 and CD312 (left) or using MOLM13 expressing CD70 without CD312 (right). DETAILED DESCRIPTION OF THE INVENTION The presently disclosed subject matter provides compositions, e.g., modified immune cells, useful for immunotherapy (e.g., T cell immunotherapy). The presently disclosed compositions, e.g., modified immune cells, comprise: (a) an antigen-recognizing receptor (e.g., a HIT receptor) that targets an antigen, and (b) an inhibitory polynucleotide that targets an endogenous TCR locus (e.g., TRAC, TRBC1, TRBC2, etc.). The presently disclosed subject matter also provides methods for producing such compositions, and methods of using such compositions for treating and / or preventing tumors (e.g., cancer, e.g., a solid tumor or a blood cancer, e.g., a myeloid disorder, e.g., acute myeloid leukemia (AML)). The presently disclosed subject matter is based, at least in part, on the discovery that removal of endogenous TCR can be achieved by knockdown of their genes (e.g., TRAC, TRBC1, TRBC2, etc.) without altering the transgenic TRAC and TRBC expression required for the antigen-recognizing receptor (e.g., the HIT receptor). This approach allows the elimination of targeted genome editing significantly improving manufacturing operations, reducing costs, and increasing safety profile. Non-limiting embodiments of the presently disclosed subject matter are described by the present specification and Examples.ACTIVE 509948342.214 072734.1771 PATENT For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections: 1. Definitions; 2. Antigen-Recognizing Receptor; 3. Inhibitory Polynucleotides; 4. Cells; 5. Nucleic Acid Compositions and Vectors; 6. Formulations and Administration; 7. Methods of Treatment; 8. Kits; and 9. Exemplary Embodiments. 1. Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art. The following references provide one of skill with a general definition of many of the terms used in the presently disclosed subject matter: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, e.g., up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, e.g., within 5-fold or within 2-fold, of a value. As used herein, a “co-stimulatory molecule” refers to a cell surface molecule other than an antigen receptor or its ligand that can provide an efficient response of lymphocytes to an antigen. In certain embodiments, a co-stimulatory molecule can provide optimal lymphocyte activation. As used herein, a “co-stimulatory ligand” refers to a molecule that upon binding to its receptor (e.g., a co-stimulatory molecule) produces a co-stimulatory response, e.g., an intracellularACTIVE 509948342.215 072734.1771 PATENT response that effects the stimulation provided when an antigen-recognizing receptor (e.g., a chimeric antigen receptor (CAR)) binds to its target antigen. By “immunoresponsive cell” is meant a cell that functions in an immune response or a progenitor, or progeny thereof. In certain embodiments, the immunoresponsive cell is a cell of lymphoid lineage. Non-limiting examples of cells of lymphoid lineage include T cells, Natural Killer (NK) cells, B cells, and stem cells from which lymphoid cells may be differentiated. In certain embodiments, the immunoresponsive cell is a cell of myeloid lineage. By “activates an immunoresponsive cell” is meant induction of signal transduction or changes in protein expression in the cell resulting in initiation of an immune response. For example, when CD3 Chains cluster in response to ligand binding and immunoreceptor tyrosine- based inhibition motifs (ITAMs) a signal transduction cascade is produced. In certain embodiments, when an endogenous TCR or an exogenous CAR binds to an antigen, a formation of an immunological synapse occurs that includes clustering of many molecules near the bound receptor (e.g. CD4 or CD8, CD3^ / ^ / ^ / ^, etc.). This clustering of membrane bound signaling molecules allows for ITAM motifs contained within the CD3 chains to become phosphorylated. This phosphorylation in turn initiates a T cell activation pathway ultimately activating transcription factors, such as NF-^B and AP-1. These transcription factors induce global gene expression of the T cell to increase IL-2 production for proliferation and expression of master regulator T cell proteins in order to initiate a T cell mediated immune response. By “stimulates an immunoresponsive cell” is meant a signal that results in a robust and sustained immune response. In various embodiments, this occurs after immune cell (e.g., T-cell) activation or concomitantly mediated through receptors including, but not limited to, CD28, CD137 (4-1BB), OX40, CD40, ICOS, DAP-10, CD27, NKG2D, CD2, CD150, CD226. Receiving multiple stimulatory signals can be important to mount a robust and long-term T cell mediated immune response. T cells can quickly become inhibited and unresponsive to antigen. While the effects of these co-stimulatory signals may vary, they generally result in increased gene expression in order to generate long lived, proliferative, and anti-apoptotic T cells that robustly respond to antigen for complete and sustained eradication. As used herein, the term “antigen heterogeneity” refers to the differential expression of a number of antigens (e.g., tumor antigens, e.g., CD70, CD312) which results in variation in the tumor cell phenotype and distribution of tumor antigen-positive cells. As used herein, the term “low antigen density” refers to a target molecule (e.g., an antigen) having a cell surface density of less than about 5,000 molecules per cell. In certain embodiments, the low antigen density is a cell surface density is less than about 4,000 molecules per cell, less than about 3,000 molecules per cell, less than about 2,000 molecules per cell, less than about 1,500ACTIVE 509948342.216 072734.1771 PATENT molecules per cell, less than about 1,000 molecules per cell, less than about 500 molecules per cell, less than about 200 molecules per cell, or less than about 100 molecules per cell. In certain embodiments, the low antigen density is a cell surface density is less than about 2,000 molecules per cell. In certain embodiments, the low antigen density is a cell surface density is less than about 1,500 molecules per cell. In certain embodiments, the low antigen density is a cell surface density is less than about 1,000 molecules per cell. In certain embodiments, the low antigen density is a cell surface density is between about 4,000 molecules per cell and about 2,000 molecules per cell, between about 2,000 molecules per cell and about 1,000 molecules per cell, between about 1,500 molecules per cell and about 1,000 molecules per cell, between about 2,000 molecules per cell and about 500 molecules per cell, between about 1,000 molecules per cell and about 200 molecules per cell, or between about 1,000 molecules per cell and about 100 molecules per cell. As used herein, the term “low tumor cell frequency” refers to a target cell having a target cell frequency of less than about 50% per tumor. In certain embodiments, the low tumor cell frequency is less than about 40% per tumor, less than about 30% per tumor, less than about 20% per tumor, less than about 15% per tumor, less than about 10% per tumor, less than about 5% per tumor, less than about 2% per tumor, or less than about 1% per tumor. In certain embodiments, the low tumor cell frequency is less than about 2% per tumor. In certain embodiments, the low tumor cell frequency is less than about 1.5% per tumor. In certain embodiments, the low tumor cell frequency is less than about 1% per tumor. In certain embodiments, the low tumor cell frequency is between about 40% per tumor and about 20% per tumor, between about 20% per tumor and about 10% per tumor, between about 15% per tumor and about 10% per tumor, between about 20% per tumor and about 5% per tumor, between about 10% per tumor and about 2% per tumor, or between about 10% per tumor and about 1% per tumor. The term “antigen-recognizing receptor” as used herein refers to a receptor that is capable of activating an immune or immunoresponsive cell (e.g., a T-cell) in response to its binding to an antigen. As used herein, the term “antibody” means not only intact antibody molecules, but also fragments of antibody molecules that retain immunogen-binding ability. Such fragments are also well known in the art and are regularly employed both in vitro and in vivo. Accordingly, as used herein, the term “antibody” means not only intact immunoglobulin molecules but also the well- known active fragments F(ab')2, and Fab. F(ab')2, and Fab fragments that lack the Fe fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding of an intact antibody (Wahl et al., J. Nucl. Med. 24:316-325 (1983). As used herein, antibodies include whole native antibodies, bispecific antibodies; chimeric antibodies; Fab, Fab’, single chain variable fragment (scFv), fusion polypeptides, and unconventional antibodies. InACTIVE 509948342.217 072734.1771 PATENT certain embodiments, an antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant (CH) region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant CLregion. The light chain constant region is comprised of one domain, CL. The VHand VLregions can be further sub-divided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1 q) of the classical complement system. As used herein, “CDRs” are defined as the complementarity determining region amino acid sequences of an antibody which are the hypervariable regions of immunoglobulin heavy and light chains. See, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 4th U. S. Department of Health and Human Services, National Institutes of Health (1987). Generally, antibodies comprise three heavy chain and three light chain CDRs or CDR regions in the variable region. CDRs provide the majority of contact residues for the binding of the antibody to the antigen or epitope. In certain embodiments, the CDRs regions are delineated using the Kabat system (Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). In certain embodiments, the CDRs regions are delineated using the PyIgClassify system (Adolf-Bryfogle et al., Nucleic acids research 43.D1 (2015): D432-D438). As used herein, the term “Linker” shall mean a functional group (e.g., chemical or polypeptide) that covalently attaches two or more polypeptides or nucleic acids so that they are connected to one another. As used herein, a “peptide linker” refers to one or more amino acids used to couple two proteins together (e.g., to couple VH and VL domains). In certain embodiments, the linker is a G4S linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, which is provided below: GGGGSGGGGSGGGGS [SEQ ID NO: 1] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 2, which is provided below: GGGGSGGGGSGGGSGGGGS [SEQ ID NO: 2]ACTIVE 509948342.218 072734.1771 PATENT In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 3, which is provided below: GGGGSGGGGSGGGGSGGGSGGGGS [SEQ ID NO: 3] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 4, which is provided below: GGGGSGGGGSGGGGSGGGGSGGGSGGGGS [SEQ ID NO: 4] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 5, which is provided below: GGGGS [SEQ ID NO: 5] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 6, which is provided below: GGGGSGGGGS [SEQ ID NO: 6] As used herein, the term “single-chain variable fragment” or “scFv” is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of an immunoglobulin covalently linked to form a VH::VL heterodimer. The VH and VL are either joined directly or joined by a peptide-encoding linker (e.g., 10, 15, 20, 25 amino acids), which connects the N-terminus of the VH with the C­terminus of the VL, or the C-terminus of the VH with the N-terminus of the VL. The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility. Despite removal of the constant regions and the introduction of a linker, scFv proteins retain the specificity of the original immunoglobulin. Single chain Fv polypeptide antibodies can be expressed from a nucleic acid including VH- and VL­encoding sequences as described by Huston, et al. (Proc. Nat. Acad. Sci. USA, 85:5879-5883, 1988). See, also, U.S. Patent Nos. 5,091,513, 5,132,405 and 4,956,778; and U.S. Patent Publication Nos.20050196754 and 20050196754. Antagonistic scFvs having inhibitory activity have been described (see, e.g., Zhao et al., Hyrbidoma (Larchmt) 2008 27(6):455-51; Peter et al., J Cachexia Sarcopenia Muscle 2012 August 12; Shieh et al., J Imunol2009183(4):2277-85; Giomarelli et al., Thromb Haemost 200797(6):955-63; Fife eta., J Clin Invst 2006116(8):2252-61; Brocks et al., Immunotechnology 19973(3):173-84; Moosmayer et al., Ther Immunol 19952(10:31-40). Agonistic scFvs having stimulatory activity have been described (see, e.g., Peter et al., J Bioi Chern 200325278(38):36740-7; Xie et al., Nat Biotech 199715(8):768-71; Ledbetter et al., Crit Rev Immunol199717(5-6):427-55; Ho et al., BioChim Biophys Acta 20031638(3):257-66). As used herein, the term “affinity” is meant a measure of binding strength. Affinity can depend on the closeness of stereochemical fit between antibody combining sites and antigen determinants, on the size of the area of contact between them, and / or on the distribution of chargedACTIVE 509948342.219 072734.1771 PATENT and hydrophobic groups. As used herein, the term “affinity” also includes “avidity”, which refers to the strength of the antigen-antibody bond after formation of reversible complexes. Methods for calculating the affinity of an antibody for an antigen are known in the art, including, but not limited to, various antigen-binding experiments, e.g., functional assays (e.g., flow cytometry assay). The term “chimeric antigen receptor” or “CAR” as used herein refers to a molecule comprising an extracellular antigen-binding domain that is fused to an intracellular signaling domain that is capable of activating or stimulating an immune or immunoresponsive cell, and a transmembrane domain. In certain embodiments, the extracellular antigen-binding domain of a CAR comprises an scFv. The scFv can be derived from fusing the variable heavy and light regions of an antibody. Alternatively or additionally, the scFv may be derived from Fab’s (instead of from an antibody, e.g., obtained from Fab libraries). In certain embodiments, the scFv is fused to the transmembrane domain and then to the intracellular signaling domain. In certain embodiments, the CAR is selected to have high binding affinity or avidity for the antigen. As used herein, the term “substantially identical” or “substantially homologous” refers to a polypeptide or a nucleic acid molecule exhibiting at least about 50% identical or homologous to a reference amino acid sequence (for example, any of the amino acid sequences described herein) or a reference nucleic acid sequence (for example, any of the nucleic acid sequences described herein). In certain embodiments, such a sequence is at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% identical or homologous to the amino acid sequence or the nucleic acid sequence used for comparison. Sequence identity can be measured by using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis.53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e-3 and e-100 indicating a closely related sequence. The percent homology between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent homology between two aminoACTIVE 509948342.220 072734.1771 PATENT acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Additionally or alternatively, the amino acids sequences of the presently disclosed subject matter can further be used as a “query sequence” to perform a search against public databases to, for example, identify related sequences. Such searches can be performed using the XBLAST program (version 2.0) of Altschul, et al. (1990) J. Mol. Biol.215:403-10. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to the specified sequences (e.g., heavy and light chain variable region sequences) disclosed herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res.25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. As used herein, the term “a conservative sequence modification” refers to an amino acid modification that does not significantly affect or alter the binding characteristics of the presently disclosed antigen recognizing receptors (e.g., the extracellular antigen-binding domain of the CAR) comprising the amino acid sequence. Conservative modifications can include amino acid substitutions, additions and deletions. Modifications can be introduced into the extracellular antigen-binding domain of the presently disclosed CAR by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Amino acids can be classified into groups according to their physicochemical properties such as charge and polarity. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid within the same group. For example, amino acids can be classified by charge: positively-charged amino acids include lysine, arginine, histidine, negatively-charged amino acids include aspartic acid, glutamic acid, neutral charge amino acids include alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In addition, amino acids can be classified by polarity: polar amino acids include arginine (basic polar), asparagine, aspartic acid (acidic polar), glutamic acid (acidic polar), glutamine, histidine (basic polar), lysine (basic polar), serine, threonine, and tyrosine; non-polar amino acids include alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine. Thus, one or more amino acid residues within a CDR region can be replaced with other amino acid residues from the same group and the altered antibody can be tested for retained function (i.e., the functions set forth in (c) through (l) above) using the functional assays described herein. In certain embodiments, no more than one, no moreACTIVE 509948342.221 072734.1771 PATENT than two, no more than three, no more than four, no more than five residues within a specified sequence or a CDR region are altered. By “disease” is meant any condition, disease or disorder that damages or interferes with the normal function of a cell, tissue, or organ, e.g., neoplasm, and pathogen infection of cell. By “effective amount” is meant an amount sufficient to have a therapeutic effect. In certain embodiments, an “effective amount” is an amount sufficient to arrest, ameliorate, or inhibit the continued proliferation, growth, or metastasis (e.g., invasion, or migration) of a neoplasm. By “endogenous” is meant a nucleic acid molecule or polypeptide that is normally expressed in a cell or tissue. By “exogenous” is meant a nucleic acid molecule or polypeptide that is not endogenously present in a cell. The term “exogenous” would therefore encompass any recombinant nucleic acid molecule or polypeptide expressed in a cell, such as foreign, heterologous, and over-expressed nucleic acid molecules and polypeptides. By “exogenous” nucleic acid is meant a nucleic acid not present in a native wild-type cell; for example, an exogenous nucleic acid may vary from an endogenous counterpart by sequence, by position / location, or both. For clarity, an exogenous nucleic acid may have the same or different sequence relative to its native endogenous counterpart; it may be introduced by genetic engineering into the cell itself or a progenitor thereof, and may optionally be linked to alternative control sequences, such as a non-native promoter or secretory sequence. By “increase” is meant to alter positively by at least about 5%. An alteration may be by about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, about 100% or more. By “reduce” is meant to alter negatively by at least about 5%. An alteration may be by about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or even by about 100%. The terms “isolated,” “purified,” or “biologically pure” refer to material that is free to varying degrees from components which normally accompany it as found in its native state. “Isolate” denotes a degree of separation from original source or surroundings. “Purify” denotes a degree of separation that is higher than isolation. A “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high-performance liquid chromatography. The term “purified” can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications,ACTIVE 509948342.222 072734.1771 PATENT for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified. By “isolated cell” is meant a cell that is separated from the molecular and / or cellular components that naturally accompany the cell. The term “antigen-binding domain” as used herein refers to a domain capable of specifically binding a particular antigenic determinant or set of antigenic determinants present on a cell. By “neoplasm” or “malignancy” is meant a disease characterized by the pathological proliferation of a cell or tissue and its subsequent migration to or invasion of other tissues or organs. Neoplasm growth is typically uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells. Neoplasm can affect a variety of cell types, tissues, or organs, including but not limited to an organ selected from bladder, bone, brain, breast, cartilage, glia, esophagus, fallopian tube, gallbladder, heart, intestines, kidney, liver, lung, lymph node, nervous tissue, ovaries, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, urogenital tract, ureter, urethra, uterus, and vagina, or a tissue or cell type thereof. Neoplasms include cancers, such as sarcomas, carcinomas, or plasmacytomas (malignant tumor of the plasma cells). In certain embodiments, the neoplasm is cancer. By “specifically binds” is meant a polypeptide or a fragment thereof that recognizes and binds to a biological molecule of interest (e.g., a polypeptide), but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample, which naturally includes a presently disclosed polypeptide. The term “tumor antigen” as used herein refers to an antigen (e.g., a polypeptide) that is uniquely or differentially expressed on a tumor cell compared to a normal or non- neoplastic cell. In certain embodiments, a tumor antigen includes any polypeptide expressed by a tumor that is capable of activating or inducing an immune response via an antigen recognizing receptor or capable of suppressing an immune response via receptor-ligand binding. The terms “comprises”, “comprising”, and are intended to have the broad meaning ascribed to them in U.S. Patent Law and can mean “includes”, “including” and the like. As used herein, “treatment” refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Therapeutic effects of treatment include, without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission orACTIVE 509948342.223 072734.1771 PATENT improved prognosis. By preventing progression of a disease or disorder, a treatment can prevent deterioration due to a disorder in an affected or diagnosed subject or a subject suspected of having the disorder, but also a treatment may prevent the onset of the disorder or a symptom of the disorder in a subject at risk for the disorder or suspected of having the disorder. An “individual” or “subject” herein is a vertebrate, such as a human or non-human animal, for example, a mammal. Mammals include, but are not limited to, humans, primates, farm animals, sport animals, rodents and pets. Non-limiting examples of non-human animal subjects include rodents such as mice, rats, hamsters, and guinea pigs; rabbits; dogs; cats; sheep; pigs; goats; cattle; horses; and non-human primates such as apes and monkeys. The term “immunocompromised” as used herein refers to a subject who has an immunodeficiency. The subject is very vulnerable to opportunistic infections, infections caused by organisms that usually do not cause disease in a person with a healthy immune system, but can affect people with a poorly functioning or suppressed immune system. As used herein, “a functional fragment” of a molecule or polypeptide includes a fragment of the molecule or polypeptide that retains at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% of the primary function of the molecule or polypeptide. Other aspects of the presently disclosed subject matter are described in the following disclosure and are within the ambit of the presently disclosed subject matter. 2. Antigen-Recognizing Receptor The presently disclosed subject matter provides cells comprising an antigen-recognizing receptor that targets an antigen. The antigen can be a tumor antigen or a pathogen antigen. In certain embodiments, the antigen-recognizing receptor is a TCR-like fusion molecule (or HIT receptor). 2.1. Antigens In certain embodiments, the antigen is a tumor antigen. In certain embodiments, the tumor antigen is an antigen with low antigen density. In certain embodiments, the tumor antigen is expressed on a cell with low tumor cell frequency. In certain embodiments, the antigen is selected from the group consisting of CD19, CD70, IL1RAP, ABCG2, AChR, ACKR6, ADAMTS13, ADGRE2, ADGRE2 (EMR2), ADORA3, ADRA1D, AGER, ALS2, an antigen of a cytomegalovirus (CMV) infected cell (e.g. a cell surface antigen), ANO9, AQP2, ASIC3, ASPRV1, ATP6V0A4, B3GNT4, B7-H3, BCMA, BEST4, C3orf35, CADM3, CAIX, CAPN3, CCDC155, CCR1, CD10, CD117, CD123, CD133, CD135 (FLT3), CD138, CD20, CD22, CD244 (2B4), CD25, CD26, CD276, CD30, CD300LF, CD312,ACTIVE 509948342.224 072734.1771 PATENT CD32, CD321, CD33, CD34, CD36, CD38, CD41, CD44, CD44V6, CD47, CD49f, CD56, CD7, CD71, CD74, CD8, CD82, CD96, CD98, CD99, CDH13, CDHR1, CEA, CEACAM6, CHST3, CLEC12A, CLEC1A, CLL1, CNIH2, COL15A1, COLEC12, CPM, CR1, CX3CR1, CXCR4, CYP4F11, DAGLB, DARC, DFNB31, DGKI, EGF1R, EGFR-VIII, EGP-2, EGP-40, ELOVL6, EMB, EMC10, EMR2, ENG, EpCAM, EphA2, EPHA4, ERBB, ERBB2, Erb-B3, Erb-B4, E- selectin, EXOC3L4, EXTL3, FAM186B, FBP, FCGR1A, FCRL5, FKBP1B, FLRT1, folate receptor-a, FOLR2, FRMD5, GABRB2, GAS2, GD2, GD3, GDPD3, GNA14, GNAZ, GPC2, GPC3, GPR153, GPR56, GYPA, HEPHL1, HER-2, hERT, HILPDA, HLA-DR, HOOK1, hTERT, HTR2A, ICAM1, IGFBP3, IL10RB, IL20RB, IL23R, ILDR1, Interleukin-13 receptor subunit alpha-2 (IL-13Rα2), ITFG3, ITGA4, ITGA5, ITGA8, ITGAX, ITGB5, ITGB8, JAM3, KCND1, KCNJ5, KCNK13, KCNN4, KCNV2, KDR, KIF19, KIF26B, κ-light chain, L1CAM, LAX1, LEPR, Lewis Y (CD174), Lewis Y (LeY), LILRA2, LILRA6, LILRB2, LILRB3, LILRB4, LOXL4, LPAR2, LRRC37A3, LRRC8E, LRRN2, LRRTM2, LTB4R, MAGE-A1, MAGEA3, MANSC1, MART1,GP100, MBOAT1, MBOAT7, melanoma antigen family A, Mesothelin (MSLN), MFAP3L, MMP25, MRP1, MT-ND1, Mucin 1 (MUC1), Mucin 16 (MUC16), MYADM, MYADML2, NGFR, NKCS1, NKG2D ligands, NLGN3, NPAS2, NY- ESO-1, oncofetal antigen (h5T4), OTOA, P2RY13, p53, PDE3A, PEAR1, PIEZO1, PLXNA4, PLXNC1, PNPLA3, PPFIA4, PPP2R5B, PRAME, PRAME , prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), Proteinase3 (PR1), PSD2, PTPRJ, RDH16, receptor tyrosine-protein kinase Erb-B2, RHBDL3, RNF173, RNF183, ROR1, RYR2, SCIN, SCN11A, SCN2A, SCNN1D, SEC31B, SEMA4A, SH3PXD2A, SIGLEC6, SIGLEC11, SIRPB1, SLC16A6, SLC19A1, SLC22A5, SLC25A36, SLC25A41, SLC30A1, SLC34A3, SLC43A3, SLC44A1, SLC44A3, SLC45A3, SLC6A16, SLC6A6, SLC8A3, SLC9A1, SLCO2B1, SPAG17, STC1, STON2, SUN3, Survivin, SUSD2, SYNC, TACSTD2, TAS1R3, TEX29, TFR2, TIM-3 (HAVCR2), TLR2, TMEFF2, TMEM145, TMEM27, TMEM40, TMEM59L, TMEM89, TMPRSS5, TNFRSF14, TNFRSF1B, TRIM55, TSPEAR, TTYH3, tumor-associated glycoprotein 72 (TAG-72), Tyrosinase, vascular endothelial growth factor R2 (VEGF-R2), VLA- 4, Wilms tumor protein (WT-1), WNT4, WT1, and ZDHHC11. In certain embodiments, the antigen is selected from the group consisting of CD312, CLEC12A, CD276, CD33, CD123, IL1RAP, SIGLEC-6, GRP78, TIM3, CD70, CD20, CD22, CD19, GPRC5D, SLAMF7, BCMA, CD276, and CAIX. In certain embodiments, the antigen is CD19. In certain embodiments, the antigen is CD70. In certain embodiments, the antigen is CD312. In certain embodiments, the antigen is CD276. In certain embodiments, the antigen is CD22.ACTIVE 509948342.225 072734.1771 PATENT In certain embodiments, the antigen is a pathogen antigen. Non-limiting examples of viruses include, Retroviridae (e.g. human immunodeficiency viruses, such as HIV-1 (also referred to as HDTV-III, LAVE or HTLV-III / LAV, or HIV-III; and other isolates, such as HIV-LP; Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses); Coronoviridae (e.g. coronaviruses); Rhabdoviridae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g. ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bungaviridae (e.g. Hantaan viruses, bunga viruses, phleboviruses and Naira viruses); Arena viridae (hemorrhagic fever viruses); Reoviridae (e.g. reoviruses, orbiviurses and rotaviruses); Birnaviridae; Hepadnaviridae (Hepatitis B virus); Parvovirida (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxviridae (variola viruses, vaccinia viruses, pox viruses); and Iridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g. the agent of delta hepatitis (thought to be a defective satellite of hepatitis B virus), the agents of non-A, non-B hepatitis (class 1 =internally transmitted; class 2 =parenterally transmitted (i.e. Hepatitis C); Norwalk and related viruses, and astroviruses). Non-limiting examples of bacteria include Pasteurella, Staphylococci, Streptococcus, Escherichia coli, Pseudomonas species, and Salmonella species. Specific examples of infectious bacteria include but are not limited to, Helicobacter pyloris, Borelia burgdorferi, Legionella, Legionella pneumophilia, Mycobacteria sps (e.g. M. tuberculosis, M. avium, M. intracellulare, M. kansaii, M. gordonae, M. leprae), Staphylococcus aureus, Staphylococcus epidermidis, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus pyogenes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus), Streptococcus (viridans group), Streptococcus faecalis, Streptococcus bovis, Streptococcus (anaerobic sps.), Streptococcus pneumoniae, pathogenic Campylobacter sp., Campylobacter jejuni, Enterococcus sp., Haemophilus influenzae, Bacillus antracis, corynebacterium diphtheriae, corynebacterium sp., Erysipelothrix rhusiopathiae, Clostridium spp., Clostridium perfringers, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides sp., Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidium, Treponema pertenue, Leptospira, Rickettsia, and Actinomyces israelli. Mycoplasma, Pseudomonas aeruginosa, Pseudomonas fluorescens, Corynobacteria diphtheriae, Bartonella henselae, Bartonella quintana, Coxiella burnetii, chlamydia, shigella, Yersinia enterocolitica, YersiniaACTIVE 509948342.226 072734.1771 PATENT pseudotuberculosis, Listeria monocytogenes, Mycoplasma spp., Vibrio cholerae, Borrelia, Francisella, Brucella melitensis, Proteus mirabilis, and Proteus. In certain embodiments, the pathogen antigen is a viral antigen present in Cytomegalovirus (CMV), a viral antigen present in Epstein Barr Virus (EBV), a viral antigen present in Human Immunodeficiency Virus (HIV), or a viral antigen present in influenza virus. 2.2. TCR-Like Fusion Molecules In certain embodiments, the antigen-recognizing receptor is a TCR-like fusion molecule. Non-limiting examples of TCR fusion molecules include HLA-Independent TCR-based Chimeric Antigen Receptor (also known as “HIT” or “HIT receptor”, e.g., those disclosed in International Patent Application No. PCT / US19 / 017525, which is incorporated by reference in its entirety), and T cell receptor fusion constructs (TRuCs) (e.g., those disclosed in Baeuerle et al., “Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response,” Nature Communications volume 10, Article number: 2087 (2019), which is incorporated by reference in its entirety). In certain embodiments, the TCR-like fusion molecule is a recombinant T cell receptor (TCR). In certain embodiments, the recombinant TCR comprises at least one antigen-binding chain. In certain embodiments, the antigen-binding domain of the recombinant TCR comprises a ligand for a cell-surface receptor, a receptor for a cell surface ligand, an antigen binding portion of an antibody or a fragment thereof, or an antigen binding portion of a TCR. In certain embodiments, the recombinant TCR comprises two antigen binding chains, i.e., a first antigen binding chain and a second antigen binding chain. In certain embodiments, the first and second antigen-binding chains each comprises a constant domain. In certain embodiments, the recombinant TCR binds to an antigen (e.g., a first antigen or a second antigen) in an HLA- independent manner. Thus, in certain embodiments, the recombinant TCR is an HLA- independent (or non-HLA restricted) TCR (referred to as “HIT receptor”). In certain embodiments, the first antigen-binding chain comprises an antigen-binding fragment of a heavy chain variable region (VH) of an antibody. In certain embodiments, the second antigen-binding chain comprises an antigen-binding fragment of a light chain variable region (VL) of an antibody. In certain embodiments, the first antigen-binding chain comprises an antigen- binding fragment of a VH of an antibody, and the second antigen-binding chain comprises an antigen-binding fragment of a VL of the antibody. In certain embodiments, the constant domain comprises a TCR constant region selected from the group consisting of a native or modified TRAC polypeptide, a native or modified TRBC polypeptide, a native or modified TRDC polypeptide, a native or modified TRGC polypeptide andACTIVE 509948342.227 072734.1771 PATENT any variants or functional fragments thereof. In certain embodiments, the constant domain comprises a native or modified TRAC polypeptide. In certain embodiments, the constant domain comprises a native or modified TRBC polypeptide. In certain embodiments, the first antigen- binding chain comprises a TRAC polypeptide, and the second antigen-binding chain comprises a TRBC polypeptide. In certain embodiments, the first antigen-binding chain comprises a TRBC polypeptide, and the second antigen-binding chain comprises a TRAC polypeptide. In certain embodiments, the first antigen-binding chain comprises a VH of an antibody and a TRAC polypeptide, and the second antigen-binding chain comprises a VLof an antibody and a TRBC polypeptide. In certain embodiments, the first antigen-binding chain comprises a VHof an antibody and a TRBC polypeptide, and the second antigen-binding chain comprises a VL of an antibody and a TRAC polypeptide. In certain embodiments, at least one of the TRAC polypeptide and the TRBC polypeptide is endogenous. In certain embodiments, the TRAC polypeptide is endogenous. In certain embodiments, the TRBC polypeptide is endogenous. In certain embodiments, both the TRAC polypeptide and the TRBC polypeptide are endogenous. In certain embodiments, both the TRAC polypeptide and the TRBC polypeptide are exogenous. In certain embodiments, the first antigen-binding chain comprises a VH of an antibody and an exogenous TRAC polypeptide, and the second antigen-binding chain comprises a VLof an antibody and an exogenous TRBC polypeptide. In certain embodiments, the first antigen-binding chain comprises a VHof an antibody and an exogenous TRBC polypeptide, and the second antigen-binding chain comprises a VL of an antibody and an exogenous TRAC polypeptide. In certain embodiments, the antigen binding chain is capable of associating with a CD3ζ polypeptide. In certain embodiments, the antigen binding chain, upon binding to an antigen, is capable of activating the CD3ζ polypeptide associated to the antigen binding chain. In certain embodiments, the activation of the CD3ζ polypeptide is capable of activating an immunoresponsive cell. In certain embodiments, the HIT receptor is capable of integrating with a CD3 complex and providing HLA-independent antigen recognition. In certain embodiments, the HIT receptor replaces an endogenous TCR in a CD3 / TCR complex. In certain embodiments, the first and second antigen binding chains bind to an antigen with a dissociation constant (KD) of about 2 × 10-7M or less. In certain embodiments, the first and second antigen binding chains bind to an antigen with a high binding affinity. In certain embodiments, the KD is about 2 × 10-7M or less, about 1 × 10-7M or less, about 9 × 10-8M or less, about 1 × 10-8M or less, about 9 × 10-9M or less, about 5 × 10-9M or less, about 4 × 10-9M or less, about 3 × 10-9or less, about 2 ×10-9M or less, or about 1 × 10-9M or less. In certainACTIVE 509948342.228 072734.1771 PATENT embodiments, the KDis about 1 × 10-8M or less. In certain embodiments, the KDis about 3 × 10-9M or less. In certain embodiments, the KD is about 5 × 10-9M or less. In certain embodiments, the KD is from about 1 × 10-9M to about 1 × 10-8M. In certain embodiments, the KD is from about 1.5 × 10-9M to about 1 × 10-8M. In certain embodiments, the KD is from about 5 × 10-9M to about 1 × 10-8M. In certain embodiments, the constant domain comprises a TCR constant region, e.g., T cell receptor alpha constant region (TRAC), T cell receptor beta constant region (TRBC, e.g., TRBC1 or TRBC2), T cell receptor gamma constant region (TRGC, e.g., TRGC1 or TRGC2), T cell receptor delta constant region (TRDC) or any variants or functional fragments thereof. In certain embodiments, the first antigen binding chain or the second antigen binding chain comprises a constant domain that comprises a native or modified TRAC polypeptide. In certain embodiments, the TRAC polypeptide comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 7. SEQ ID NO: 7 is provided below. NIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSD FACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWS S [SEQ ID NO: 7] In certain embodiments, the TRAC polypeptide is encoded by a nucleotide sequence that is not targeted by an inhibitory polynucleotide (e.g., shRNA targeting TRAC, e.g., shRNA disclosed in Section 3). In certain embodiments, the TRAC polypeptide is encoded by a nucleotide sequence that is not targeted by a mismatched inhibitory polynucleotide (e.g., shRNA targeting TRAC, e.g., shRNA disclosed in Section 3). In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRAC (e.g., a TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 7) in the cell by at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRAC (e.g., a TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 7) in the cell by at least about 10%, about 15%, about 20%, about 25%,ACTIVE 509948342.229 072734.1771 PATENT about 30%, about 35%, about 40%, about 45%, or about 50% as compared to a control cell that does not comprise the shRNA. An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 7 is set forth in SEQ ID NO: 8. In certain embodiments, the first antigen binding chain or the second antigen binding chain comprises a constant domain that comprises a native or modified TRAC polypeptide. In certain embodiments, the TRAC polypeptide comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 9 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 9. SEQ ID NO: 9 is provided below. IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDF ACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS [SEQ ID NO: 9] In certain embodiments, the TRAC polypeptide is encoded by a nucleotide sequence that is not targeted by an inhibitory polynucleotide (e.g., shRNA targeting TRAC, e.g., shRNA disclosed in Section 3). In certain embodiments, the TRAC polypeptide is encoded by a nucleotide sequence that is not targeted by a mismatched inhibitory polynucleotide (e.g., shRNA targeting TRAC, e.g., shRNA disclosed in Section 3). In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRAC (e.g., a TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 9) in the cell by at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRAC (e.g., a TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 9) in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to a control cell that does not comprise the shRNA. An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 9 is set forth in SEQ ID NO: 10. In certain embodiments, the TRAC polypeptide comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%,ACTIVE 509948342.230 072734.1771 PATENT at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 11 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 11. SEQ ID NO: 11 is provided below. IPNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNK SDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRL WSS [SEQ ID NO: 11] In certain embodiments, the TRAC polypeptide is encoded by a nucleotide sequence that is not targeted by an inhibitory polynucleotide (e.g., shRNA targeting TRAC, e.g., shRNA disclosed in Section 3). In certain embodiments, the TRAC polypeptide is encoded by a nucleotide sequence that is not targeted by a mismatched inhibitory polynucleotide (e.g., shRNA targeting TRAC, e.g., shRNA disclosed in Section 3). In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRAC (e.g., a TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 11) in the cell by at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRAC (e.g., a TRAC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 11) in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to a control cell that does not comprise the shRNA. An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 11 is set forth in SEQ ID NO: 12. In certain embodiments, the TRAC polypeptide comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence encoded by a transcript expressed by the gene of NCBI Genbank ID: 28755, NG_001332.3, range 925603 to 930229 (SEQ ID NO: 13) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRAC polypeptide comprises or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 13. In certain embodiments, the first antigen binding chain or the second antigen binding chain comprises a constant domain comprising a native or modified TRBC polypeptide. In certainACTIVE 509948342.231 072734.1771 PATENT embodiments, the TRBC polypeptide is a TRBC2 polypeptide. In certain embodiments, the TRBC polypeptide is a TRBC2 polypeptide. In certain embodiments, the TRBC2 polypeptide comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 14 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRBC2 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 14. SEQ ID NO: 14 is provided below. LEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPAL NDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQ QGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG [SEQ ID NO: 14] In certain embodiments, the TRBC2 polypeptide is encoded by a nucleotide sequence that is not targeted by an inhibitory polynucleotide (e.g., shRNA targeting TRBC2, e.g., shRNA disclosed in Section 3). In certain embodiments, the TRBC2 polypeptide is encoded by a nucleotide sequence that is not targeted by a mismatched inhibitory polynucleotide (e.g., shRNA targeting TRBC2, e.g., shRNA disclosed in Section 3). In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRBC2 (e.g., a TRBC2 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 14) in the cell by at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRBC2 (e.g., a TRBC2 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 14) in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to a control cell that does not comprise the shRNA. An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 14 is set forth in SEQ ID NO: 15. In certain embodiments, the TRBC2 polypeptide comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative aminoACTIVE 509948342.232 072734.1771 PATENT acid substitutions. In certain embodiments, the TRBC2 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 16. SEQ ID NO: 16 is provided below. DLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALND SRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQG VLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG [SEQ ID NO: 16] In certain embodiments, the TRBC2 polypeptide is encoded by a nucleotide sequence that is not targeted by an inhibitory polynucleotide (e.g., shRNA targeting TRBC2, e.g., shRNA disclosed in Section 3). In certain embodiments, the TRBC2 polypeptide is encoded by a nucleotide sequence that is not targeted by a mismatched inhibitory polynucleotide (e.g., shRNA targeting TRBC2, e.g., shRNA disclosed in Section 3). In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRBC2 (e.g., a TRBC2 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 16) in the cell by at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRBC2 (e.g., a TRBC2 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 16) in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to a control cell that does not comprise the shRNA. An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 16 is set forth in SEQ ID NO: 17. In certain embodiments, the TRBC polypeptide is a TRBC1 polypeptide. In certain embodiments, the TRBC1 polypeptide comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 18 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRBC1 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 18. SEQ ID NO: 18 is provided below. LNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDS RYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGV LSATILYEILLGKATLYAVLVSALVLMAMVKRKDF [SEQ ID NO: 18] In certain embodiments, the TRBC1 polypeptide comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, atACTIVE 509948342.233 072734.1771 PATENT least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 19 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRBC1 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 19. SEQ ID NO: 19 is provided below. DLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALND SRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQG VLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF [SEQ ID NO: 19] In certain embodiments, the TRBC1 polypeptide is encoded by a nucleotide sequence that is not targeted by an inhibitory polynucleotide (e.g., shRNA targeting TRBC1, e.g., shRNA disclosed in Section 3). In certain embodiments, the TRBC1 polypeptide is encoded by a nucleotide sequence that is not targeted by a mismatched inhibitory polynucleotide (e.g., shRNA targeting TRBC1, e.g., shRNA disclosed in Section 3). In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRBC1 (e.g., a TRBC1 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 19) in the cell by at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the mismatched inhibitory polynucleotide reduces the expression of an exogenous TRBC1 (e.g., a TRBC1 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 19) in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% as compared to a control cell that does not comprise the shRNA. An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 19 is set forth in SEQ ID NO: 20. In certain embodiments, the TRBC polypeptide comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 100% homologous or identical to the amino acid sequence encoded by a transcript expressed by a gene of NCBI Genbank ID: 28639, NG_001333.2, range 645749 to 647196 (TRBC1, SEQ ID NO: 21), NCBI Genbank ID: 28638, NG_001333.2 range 655095 to 656583 (TRBC2, SEQ ID NO: 22) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRBC polypeptide comprises or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 21. In certain embodiments, the TRBC polypeptide comprises or consists of the amino acid sequenceACTIVE 509948342.234 072734.1771 PATENT encoded by the nucleotide sequence of SEQ ID NO: 22. In certain embodiments, the first antigen binding chain or the second antigen binding chain comprises a constant domain comprising a native or modified TRGC polypeptide. In certain embodiments, the TRGC polypeptide is a native or modified TRGC1 polypeptide. In certain embodiments, the TRGC1 polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23, which is provided below. In certain embodiments, the TRGC1 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 23. DKQLDADVSPKPTIFLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWQEKKSNTILGSQEGNTMKTNDTYM KFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDTLLLQLTNTSAYY MYLLLLLKSVVYFAIITCCLLRRTAFCCNGEKS [SEQ ID NO: 23] In certain embodiments, the TRGC polypeptide is a native or modified TRGC2 polypeptide. In certain embodiments, the TRGC2 polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24, which is provided below. In certain embodiments, the TRGC2 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 24. DKQLDADVSPKPTIFLPSIAETKLQKAGTYLCLLEKFFPDIIKIHWQEKKSNTILGSQEGNTMKTNDTYM KFSWLTVPEESLDKEHRCIVRHENNKNGIDQEIIFPPIKTDVTTVDPKYNYSKDANDVITMDPKDNWSKD ANDTLLLQLTNTSAYYTYLLLLLKSVVYFAIITCCLLRRTAFCCNGEKS [SEQ ID NO: 24] In certain embodiments, the TRGC polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or 100% homologous or identical to the amino acid sequence encoded by a transcript expressed by a gene of NCBI Genbank ID: 6966, NG_001336.2, range 108270 to 113860 (TRGC1, SEQ ID NO: 25), NCBI Genbank ID: 6967, NG_001336.2, range 124376 to 133924 (TRGC2, SEQ ID NO: 26) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the TRGC polypeptide comprises or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 25. In certain embodiments, the TRGC polypeptide comprises or consists of the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26. In certain embodiments, the first antigen binding chain or the second antigen binding chain comprises a constant domain comprising a native or modified TRDC polypeptide. In certain embodiments, the TRDC polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 27, which is providedACTIVE 509948342.235 072734.1771 PATENT below. In certain embodiments, the TRDC polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 27. SQPHTKPSVFVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVT CSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKSCHKPKAIVHTEKVNMMSLTVLGLRMLFAKTV AVNFLLTAKLFFL [SEQ ID NO: 27] In certain embodiments, the HIT receptor comprises a hinge / spacer region that links the first antigen binding chain to the constant domain. In certain embodiments, the HIT receptor comprises a hinge / spacer region that links the second antigen binding chain to the constant domain. The hinge / spacer region can be flexible enough to allow the antigen binding chain to orient in different directions to facilitate antigen recognition. In certain embodiments, the hinge / spacer region can be the hinge region from IgG1, the CH2CH3 region of immunoglobulin and portions of CD3, a portion of a TCRα polypeptide, a portion of a TCRβ polypeptide, a portionof a CD28 polypeptide, a portion of a CD8 polypeptide, or a synthetic spacer sequence. In certainembodiments, the hinge / spacer region comprises a portion of a TCRα polypeptide. In certain embodiments, the hinge / spacer region comprises a portion of the variable region (TRAV), a portion of the diversity region (TRAD), a portion of the joining region (TRAJ), a portion of the constant region (TRAC), or a combination thereof. In certain embodiments, the hinge / spacer region comprises a portion of the TRAJ region and a portion of the TRAC region of the TCRα polypeptide. In certain embodiments, the hinge / spacer region comprises or consists of the amino acid sequence set forth in SEQ ID NO: 28. In certain embodiments, the hinge / spacer region comprises or consists of amino acids 1 to 3 of the sequence set forth in SEQ ID NO: 28. An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 28 is set forth in SEQ ID NO: 29. SEQ ID NO: 28 and 29 are provided below. IPNIQNPDPA [SEQ ID NO: 28] ATTCCCAATATCCAGAACCCTGACCCTGCC [SEQ ID NO: 29] In certain embodiments, the hinge / spacer region comprises a portion of a TCRβ polypeptide. In certain embodiments, the hinge / spacer region comprises a portion of the variable region (TRBV), a portion of the diversity region (TRBD), a portion of the joining region (TRBJ), a portion of the constant region (TRBC), or a combination thereof. In certain embodiments, the hinge / spacer region comprises a portion of the TRBJ region and a portion of the TRAC region (C) of the TCRβ polypeptide. In certain embodiments, the hinge / spacer region comprises or consists of the amino acid sequence set forth in SEQ ID NO: 30. In certain embodiments, the hinge / spacer region comprises or consists of amino acid 1 to 2 of the sequence set forth in SEQ ID NO: 30.ACTIVE 509948342.236 072734.1771 PATENT An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 30 is set forth in SEQ ID NO: 31. SEQ ID NO: 30 and 31 are provided below. LEDLKNVFPPE [SEQ ID NO: 30] CTGGAGGATCTGAAAAACGTGTTCCCTCCTGAA [SEQ ID NO: 31] In addition, the first antigen binding chain and the second antigen binding chain can comprise a leader or a signal peptide that directs the nascent protein into the endoplasmic reticulum. Signal peptide or leader can be essential if the HIT is to be glycosylated and anchored in the cell membrane. The signal sequence or leader can be a peptide sequence (about 5, about 10, about 15, about 20, about 25, or about 30 amino acids long) present at the N-terminus of newly synthesized proteins that directs their entry to the secretory pathway. In certain embodiments, the signal peptide is covalently joined to the 5’ terminus (N-terminus) of the first antigen binding chain and the second antigen binding chain. Exemplary leader sequences include, but is not limited to, a human IL-2 signal sequence (e.g., a human IL-2 signal sequence comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 32), a mouse IL-2 signal sequence (e.g., a mouse IL-2 signal sequence comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 33); a human kappa leader sequence (e.g., a human kappa leader sequence comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 34), a mouse kappa leader sequence (e.g., a mouse kappa leader sequence comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 35); a human CD8 leader sequence (e.g., a human CD8 leader sequence comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 36); a truncated human CD8 signal peptide (e.g., a truncated human CD8 signal peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 37); a human albumin signal sequence (e.g., a human albumin signal sequence comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 38); and a human prolactin signal sequence (e.g., a human prolactin signal sequence comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 39). SEQ ID NO: 32-39 are provided below. MYRMQLLSCIALSLALVTNS [SEQ ID NO: 32] MYSMQLASCVTLTLVLLVNS [SEQ ID NO: 33] METPAQLLFLLLLWLPDTTG [SEQ ID NO: 34] METDTLLLWVLLLWVPGSTG [SEQ ID NO: 35] MALPVTALLLPLALLLHAARP [SEQ ID NO: 36] MALPVTALLLPLALLLHA [SEQ ID NO: 37] MKWVTFISLLFSSAYS [SEQ ID NO: 38]ACTIVE 509948342.237 072734.1771 PATENT MDSKGSSQKGSRLLLLLVVSNLLLCQGVVS [SEQ ID NO: 39] In certain embodiments, the first antigen binding chain comprises a truncated CD8 signal peptide. In certain embodiments, the second antigen binding chain comprises a truncated CD8 polypeptide. In certain embodiments, the signal peptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 37. In certain embodiments, the antigen binding chain does not comprise an intracellular domain. In certain embodiments, the antigen binding chain is capable of associating with a CD3ζ polypeptide. In certain embodiments, the antigen binding chain associating with the CD3ζ polypeptide via the constant domain. In certain embodiments, the CD3ζ polypeptide is endogenous. In certain embodiments, the CD3ζ polypeptide is exogenous. In certain embodiments, binding of the antigen binding chain to a target antigen is capable of activating the CD3ζ polypeptide associated to the antigen binding chain. In certain embodiments, the exogenous CD3ζ polypeptide is fused to or integrated with a costimulatory molecule disclosed herein. In certain embodiments, the HIT receptor comprises an antigen binding chain that comprises an intracellular domain. In certain embodiments, the intracellular domain comprises a CD3ζ polypeptide. In certain embodiments, binding of the antigen binding chain to an antigen is capable of activating the CD3ζ polypeptide of the antigen binding chain. In certain embodiments, the CD3ζ polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% homologous to the amino acid sequence set forth in SEQ ID NO: 40 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD3ζ polypeptide comprises or consists of an amino acid sequence that is a consecutive portion of SEQ ID NO: 40, which is at least about 20, or at least about 30, or at least about 40, or at least about 50, and up to about 164 amino acids in length. In certain embodiments, the CD3ζ comprises or consists of the amino acid sequence of amino acids 1 to 164, 1 to 50, 50 to 100, 52 to 164, 100 to 150, or 150 to 164 of SEQ ID NO: 40. In certain embodiments, the CD3ζ polypeptide comprises or consists of amino acids 52 to 164 of SEQ ID NO: 40. SEQ ID NO: 40 is provided below: MKWKALFTAAILQAQLPITEAQSFGLLDPKLCYLLDGILFIYGVILTALFLRVKFSRSADAPAYQQGQNQ LYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG LYQGLSTATKDTYDALHMQALPPR [SEQ ID NO: 40] In certain embodiments, the CD3ζ polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% homologous or identical to SEQ ID NO: 41 or a fragment thereof,ACTIVE 509948342.238 072734.1771 PATENT and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD3ζ polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 41. SEQ ID NO: 41 is provided below: RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEA YSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR [SEQ ID NO: 41] In certain embodiments, the HIT receptor comprises an antigen binding chain that comprises an intracellular domain, wherein the intracellular domain comprises a co-stimulatory signaling region. In certain embodiments, the intracellular domain comprises a co-stimulatory signaling region and a CD3ζ polypeptide. In certain embodiments, the intracellular domain comprises a co-stimulatory signaling region and does not comprise a CD3ζ polypeptide. In certain embodiments, the co-stimulatory signaling region comprises at least an intracellular domain of a co-stimulatory molecule disclosed herein. In certain embodiments, the HIT receptor is capable of associating with a CD3 complex (also known as “T-cell co-receptor”). In certain embodiments, the HIT receptor and the CD3 complex form an antigen recognizing receptor complex similar to a native TCR / CD3 complex. In certain embodiments, the CD3 complex is endogenous. In certain embodiments, the CD3 complex is exogenous. In certain embodiments, the HIT receptor replaces a native and / or an endogenous TCR in the CD3 / TCR complex. In certain embodiments, the CD3 complex comprises a CD3γ chain, a CD3δ chain, and two CD3ε chains. In certain embodiments, the CD3γ chain comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% homologous or identical to the amino acid sequence having a NCBI reference number: NP_000064.1 (SEQ ID NO: 42) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. SEQ ID NO: 42 is provided below. MEQGKGLAVLILAIILLQGTLAQSIKGNHLVKVYDYQEDGSVLLTCDAEAKNITWFKDGKMIGFLTEDKK KWNLGSNAKDPRGMYQCKGSQNKSKPLQVYYRMCQNCIELNAATISGFLFAEIVSIFVLAVGVYFIAGQD GVRQSRASDKQTLLPNDQLYQPLKDREDDQYSHLQGNQLRRN [SEQ ID NO: 42] In certain embodiments, the CD3δ chain comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% homologous or identical to the amino acid sequence having a NCBI reference numbers: NP_000723.1 (SEQ ID NO: 43) or a fragment thereof, or the amino acid sequence having a NCBI reference numbers: NP_001035741.1 (SEQ ID NO: 44) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. SEQ ID NO: 43 and 44 are provided below.ACTIVE 509948342.239 072734.1771 PATENT MEHSTFLSGLVLATLLSQVSPFKIPIEELEDRVFVNCNTSITWVEGTVGTLLSDITRLDLGKRILDPRGI YRCNGTDIYKDKESTVQVHYRMCQSCVELDPATVAGIIVTDVIATLLLALGVFCFAGHETGRLSGAADTQ ALLRNDQVYQPLRDRDDAQYSHLGGNWARNK [SEQ ID NO: 43] MEHSTFLSGLVLATLLSQVSPFKIPIEELEDRVFVNCNTSITWVEGTVGTLLSDITRLDLGKRILDPRGI YRCNGTDIYKDKESTVQVHYRTADTQALLRNDQVYQPLRDRDDAQYSHLGGNWARNK [SEQ ID NO: 44] In certain embodiments, the CD3ε chain comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% homologous or identical to the amino acid sequence having a NCBI reference number: NP_000724.1 (SEQ ID NO: 45) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. SEQ ID NO: 45 is provided below. MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDE DDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICI TGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI [SEQ ID NO: 45] In certain embodiments, the HIT receptor exhibits a greater antigen sensitivity than a CAR targeting the same antigen. In certain embodiments, the HIT receptor is capable of inducing an immune response when binding to an antigen that has a low antigen density on the surface of a tumor cell. In certain embodiments, cells comprising the HIT receptor can be used to treat a subject having tumor cells with a low expression level of a surface antigen, e.g., from a relapse of a disease, wherein the subject received treatment which leads to residual tumor cells. In certain embodiments, the tumor cells have a low antigen density of a target molecule on the surface of the tumor cells. In certain embodiments, a target molecule having a low antigen density on the cell surface has a density of less than about 5,000 molecules per cell, less than about 4,000 molecules per cell, less than about 3,000 molecules per cell, less than about 2,000 molecules per cell, less than about 1,500 molecules per cell, less than about 1,000 molecules per cell, less than about 500 molecules per cell, less than about 200 molecules per cell, or less than about 100 molecules per cell. In certain embodiments, a target molecule having a low antigen density on the cell surface has a density of less than about 2,000 molecules per cell. In certain embodiments, a target molecule having a low antigen density on the cell surface has a density of less than about 1,500 molecules per cell. In certain embodiments, a target molecule having a low antigen density on the cell surface has a density of less than about 1,000 molecules per cell. In certain embodiments, a target molecule having a low antigen density on the cell surface has a density of between about 4,000 molecules per cell and about 2,000 molecules per cell, between about 2,000ACTIVE 509948342.240 072734.1771 PATENT molecules per cell and about 1,000 molecules per cell, between about 1,500 molecules per cell and about 1,000 molecules per cell, between about 2,000 molecules per cell and about 500 molecules per cell, between about 1,000 molecules per cell and about 200 molecules per cell, or between about 1,000 molecules per cell and about 100 molecules per cell. In certain embodiments, the HIT receptor is capable of inducing an immune response when binding to an antigen that is expressed on the surface of a tumor cell having a low tumor cell frequency. In certain embodiments, cells comprising the HIT receptor can be used to treat a subject having tumor cells with a low tumor cell frequency, e.g., from a relapse of a disease, wherein the subject received treatment which leads to residual tumor cells. In certain embodiments, the tumor having a low tumor cell frequency has a frequency that is less than about 40% per tumor, less than about 30% per tumor, less than about 20% per tumor, less than about 15% per tumor, less than about 10% per tumor, less than about 5% per tumor, less than about 2% per tumor, or less than about 1% per tumor. In certain embodiments, the low tumor cell frequency is less than about 2% per tumor. In certain embodiments, the low tumor cell frequency is less than about 1.5% per tumor. In certain embodiments, the low tumor cell frequency is less than about 1% per tumor. In certain embodiments, the low tumor cell frequency is between about 40% per tumor and about 20% per tumor, between about 20% per tumor and about 10% per tumor, between about 15% per tumor and about 10% per tumor, between about 20% per tumor and about 5% per tumor, between about 10% per tumor and about 2% per tumor, or between about 10% per tumor and about 1% per tumor. In certain embodiments, the antigen-recognizing receptor is a HIT receptor that comprises a first antigen binding chain comprising a VH of an antibody and a constant domain comprising a TRBC polypeptide; and a second antigen binding chain comprising a VLof an antibody and a constant domain comprising a TRAC polypeptide. In certain embodiments, the first antigen binding chain is designated as “VH-TRBC chain”. In certain embodiments, the second antigen binding chain is designated as “VL-TRAC chain”. In certain embodiments, the first antigen binding chain comprises a hinge region between the VHand the TRBC polypeptide. In certain embodiments, the hinge region comprises or consists of the amino acid sequence set forth in SEQ ID NO: 28 or SEQ ID NO: 29. In certain embodiments, the second antigen binding chain comprises a hinge region between the VLand the TRAC polypeptide. In certain embodiments, the hinge region comprises or consists of the amino acid sequence set forth in SEQ ID NO: 28 or SEQ ID NO: 29. In certain embodiments, the antigen-recognizing receptor is a HIT receptor that comprises a first antigen binding chain comprising a VHof an antibody and a constant domain comprising a TRAC polypeptide; and a second antigen binding chain comprising a VL of an antibody and aACTIVE 509948342.241 072734.1771 PATENT constant domain comprising a TRBC polypeptide. In certain embodiments, the first antigen binding chain is designated as “VH-TRAC chain”. In certain embodiments, the second antigen binding chain is designated as “VL-TRBC chain”. In certain embodiments, the first antigen binding chain comprises a hinge region between the VH and the TRAC polypeptide. In certain embodiments, the second antigen binding chain comprises a hinge region between the VL and the TRBC polypeptide. In certain embodiments, the first antigen binding chain and the second antigen binding chain bind to a first antigen (e.g., one disclosed in Section 2.1.1). In certain embodiments, the antigen-recognizing receptor is a HIT receptor that comprises a first antigen binding chain comprising a VH of an antibody and a constant domain comprising a TRBC polypeptide; and a second antigen binding chain comprising a VLof an antibody and a constant domain comprising a TRAC polypeptide. In certain embodiments, the first antigen binding chain is designated as “VH-TRBC chain”. In certain embodiments, the second antigen binding chain is designated as “VL-TRAC chain”. In certain embodiments, the first antigen binding chain comprises a hinge region between the VHand the TRAC polypeptide. In certain embodiments, the second antigen binding chain comprises a hinge region between the VL and the TRBC polypeptide. In certain embodiments, the first antigen binding chain and the second antigen binding chain bind to a first antigen (e.g., one disclosed in Section 2.1.1). 2.2.1. Exemplary HIT receptor In certain embodiments, the antigen-recognizing receptor is a HIT receptor that binds to CD19 (e.g., human CD19) and comprises two antigen binding chains, e.g., a first antigen binding chain that comprises a VH and a TRBC polypeptide (“VH-TRBC chain”) and a second antigen binding chain that comprises a VLand a TRBC polypeptide (“VL-TRAC chain”), which are capable of dimerizing and binding to CD19. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 52 or SEQ ID NO: 53. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51. In certain embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO: 56 or SEQ ID NO: 57. In certain embodiments, the TRAC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7. In certain embodiments, the TRBC polypeptide is a TRBC2 polypeptide. In certain embodiments, the TRBC2 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14.ACTIVE 509948342.242 072734.1771 PATENT In certain embodiments, the HIT receptor comprises a VH-TRBC chain comprising the amino acid sequence set forth in SEQ ID NO: 60. In certain embodiments, the HIT receptor comprises a VL-TRAC chain comprising the amino acid sequence set forth in SEQ ID NO: 62. In certain embodiments, the HIT receptor comprises a VH-TRBC chain comprising the amino acid sequence set forth in SEQ ID NO: 60 and a VL-TRAC chain comprising the amino acid sequence set forth in SEQ ID NO: 62. In certain embodiments, the HIT receptor is designated as “19-HIT” or “19H”. SEQ ID NO: 46-63 are provided in Table 1 below. In certain embodiments, the CDRs regions / sequences disclosed herein are designated using the Kabat system (Swindells et al., J Mol Biol.2017 Feb 3;429(3):356-364). Table 1 CDRs 1 2 3 EQ D Q V N A A G T G A : T C T C G ACTIVE 509948342.243 072734.1771 PATENT TTCGGTAGTAGATTTCTACTTTGACTACTGGGGCCAAGGGACCACGGTCACCGTC [SEQ ID NO: 55] S L R ] G G T G C G G G C G C Q V S E L A A G T G A A C T G ACTIVE 509948342.244 072734.1771 PATENT AGCAGCCTGCTCTCAACGATTCTCGGTACTGCCTGTCATCTCGACTGAGAGTGTCTGCCAC CTTCTGGCAGAACCCTAGAAACCACTTTAGGTGCCAGGTGCAATTTTACGGCCTGAGCGAG T C G S L F I G G T G C G T G C A A T T In certain embodiments, the antigen-recognizing receptor is a HIT receptor that binds to CD19 (e.g., human CD19) and comprises two antigen binding chains, e.g., a first antigen binding chain that comprises a VH and a TRBC polypeptide (“VH-TRBC chain”) and a second antigen binding chain that comprises a VLand a TRBC polypeptide (“VL-TRAC chain”), which are capable of dimerizing and binding to CD19. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51. In certainACTIVE 509948342.245 072734.1771 PATENT embodiments, the HIT receptor comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 189. In certain embodiments, the HIT receptor comprises or consists of the amino acid sequence set forth in SEQ ID NO: 189. An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 189 is set forth in SEQ ID NO: 190. SEQ ID NO: 189 and SEQ ID NO: 190 are provided below. MALPVTALLLPLALLLHAEVKLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIY PGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYFCARKTISSVVDFYFDYWGQGTTVTVLE DLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALND SRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQG VLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRGGSGATNFSLLKQAGDVEENPGPMALPVTALLL PLALLLHADIELTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRF TGSGSGTDFTLTITNVQSKDLADYFCQQYNRYPYTSGGGTKLEIIPNIQNPDPAVYQLRDSKSSDKSVCL FTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESS CDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS [SEQ ID NO: 189] ATGGCTCTCCCAGTGACTGCCCTACTGCTTCCCCTAGCGCTTCTCCTGCATGCAGAGGTGAAGCTGCAGC AGTCTGGGGCTGAGCTGGTGAGGCCTGGGTCCTCAGTGAAGATTTCCTGCAAGGCTTCTGGCTATGCATT CAGTAGCTACTGGATGAACTGGGTGAAGCAGAGGCCTGGACAGGGTCTTGAGTGGATTGGACAGATTTAT CCTGGAGATGGTGATACTAACTACAATGGAAAGTTCAAGGGTCAAGCCACACTGACTGCAGACAAATCCT CCAGCACAGCCTACATGCAGCTCAGCGGCCTAACATCTGAGGACTCTGCGGTCTATTTCTGTGCAAGAAA GACCATTAGTTCGGTAGTAGATTTCTACTTTGACTACTGGGGCCAAGGGACCACGGTCACCGTCCTGGAG GATCTGAAAAACGTGTTCCCTCCTGAAGTGGCTGTCTTTGAACCATCCGAGGCCGAGATTTCCCATACCC AGAAAGCAACTCTGGTCTGTCTGGCCACTGGATTCTACCCCGATCACGTGGAACTGTCTTGGTGGGTGAA CGGCAAGGAAGTCCATTCCGGAGTCTCTACCGACCCTCAGCCCCTCAAGGAGCAGCCTGCTCTCAACGAT TCTCGGTACTGCCTGTCATCTCGACTGAGAGTGTCTGCCACCTTCTGGCAGAACCCTAGAAACCACTTTA GGTGCCAGGTGCAATTTTACGGCCTGAGCGAGAACGATGAGTGGACACAGGATAGAGCCAAACCTGTGAC ACAGATTGTGAGCGCCGAGGCTTGGGGACGAGCCGATTGTGGCTTCACATCCGAGTCTTACCAGCAGGGA GTGCTGTCTGCTACAATCCTCTACGAAATTCTCCTGGGGAAGGCCACCCTGTACGCTGTCCTCGTGTCTG CTCTGGTGCTCATGGCTATGGTCAAACGAAAGGACTCTAGAGGCGGCTCTGGCGCTACCAATTTTTCCCT CCTCAAACAGGCTGGAGATGTCGAAGAGAACCCCGGACCTATGGCACTGCCCGTGACCGCTCTGCTTCTC CCACTAGCTCTGCTTCTCCACGCAGACATTGAGCTCACCCAGTCTCCAAAATTCATGTCCACATCAGTAG GAGACAGGGTCAGCGTCACCTGCAAGGCCAGTCAGAATGTGGGTACTAATGTAGCCTGGTATCAACAGAA ACCAGGACAATCTCCTAAACCACTGATTTACTCGGCAACCTACCGGAACAGTGGAGTCCCTGATCGCTTC ACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCACTAACGTGCAGTCTAAAGACTTGGCAGACT ATTTCTGTCAACAATATAACAGGTATCCGTACACGTCCGGAGGGGGGACCAAGCTGGAGATCATTCCCAA TATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTA TTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAAACTIVE 509948342.246 072734.1771 PATENT CTGTGCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTT TGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCC TGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGA TTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGGTCCAG C [SEQ ID NO: 190] In certain embodiments, the antigen-recognizing receptor is a HIT receptor that binds to CD70 (e.g., human CD70) and comprises two antigen binding chains, e.g., a first antigen binding chain that comprises a VH and a TRBC polypeptide (“VH-TRBC chain”) and a second antigen binding chain that comprises a VL and a TRBC polypeptide (“VL-TRAC chain”), which are capable of dimerizing and binding to CD70. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 70. In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 67, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 68, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 69. In certain embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO: 72. In certain embodiments, the TRAC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7. In certain embodiments, the TRBC polypeptide is a TRBC2 polypeptide. In certain embodiments, the TRBC2 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the HIT receptor is designated as “70-HIT” or “70H”. SEQ ID NO: 64-73 are provided in Table 2 below. In certain embodiments, the CDRs regions / sequences disclosed herein are delineated using the Kabat system (Swindells et al., J Mol Biol.2017 Feb 3;429(3):356-364). Table 2 CDRs 1 2 3 Q Q P W Y ACTIVE 509948342.247 072734.1771 PATENT LQMNSLRAEDTAVYYCARDTDGYDFDYWGQGTL VTV [SEQ ID NO: 70] T G T T G G A C T G C G L G G G T G G G C C G G G G In certain embodiments, the antigen-recognizing receptor is a HIT receptor that binds to CD70 (e.g., human CD70) and comprises two antigen binding chains, e.g., a first antigen binding chain that comprises a VHand a TRBC polypeptide (“VH-TRBC chain”) and a second antigen binding chain that comprises a VL and a TRBC polypeptide (“VL-TRAC chain”), which areACTIVE 509948342.248 072734.1771 PATENT capable of dimerizing and binding to CD70. In certain embodiments, the VHcomprises a CDR1, a CDR2, and a CDR3 of a VH sequence of an anti-CD70 antibody disclosed in International Patent Publication No. WO 2007 / 038637, which is incorporated by reference in its entirety. In certain embodiments, the VH comprises a CDR1, a CDR2, and a CDR3 of a VH sequence of an anti-CD70 antibody 2H5 disclosed in International Patent Publication No. WO 2007 / 038637. In certain embodiments, the VLcomprises a CDR1, a CDR2, and a CDR3 of a VHsequence of an anti-CD70 antibody disclosed in International Patent Publication No. WO 2007 / 038637. In certain embodiments, the VLcomprises a CDR1, a CDR2, and a CDR3 of a VHsequence of an anti-CD70 antibody 2H5 disclosed in International Patent Publication No. WO 2007 / 038637. In certain embodiments, the antigen-recognizing receptor is a HIT receptor that binds to CD312 (e.g., human CD312) and comprises two antigen binding chains, e.g., a first antigen binding chain that comprises a VHand a TRBC polypeptide (“VH-TRBC chain”) and a second antigen binding chain that comprises a VL and a TRBC polypeptide (“VL-TRAC chain”), which are capable of dimerizing and binding to CD312. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 75, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 80. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 77, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 78, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 79. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 82. In certain embodiments, the TRAC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7. In certain embodiments, the TRBC polypeptide is a TRBC2 polypeptide. In certain embodiments, the TRBC2 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the HIT receptor is designated as “312- HIT” or “312H”. SEQ ID NO: 74-83 are provided in Table 3 below. In certain embodiments, the CDRs regions / sequences disclosed herein are delineated using the Kabat system (Swindells et al., J Mol Biol.2017 Feb 3;429(3):356-364). Table 3 anti-CD312 scFv ACTIVE 509948342.249 072734.1771 PATENT VHNYWMQ [SEQ ID AVYPGDGDTRHTQKF GFTAYGMDY [SEQ NO: 74] KG [SEQ ID NO: ID NO: 76] Q W G G : T T G A C C C C C G D H S A G C C G C T G G C ACTIVE 509948342.250 072734.1771 PATENT GGCACCAAGCTGGAACTGAAGAGA [SEQ ID NO: 83] to CD276 (e.g., human CD276) and comprises two antigen binding chains, e.g., a first antigen binding chain that comprises a VHand a TRBC polypeptide (“VH-TRBC chain”) and a second antigen binding chain that comprises a VL and a TRBC polypeptide (“VL-TRAC chain”), which are capable of dimerizing and binding to CD276. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 85, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 86. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 90. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 92. In certain embodiments, the TRAC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7. In certain embodiments, the TRBC polypeptide is a TRBC2 polypeptide. In certain embodiments, the TRBC2 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the HIT receptor is designated as “276- HIT” or “276H”. SEQ ID NO: 84-93 are provided in Table 4 below. In certain embodiments, the CDRs regions / sequences disclosed herein are delineated using the Kabat system (Swindells et al., J Mol Biol.2017 Feb 3;429(3):356-364). Table 4 anti-CD276 scFv Q D V G ACTIVE 509948342.251 072734.1771 PATENT SGTDFTFTISSVQAEDLAVYYCQQHYGTPPWTF GGGTKLEIK [SEQ ID NO: 90] G C A T C A T T C Q A G H ] A T C G T T T T C C : In certain embodiments, the antigen-recognizing receptor is a HIT receptor that binds to CD22 (e.g., human CD22) and comprises two antigen binding chains, e.g., a first antigen binding chain that comprises a VH and a TRBC polypeptide (“VH-TRBC chain”) and a second antigen binding chain that comprises a VLand a TRBC polypeptide (“VL-TRAC chain”), which are capable of dimerizing and binding to CD22. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a CDR2 comprising the aminoACTIVE 509948342.252 072734.1771 PATENT acid sequence set forth in SEQ ID NO: 95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 100. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the TRAC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7. In certain embodiments, the TRBC polypeptide is a TRBC2 polypeptide. In certain embodiments, the TRBC2 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the HIT receptor is designated as “22-HIT” or “22H”. SEQ ID NO: 94-103 are provided in Table 5 below. In certain embodiments, the CDRs regions / sequences disclosed herein are delineated using the Kabat system (Swindells et al., J Mol Biol.2017 Feb 3;429(3):356-364). Table 5 anti-CD22 scFv Q S S C D G G C T C C C T ACTIVE 509948342.253 072734.1771 PATENT AACAGTGTGACACCTGAAGATACGGCAGTATAT TATTGCGCGAGAGAGGTTACTGGGGACCTCGAA G L G G T T G T G C T C A D Various TCR-like fusion molecules and HIT receptors are disclosed in International Patent Application Publication No. WO 2019 / 133969 and International Patent Application Publication No. WO 2024 / 086842A2, which are incorporated by reference hereby in their entireties. 2.3. Delivery of the Antigen-Recognizing Receptor In certain embodiments, the antigen-recognizing receptor is delivered to the cell by a viral method. In certain embodiments, the viral method comprises a viral vector. In certain embodiments, the viral vector is a retroviral vector (e.g., a gammaretroviral vector or a lentiviral vector). Other viral vectors include adenoviral vectors, adeno-associated viral vectors, vaccinia viruses, bovine papilloma viruses, and herpes viruses (e.g., such as Epstein-Barr Virus). In certain embodiments, the antigen-recognizing receptor is delivered to the cell by a non- viral method. Any targeted genome editing methods can also be used to deliver the first antigen- recognizing receptor to the cell. In certain embodiments, the cell is a T cell, and the antigen-recognizing receptor is integrated at a locus within the genome of the T cell. In certain embodiments, the locus is not aACTIVE 509948342.254 072734.1771 PATENT TRAC locus or a TRBC locus. In certain embodiments, the cell is a T cell, and the first antigen- recognizing receptor is not integrated at a TRAC locus. 3. Inhibitory Polynucleotides The presently disclosed subject matter provides cells comprising an antigen-recognizing receptor that targets an antigen further comprising an inhibitory polynucleotide that downregulates the expression levels of a gene. In certain embodiments, the gene is TRAC. In certain embodiments, the gene is TRBC1. In certain embodiments, the gene is TRBC2. In certain embodiments, the gene is CD70. In certain embodiments, the inhibitory polynucleotide downregulates the expression levels of two of more genes. For example, but without any limitation, the inhibitory polynucleotide downregulates the expression levels of TRBC1 and TRBC2. In certain embodiments, the inhibitory polynucleotide comprises an RNA interference (RNAi) molecule. Non-limiting examples of RNAi molecules include short hairpin RNA (shRNA), small interfering RNA (siRNA), double stranded RNA (dsRNA), or antisense oligonucleotide. In certain embodiments, the inhibitory polynucleotide is a short hairpin RNA (shRNA). Single-stranded hairpin ribonucleic acids (shRNAs) are short duplexes where the sense and antisense strands are linked by a hairpin loop. shRNAs include a stem-loop structure that can be transcribed in cells from an RNA polymerase II or RNA polymerase III promoter on a vector (e.g., a plasmid, a viral vector, etc.). Once expressed, shRNAs are processed into RNAi species. Expression of shRNA from a vector is stable and provides advantages over the use of certain alternatives (e.g., synthetic siRNAs). shRNAs are synthesized in the nucleus of cells, further processed and transported to the cytoplasm, and then incorporated into the RNA-induced silencing complex (RISC) for activity. The shRNAs are converted into active siRNA molecules (which are capable of binding to, sequestering, and / or preventing the translation of mRNA transcripts encoded by target genes). The Argonaute family of proteins is the major component of RISC. Within the Argonaute family of proteins, only Ago2 contains endonuclease activity that is capable of cleaving and releasing the passenger strand from the stem portion of the shRNA molecule. The remaining three members of Argonaute family, Agol, Ago3 and Ago4, which do not have identifiable endonuclease activity, are also assembled into RISC and are believed to function through a cleavage-independent manner. Thus, RISC can be characterized as having cleavage-dependent and cleavage-independent pathways. Additional information on RNAi (e.g., antisense RNA, siRNA, microRNA, shRNA, etc.) can be found in Svoboda, Frontiers in plant science 11 (2020): 495350, Setten et al., NatureACTIVE 509948342.255 072734.1771 PATENT reviews Drug discovery 18.6 (2019): 421-446, Tang and Khvorova, Nature Reviews Drug Discovery (2024): 1-24, Hu et al., Signal transduction and targeted therapy 5.1 (2020): 101, and Sheng et al., Frontiers in Bioengineering and Biotechnology 8 (2020): 940, each of which is herein incorporated by reference in their entireties. In certain embodiments, the inhibitory polynucleotide comprises a nucleic acid sequence that is at least 15 nucleotides in length complementary to an mRNA encoding TRAC. An exemplary mRNA encoding TRAC is set forth in SEQ ID NO: 104. In certain embodiments, the inhibitory polynucleotide comprises an shRNA targeting TRAC. In certain embodiments, the shRNA targeting TRAC reduces the expression of an endogenous TRAC in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the shRNA targeting TRAC reduces the expression of an endogenous TRAC in the cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% without altering the expression of an exogenous TRAC (e.g., a TRAC polypeptide of a HIT receptor). In certain embodiments, the shRNA targeting TRAC reduces the expression of an endogenous TRAC in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%, and the expression of an exogenous TRAC (e.g., a TRAC polypeptide of a HIT receptor) in the cell by at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the shRNA targeting TRAC comprises the nucleotide sequence set forth in SEQ ID NO.105, SEQ ID NO.106, SEQ ID NO.107, SEQ ID NO.108, SEQ ID NO. 109, SEQ ID NO.110, SEQ ID NO.111, SEQ ID NO.112, SEQ ID NO.113, SEQ ID NO.114, SEQ ID NO.115, or SEQ ID NO.116. SEQ ID Nos: 105-116 are provided below. TTTGAGAATCAAAATCGGTGAA [SEQ ID NO: 105] TTTCAAAGCTTTTCTCGACCAG [SEQ ID NO: 106] TTTGTTTGAGAATCAAAATCGG [SEQ ID NO: 107] TTGAGAATCAAAATCGGTGAAT [SEQ ID NO: 108] TGAAAGTTTAGGTTCGTATCTG [SEQ ID NO: 109]ACTIVE 509948342.256 072734.1771 PATENT TTGAGAAGAAGAATACTATGTA [SEQ ID NO: 110] TTAATCATAAATTCGGGTAGGA [SEQ ID NO: 111] TAATCATAAATTCGGGTAGGAT [SEQ ID NO: 112] ATGTATTTCTTTATGAACACTA [SEQ ID NO: 113] ATCTTAATCATAAATTCGGGTA [SEQ ID NO: 114] TTTAATGAAGGCATCGGCAGCA [SEQ ID NO: 115] TAATGAGATAATTTCCCCCCAC [SEQ ID NO: 116] In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO.105. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO.106. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 107. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 108. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 109. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 110. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 111. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 112. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 113. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 114. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 115. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO.116. In certain embodiments, the shRNA targeting TRAC comprises the nucleotide sequence set forth in SEQ ID NO.117, SEQ ID NO.118, SEQ ID NO.119, SEQ ID NO.120, SEQ ID NO. 121, SEQ ID NO.122, SEQ ID NO.123, SEQ ID NO.124, SEQ ID NO.125, SEQ ID NO.126, SEQ ID NO.127, or SEQ ID NO.128. SEQ ID Nos: 117-128 are provided below. TGCTGTTGACAGTGAGCGCTCACCGATTTTGATTCTCAAATAGTGAAGCCACAGATGTATTTGAGAATCA AAATCGGTGAATGCCTACTGCCTCGGA [SEQ ID NO: 117] TGCTGTTGACAGTGAGCGATGGTCGAGAAAAGCTTTGAAATAGTGAAGCCACAGATGTATTTCAAAGCTT TTCTCGACCAGTGCCTACTGCCTCGGA [SEQ ID NO: 118]ACTIVE 509948342.257 072734.1771 PATENT TGCTGTTGACAGTGAGCGACGATTTTGATTCTCAAACAAATAGTGAAGCCACAGATGTATTTGTTTGAGA ATCAAAATCGGTGCCTACTGCCTCGGA [SEQ ID NO: 119] TGCTGTTGACAGTGAGCGCTTCACCGATTTTGATTCTCAATAGTGAAGCCACAGATGTATTGAGAATCAA AATCGGTGAATTGCCTACTGCCTCGGA [SEQ ID NO: 120] TGCTGTTGACAGTGAGCGAAGATACGAACCTAAACTTTCATAGTGAAGCCACAGATGTATGAAAGTTTAG GTTCGTATCTGTGCCTACTGCCTCGGA [SEQ ID NO: 121] TGCTGTTGACAGTGAGCGCACATAGTATTCTTCTTCTCAATAGTGAAGCCACAGATGTATTGAGAAGAAG AATACTATGTATGCCTACTGCCTCGGA [SEQ ID NO: 122] TGCTGTTGACAGTGAGCGCCCTACCCGAATTTATGATTAATAGTGAAGCCACAGATGTATTAATCATAAA TTCGGGTAGGATGCCTACTGCCTCGGA [SEQ ID NO: 123] TGCTGTTGACAGTGAGCGCTCCTACCCGAATTTATGATTATAGTGAAGCCACAGATGTATAATCATAAAT TCGGGTAGGATTGCCTACTGCCTCGGA [SEQ ID NO: 124] TGCTGTTGACAGTGAGCGCAGTGTTCATAAAGAAATACATTAGTGAAGCCACAGATGTAATGTATTTCTT TATGAACACTATGCCTACTGCCTCGGA [SEQ ID NO: 125] TGCTGTTGACAGTGAGCGCACCCGAATTTATGATTAAGATTAGTGAAGCCACAGATGTAATCTTAATCAT AAATTCGGGTATGCCTACTGCCTCGGA [SEQ ID NO: 126] TGCTGTTGACAGTGAGCGCGCTGCCGATGCCTTCATTAAATAGTGAAGCCACAGATGTATTTAATGAAGG CATCGGCAGCATGCCTACTGCCTCGGA [SEQ ID NO: 127] TGCTGTTGACAGTGAGCGATGGGGGGAAATTATCTCATTATAGTGAAGCCACAGATGTATAATGAGATAA TTTCCCCCCACTGCCTACTGCCTCGGA [SEQ ID NO: 128] In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO.117. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO.118. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 119. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 120. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 121. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 122. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 123. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 124. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 125. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO.ACTIVE 509948342.258 072734.1771 PATENT 126. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 127. In certain embodiments, the shRNA targeting TRAC comprises or consists of the nucleotide sequence set forth in SEQ ID NO.128. In certain embodiments, the inhibitory polynucleotide comprises a nucleic acid sequence that is at least 15 nucleotides in length complementary to an mRNA encoding TRBC1. An exemplary mRNA encoding TRBC1 is set forth in SEQ ID NO: 129. In certain embodiments, the inhibitory polynucleotide comprises a nucleic acid sequence that is at least 15 nucleotides in length complementary to an mRNA encoding TRBC2. An exemplary mRNA encoding TRBC2 is set forth in SEQ ID NO: 130. In certain embodiments, the inhibitory polynucleotide comprises an shRNA targeting TRBC1 and TRBC2. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 reduces the expression of an endogenous TRBC1 and TRBC2 in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 reduces the expression of an endogenous TRBC1 and TRBC2 in the cell by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, or 99% without altering the expression of an exogenous TRBC (e.g., a TRBC polypeptide of a HIT receptor). In certain embodiments, the shRNA targeting TRBC1 and TRBC2 reduces the expression of an endogenous TRBC1 and TRBC2 in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%, and the expression of an exogenous TRBC (e.g., a TRBC polypeptide of a HIT receptor) in the cell by at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises the nucleotide sequence set forth in SEQ ID NO. 131, SEQ ID NO. 132, SEQ ID NO. 133, SEQ ID NO.134, SEQ ID NO.135, or SEQ ID NO.136. SEQ ID Nos: 131-136 are provided below. TAGAACTGGACTTGACAGCGGA [SEQ ID NO: 131] TATCTGGAGTCATTGAGGGCGG [SEQ ID NO: 132] TCAAACACAGCGACCTCGGGTG [SEQ ID NO: 133] TTGACAGCGGAAGTGGTTGCGG [SEQ ID NO: 134]ACTIVE 509948342.259 072734.1771 PATENT TTGGGTGTGGGAGATCTCTGCT [SEQ ID NO: 135] TCTGATGGCTCAAACACAGCGA [SEQ ID NO: 136] In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 131. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 132. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 133. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO.134. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO.135. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO.136. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises the nucleotide sequence set forth in SEQ ID NO. 137, SEQ ID NO. 138, SEQ ID NO. 139, SEQ ID NO.140, SEQ ID NO.141, or SEQ ID NO.142. SEQ ID Nos: 137-142 are provided below. TGCTGTTGACAGTGAGCGCCCGCTGTCAAGTCCAGTTCTATAGTGAAGCCACAGATGTATAGAACTGGAC TTGACAGCGGATGCCTACTGCCTCGGA [SEQ ID NO: 137] TGCTGTTGACAGTGAGCGACGCCCTCAATGACTCCAGATATAGTGAAGCCACAGATGTATATCTGGAGTC ATTGAGGGCGGTGCCTACTGCCTCGGA [SEQ ID NO: 138] TGCTGTTGACAGTGAGCGAACCCGAGGTCGCTGTGTTTGATAGTGAAGCCACAGATGTATCAAACACAGC GACCTCGGGTGTGCCTACTGCCTCGGA [SEQ ID NO: 139] TGCTGTTGACAGTGAGCGACGCAACCACTTCCGCTGTCAATAGTGAAGCCACAGATGTATTGACAGCGGA AGTGGTTGCGGTGCCTACTGCCTCGGA [SEQ ID NO: 140] TGCTGTTGACAGTGAGCGCGCAGAGATCTCCCACACCCAATAGTGAAGCCACAGATGTATTGGGTGTGGG AGATCTCTGCTTGCCTACTGCCTCGGA [SEQ ID NO: 141] TGCTGTTGACAGTGAGCGCCGCTGTGTTTGAGCCATCAGATAGTGAAGCCACAGATGTATCTGATGGCTC AAACACAGCGATGCCTACTGCCTCGGA [SEQ ID NO: 142] In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 137. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 138. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 139. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO.140. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprisesACTIVE 509948342.260 072734.1771 PATENT or consists of the nucleotide sequence set forth in SEQ ID NO.141. In certain embodiments, the shRNA targeting TRBC1 and TRBC2 comprises or consists of the nucleotide sequence set forth in SEQ ID NO.142. In certain embodiments, the inhibitory polynucleotide comprises a nucleic acid sequence that is at least 15 nucleotides in length complementary to an mRNA encoding CD70. An exemplary mRNA encoding CD70 is set forth in SEQ ID NO: 143. In certain embodiments, the inhibitory polynucleotide comprises an shRNA targeting CD70. In certain embodiments, the shRNA targeting CD70 reduces the expression of an endogenous CD70 in the cell by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% as compared to a control cell that does not comprise the shRNA. In certain embodiments, the shRNA targeting CD70 comprises the nucleotide sequence set forth in SEQ ID NO. 144, SEQ ID NO. 145, SEQ ID NO.146, SEQ ID NO. 147, or SEQ ID NO.148. SEQ ID Nos: 144-148 are provided below. TCTACTTGCTTCAACCTGTCAG [SEQ ID NO: 144] TACACTTTTTCTCTTGAACTTA [SEQ ID NO: 145] TAAAAAACCCTAATCAGCAGCA [SEQ ID NO: 146] TACCATGTAGATGCCATCACGA [SEQ ID NO: 147] TGTGTGTACACTTTTTCTCTTG [SEQ ID NO: 148] In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO.144. In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 145. In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 146. In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 147. In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 148. In certain embodiments, the shRNA targeting CD70 comprises the nucleotide sequence set forth in SEQ ID NO. 149, SEQ ID NO. 150, SEQ ID NO.151, SEQ ID NO. 152, or SEQ ID NO.153. SEQ ID Nos: 149-153 are provided below. TGCTGTTGACAGTGAGCGATGACAGGTTGAAGCAAGTAGATAGTGAAGCCACAGATGTATCTACTTGCTT CAACCTGTCAGTGCCTACTGCCTCGGA [SEQ ID NO: 149]ACTIVE 509948342.261 072734.1771 PATENT TGCTGTTGACAGTGAGCGCAAGTTCAAGAGAAAAAGTGTATAGTGAAGCCACAGATGTATACACTTTTTC TCTTGAACTTATGCCTACTGCCTCGGA [SEQ ID NO: 150] TGCTGTTGACAGTGAGCGCGCTGCTGATTAGGGTTTTTTATAGTGAAGCCACAGATGTATAAAAAACCCT AATCAGCAGCATGCCTACTGCCTCGGA [SEQ ID NO: 151] TGCTGTTGACAGTGAGCGCCGTGATGGCATCTACATGGTATAGTGAAGCCACAGATGTATACCATGTAGA TGCCATCACGATGCCTACTGCCTCGGA [SEQ ID NO: 152] TGCTGTTGACAGTGAGCGAAAGAGAAAAAGTGTACACACATAGTGAAGCCACAGATGTATGTGTGTACAC TTTTTCTCTTGTGCCTACTGCCTCGGA [SEQ ID NO: 153] In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO.149. In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 150. In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 151. In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 152. In certain embodiments, the shRNA targeting CD70 comprises or consists of the nucleotide sequence set forth in SEQ ID NO. 153. In certain embodiments, the inhibitory polynucleotide comprises an shRNA (e.g., one described above) and a microRNA. In certain embodiments, the microRNA is designated as “miR-E.” miR-E is a microRNA backbone that boosts processing efficiency and leads to stronger target knockdown when compared to standard miR-30 designs. As can be appreciated, miR-E can increase the potency of all shRNAs (e.g., shRNA targeting TRAC, TRBC, CD70, etc.). Additional information on microRNA used along with shRNA can be found in Fellmann et al., Cell reports 5.6 (2013): 1704-1713, the content of which is incorporated by reference in its entirety. In certain embodiment, the inhibitory polynucleotide comprises an shRNA and a microRNA comprising or consisting of the nucleotide sequence set forth in SEQ ID NO: 179. In certain embodiment, the inhibitory polynucleotide comprises an shRNA and a microRNA comprising or consisting of the nucleotide sequence set forth in SEQ ID NO: 180. In certain embodiment, the inhibitory polynucleotide comprises an shRNA, a first microRNA comprising or consisting of the nucleotide sequence set forth in SEQ ID NO: 179, and a second microRNA comprising or consisting of the nucleotide sequence set forth in SEQ ID NO: 180. SEQ ID NO: 179 and SEQ ID NO: 180 are provided below. TTAACCCAACAGAAGGCTCGAGAAGGTATAT [SEQ ID NO: 179] CTTCAAGGGGCTAGAATTC [SEQ ID NO: 180]ACTIVE 509948342.262 072734.1771 PATENT In certain embodiments, the inhibitory polynucleotide is operably linked to a promoter. Non-limiting examples of suitable promoters include constitutive and inducible promoters, inducible RNA polymerase II (pol II)-based promoters, EF1a promoters, RNA polymerase I or III-based promoters, the pol II dependent viral promoters (e.g., CMV-IE promoter), the pol III U6 promoters, H1 promoters, bacteriophage T7 promoters. In certain embodiments, the promoter can be active in the targeted cells, e.g., it can express at least one recombinant nucleic acid in immune cells using an immune cell-specific promoter. Introduction of such constructs into host cells can be affected under conditions whereby two or more inhibitory polynucleotides that are contained within a nucleic acid precursor transcript initially reside within a single primary transcript, such that the separate RNA molecules (for example, shRNA each comprising its own stem-loop structure) are subsequently excised from such precursor transcript by an endogenous ribonuclease. The resulting mature recombinant nucleic acids (e.g., shRNAs) can then induce degradation, and / or translation repression, of target gene mRNA transcripts produced in the cell. Alternatively, each of the precursor stemloop structures can be produced as part of a separate transcript, in which case each inhibitory polynucleotide includes its own promoter and transcription terminator sequences. The stem-loop structures of the shRNA recombinant nucleic acids described herein can be about 40 to about 100 nucleotides long. The stem region can be about 15-45 nucleotides in length (or more), or about 20 to about 30 nucleotides in length. In certain embodiments, the stem region is 22 nucleotides in length. In certain embodiments, the stem region is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 28 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 nucleotides in length. In certain embodiments, the stem can include a complementary duplex. In certain embodiments, the stem can include bulges or interior loops on either arm. The number of such bulges and asymmetric interior loops are preferably few in number (e.g., about 1, about 2, or about 3) and are about 3 nucleotides or less in size. The terminal loop portion can include about 4 or more nucleotides, but preferably not more than about 25. The loop portion can be about 6 to about 15 nucleotides in size. In certain embodiments, the presently disclosed subject matter provides inhibitory polynucleotides that downregulate the expression level of multiple genes. For example, but without any limitation, an inhibitory polynucleotide can include a set of shRNA comprising a first shRNA targeting TRAC and a second shRNA targeting TRBC. In certain embodiments, the presently disclosed subject matter provides an inhibitory polynucleotide including (a) an shRNA targeting TRAC, and (b) an shRNA targeting TRBC. In certain embodiments, inhibitory polynucleotide comprises (a) an shRNA targeting TRACACTIVE 509948342.263 072734.1771 PATENT comprising the nucleotide sequence set forth in SEQ ID NO: 110, and (b) an shRNA targeting TRBC comprising the nucleotide sequence set forth in SEQ ID NO: 131. In certain embodiments, inhibitory polynucleotide comprises (a) an shRNA targeting TRAC comprising the nucleotide sequence set forth in SEQ ID NO: 122, and (b) an shRNA targeting TRBC comprising the nucleotide sequence set forth in SEQ ID NO: 137. In certain embodiments, the presently disclosed subject matter provides an inhibitory polynucleotide including (a) an shRNA targeting TRAC, and (b) an shRNA targeting CD70. In certain embodiments, the inhibitory polynucleotide comprises (a) an shRNA targeting TRAC comprising the nucleotide sequence set forth in SEQ ID NO: 110, and (b) an shRNA targeting CD70 comprising the nucleotide sequence set forth in SEQ ID NO: 145. In certain embodiments, the inhibitory polynucleotide comprises (a) an shRNA targeting TRAC comprising the nucleotide sequence set forth in SEQ ID NO: 122, and (b) an shRNA targeting CD70 comprising the nucleotide sequence set forth in SEQ ID NO: 150. In certain embodiments, the presently disclosed subject matter provides an inhibitory polynucleotide including (a) an shRNA targeting CD70, and (b) an shRNA targeting TRBC. In certain embodiments, the inhibitory polynucleotide comprises (a) an shRNA targeting CD70 comprising the nucleotide sequence set forth in SEQ ID NO: 145, and (b) an shRNA targeting TRBC comprising the nucleotide sequence set forth in SEQ ID NO: 131. In certain embodiments, the inhibitory polynucleotide comprises (a) an shRNA targeting CD70 comprising the nucleotide sequence set forth in SEQ ID NO: 150, and (b) an shRNA targeting TRBC comprising the nucleotide sequence set forth in SEQ ID NO: 137. In certain embodiments, the presently disclosed subject matter provides an inhibitory polynucleotide including (a) an shRNA targeting TRAC, (b) an shRNA targeting TRBC, and (c) an shRNA targeting CD70. In certain embodiments, the inhibitory polynucleotide comprises (a) an shRNA targeting TRAC comprising the nucleotide sequence set forth in SEQ ID NO: 110, (b) an shRNA targeting TRBC comprising the nucleotide sequence set forth in SEQ ID NO: 131, and (c) an shRNA targeting CD70 comprising the nucleotide sequence set forth in SEQ ID NO: 145. In certain embodiments, the inhibitory polynucleotide comprises (a) an shRNA targeting TRAC comprising the nucleotide sequence set forth in SEQ ID NO: 122, (b) an shRNA targeting TRBC comprising the nucleotide sequence set forth in SEQ ID NO: 137, and (c) an shRNA targeting CD70 comprising the nucleotide sequence set forth in SEQ ID NO: 150. In certain embodiments, the inhibitory polynucleotide is delivered to the cell by a viral method. In certain embodiments, the viral method comprises a viral vector. In certain embodiments, the viral vector is a retroviral vector (e.g., a gammaretroviral vector or a lentiviralACTIVE 509948342.264 072734.1771 PATENT vector). Other viral vectors include adenoviral vectors, adeno-associated viral vectors, vaccinia viruses, bovine papilloma viruses, and herpes viruses (e.g., such as Epstein-Barr Virus). In certain embodiments, the inhibitory polynucleotide is delivered to the cell by a non- viral method. 4. Cells The presently disclosed subject matter provides cells comprising (a) an antigen- recognizing receptor that targets an antigen (e.g., one disclosed in Section 2), and (b) an inhibitory polynucleotide (e.g., one disclosed in Section 3). Additionally or alternatively, the presently disclosed subject matter provides cells comprising a) a polynucleotide encoding an antigen- recognizing receptor (e.g., one disclosed in Section 2), and (b) an inhibitory polynucleotide (e.g., one disclosed in Section 3). In certain embodiments, the cell is selected from the group consisting of cells of lymphoid lineage and cells of myeloid lineage. In certain embodiments, the cell is an immunoresponsive cell. In certain embodiments, the immunoresponsive cell is a cell of lymphoid lineage. In certain embodiments, the cell is a cell of the lymphoid lineage. Cells of the lymphoid lineage can provide production of antibodies, regulation of cellular immune system, detection of foreign agents in the blood, detection of cells foreign to the host, and the like. Non-limiting examples of cells of the lymphoid lineage include T cells, Natural Killer (NK) cells, B cells, dendritic cells, stem cells from which lymphoid cells may be differentiated. In certain embodiments, the stem cell is a pluripotent stem cell (e.g., embryonic stem cell). In certain embodiments, the cell is a T cell. T cells can be lymphocytes that mature in the thymus and are chiefly responsible for cell-mediated immunity. T cells are involved in the adaptive immune system. The T cells of the presently disclosed subject matter can be any type of T cells, including, but not limited to, helper T cells, cytotoxic T cells, memory T cells (including central memory T cells, stem-cell-like memory T cells (or stem-like memory T cells), and two types of effector memory T cells: e.g., TEMcells and TEMRAcells, Regulatory T cells (also known as suppressor T cells), tumor-infiltrating lymphocyte (TIL), Natural Killer T cells, Mucosal associated invariant T cells, and γδ T cells. Cytotoxic T cells (CTL or killer T cells) are a subset of T lymphocytes capable of inducing the death of infected somatic or tumor cells. A patient’s own T cells may be genetically modified to target specific antigens through the introduction of an antigen-recognizing receptor, e.g., a CAR or a TCR. The T cell can be a CD4+T cell or a CD8+T cell. In certain embodiments, the T cell is a CD4+T cell. In certain embodiments, the T cell is a CD8+T cell. In certain embodiments, the CD8+T cell is CD4 independent. In certain embodiments, the T cell is derived from an induced pluripotent stem cell (iPSC). In certainACTIVE 509948342.265 072734.1771 PATENT embodiments, the T cell is a CD8+T cell that is CD4 independent, and the CD8+T cell is derived from an iPSC. In certain embodiments, the T cell is a CD62L+T cell. In certain embodiments, the T cell is a CD45RA+T cell. In certain embodiments, the T cell is a CD62L+ / CD45RA+T cell. In certain embodiments, the cell is a NK cell. Natural Killer (NK) cells can be lymphocytes that are part of cell-mediated immunity and act during the innate immune response. NK cells do not require prior activation in order to perform their cytotoxic effect on target cells. Types of human lymphocytes of the presently disclosed subject matter include, without limitation, peripheral donor lymphocytes, e.g., those disclosed in Sadelain, M., et al. 2003 Nat Rev Cancer 3:35-45 (disclosing peripheral donor lymphocytes genetically modified to express CARs), in Morgan, R.A., et al. 2006 Science 314:126-129 (disclosing peripheral donor lymphocytes genetically modified to express a full-length tumor antigen-recognizing T cell receptor complex comprising the ^ and β heterodimer), in Panelli, M.C., et al. 2000 J Immunol 164:495-504; Panelli, M.C., et al. 2000 J Immunol 164:4382-4392 (disclosing lymphocyte cultures derived from tumor infiltrating lymphocytes (TILs) in tumor biopsies), and in Dupont, J., et al. 2005 Cancer Res 65:5417-5427; Papanicolaou, G.A., et al. 2003 Blood 102:2498-2505 (disclosing selectively in vitro-expanded antigen-specific peripheral blood leukocytes employing artificial antigen-presenting cells (AAPCs) or pulsed dendritic cells). In certain embodiments, the cell (e.g., T cell) is autologous. In certain embodiments, the cell (e.g., T cell) is non-autologous. In certain embodiments, the cell (e.g., T cell) is allogeneic. In certain embodiments, the cell (e.g., T cell) is derived in vitro from an engineered progenitor or stem cell. In certain embodiments, the cell is a cell of the myeloid lineage. Non-limiting examples of cells of the myeloid lineage include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes, and stem cells from which myeloid cells may be differentiated. In certain embodiments, the stem cell is a pluripotent stem cell (e.g., an embryonic stem cell or an induced pluripotent stem cell). 4.1. Second Antigen-Recognizing Receptor In certain embodiments, the presently disclosed cells comprising (a) the antigen- recognizing receptor (e.g., a HIT receptor), and (b) the inhibitory polynucleotide, further comprise a second antigen recognizing receptor that targets a second antigen. In certain embodiments, the second antigen-recognizing receptor is a chimeric receptor. In certain embodiments, the chimeric receptor is a chimeric antigen receptor (CAR). In certain embodiments, the chimeric receptor isACTIVE 509948342.266 072734.1771 PATENT a chimeric ligand receptor. In certain embodiments, the chimeric receptor is a CCR. In certain embodiments, the chimeric receptor is a T cell receptor (TCR). 4.1.1. Second Antigen In certain embodiments, the second antigen is a tumor antigen. Any tumor antigen (antigenic peptide) can be used in the tumor-related embodiments described herein. Sources of antigen include, but are not limited to, cancer proteins. The second antigen can be expressed as a peptide or as an intact protein or a portion thereof. The intact protein or portion thereof can be native or mutagenized. Non-limiting examples of tumor antigens include CD19, CD70, IL1RAP, ABCG2, AChR, ACKR6, ADAMTS13, ADGRE2, ADGRE2 (EMR2), ADORA3, ADRA1D, AGER, ALS2, an antigen of a cytomegalovirus (CMV) infected cell (e.g. a cell surface antigen), ANO9, AQP2, ASIC3, ASPRV1, ATP6V0A4, B3GNT4, B7-H3, BCMA, BEST4, C3orf35, CADM3, CAIX, CAPN3, CCDC155, CCR1, CD10, CD117, CD123, CD133, CD135 (FLT3), CD138, CD20, CD22, CD244 (2B4), CD25, CD26, CD276, CD30, CD300LF, CD312, CD32, CD321, CD33, CD34, CD36, CD38, CD41, CD44, CD44V6, CD47, CD49f, CD56, CD7, CD71, CD74, CD8, CD82, CD96, CD98, CD99, CDH13, CDHR1, CEA, CEACAM6, CHST3, CLEC12A, CLEC1A, CLL1, CNIH2, COL15A1, COLEC12, CPM, CR1, CX3CR1, CXCR4, CYP4F11, DAGLB, DARC, DFNB31, DGKI, EGF1R, EGFR-VIII, EGP-2, EGP-40, ELOVL6, EMB, EMC10, EMR2, ENG, EpCAM, EphA2, EPHA4, ERBB, ERBB2, Erb-B3, Erb-B4, E- selectin, EXOC3L4, EXTL3, FAM186B, FBP, FCGR1A, FCRL5, FKBP1B, FLRT1, folate receptor-a, FOLR2, FRMD5, GABRB2, GAS2, GD2, GD3, GDPD3, GNA14, GNAZ, GPC2, GPC3, GPR153, GPR56, GYPA, HEPHL1, HER-2, hERT, HILPDA, HLA-DR, HOOK1, hTERT, HTR2A, ICAM1, IGFBP3, IL10RB, IL20RB, IL23R, ILDR1, Interleukin-13 receptor subunit alpha-2 (IL-13Rα2), ITFG3, ITGA4, ITGA5, ITGA8, ITGAX, ITGB5, ITGB8, JAM3, KCND1, KCNJ5, KCNK13, KCNN4, KCNV2, KDR, KIF19, KIF26B, κ-light chain, L1CAM, LAX1, LEPR, Lewis Y (CD174), Lewis Y (LeY), LILRA2, LILRA6, LILRB2, LILRB3, LILRB4, LOXL4, LPAR2, LRRC37A3, LRRC8E, LRRN2, LRRTM2, LTB4R, MAGE-A1, MAGEA3, MANSC1, MART1,GP100, MBOAT1, MBOAT7, melanoma antigen family A, Mesothelin (MSLN), MFAP3L, MMP25, MRP1, MT-ND1, Mucin 1 (MUC1), Mucin 16 (MUC16), MYADM, MYADML2, NGFR, NKCS1, NKG2D ligands, NLGN3, NPAS2, NY- ESO-1, oncofetal antigen (h5T4), OTOA, P2RY13, p53, PDE3A, PEAR1, PIEZO1, PLXNA4, PLXNC1, PNPLA3, PPFIA4, PPP2R5B, PRAME, PRAME , prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), Proteinase3 (PR1), PSD2, PTPRJ, RDH16, receptor tyrosine-protein kinase Erb-B2, RHBDL3, RNF173, RNF183, ROR1, RYR2, SCIN, SCN11A, SCN2A, SCNN1D, SEC31B, SEMA4A, SH3PXD2A, SIGLEC6, SIGLEC11, SIRPB1,ACTIVE 509948342.267 072734.1771 PATENT SLC16A6, SLC19A1, SLC22A5, SLC25A36, SLC25A41, SLC30A1, SLC34A3, SLC43A3, SLC44A1, SLC44A3, SLC45A3, SLC6A16, SLC6A6, SLC8A3, SLC9A1, SLCO2B1, SPAG17, STC1, STON2, SUN3, Survivin, SUSD2, SYNC, TACSTD2, TAS1R3, TEX29, TFR2, TIM-3 (HAVCR2), TLR2, TMEFF2, TMEM145, TMEM27, TMEM40, TMEM59L, TMEM89, TMPRSS5, TNFRSF14, TNFRSF1B, TRIM55, TSPEAR, TTYH3, tumor-associated glycoprotein 72 (TAG-72), Tyrosinase, vascular endothelial growth factor R2 (VEGF-R2), VLA- 4, Wilms tumor protein (WT-1), WNT4, WT1, and ZDHHC11. In certain embodiments, the second antigen is CD22. In certain embodiments, the first antigen is CD19 and the second antigen is CD22. In certain embodiments, the second antigen is a pathogen antigen, e.g., one disclosed in Section 2.1. 4.1.2. Chimeric Antigen Receptors (CARs) CARs are engineered receptors, which graft or confer a specificity of interest onto an immune effector cell. CARs can be used to graft the specificity of a monoclonal antibody onto a T cell; with transfer of their coding sequence facilitated by retroviral vectors. There are three generations of CARs. “First generation” CARs are typically composed of an extracellular antigen-binding domain (e.g., an scFv) that binds to a target antigen, and an intracellular signaling domain. In certain embodiments, the CAR further comprises a transmembrane domain. “First generation” CARs can provide de novo antigen recognition and cause activation of both CD4+and CD8+T cells through their CD3ζ chain signaling domain in a single fusion molecule, independent of HLA-mediated antigen presentation. “Second generation” CARs include a signaling domain of a co-stimulatory molecule (e.g., CD28, 4-1BB, ICOS, OX40, CD27, CD40,NKG2D, DAP-10, CD2, CD150, CD226) to the intracellular signaling domain of the CAR to provide co-stimulation signals to the cell (e.g., T cell or NK cell). “Second generation” CARs comprise those that provide both co-stimulation (e.g., CD28 or 4-1BB) and activation (CD3ζ). “Third generation” CARs comprise those that provide multiple co-stimulation (e.g., CD28 and 4-1BB) and activation (CD3ζ). In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to the second antigen, and an intracellular signaling domain. In certain embodiments, the CAR further comprises a transmembrane domain. In certain embodiments, the CAR further comprises a hinger / spacer region. 4.1.2.1. Extracellular Antigen-Binding Domain In certain embodiments, the extracellular antigen-binding domain of the CAR (for example, an scFv) binds to the second antigen with a dissociation constant (KD) of about 5 × 10-7ACTIVE 509948342.268 072734.1771 PATENT M or less, about 1 × 10-7M or less, about 5 × 10-8M or less, about 1 × 10-8M or less, about 5 × 10-9M or less, or about 1 × 10-9M or less, or about 1 × 10-10M or less. In certain embodiments, the extracellular antigen-binding domain of the CAR (for example, an scFv) binds to the second antigen with a KD of about 1 × 10-8M or less. Binding of the extracellular antigen-binding domain (for example, in an scFv) can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay. Each of these assays generally detect the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody, or an scFv) specific for the complex of interest. For example, the scFv can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by such means as the use of a γ counter or a scintillation counter or by autoradiography. In certain embodiments, the extracellular antigen- binding domain of the CAR is labeled with a fluorescent marker. Non-limiting examples of fluorescent markers include green fluorescent protein (GFP), blue fluorescent protein (e.g., EBFP, EBFP2, Azurite, and mKalama1), cyan fluorescent protein (e.g., ECFP, Cerulean, and CyPet), and yellow fluorescent protein (e.g., YFP, Citrine, Venus, and YPet). The extracellular antigen-binding domain can comprise or be an scFv, a Fab (which is optionally crosslinked), or a F(ab)2. In certain embodiments, any of the foregoing molecules may be comprised in a fusion protein with a heterologous sequence to form the extracellular antigen- binding domain. In certain embodiments, the extracellular antigen-binding domain comprises or is an scFv. In certain embodiments, the scFv is a human scFv. In certain embodiments, the scFv is a humanized scFv. In certain embodiments, the scFv is a murine scFv. 4.1.2.1.1. Exemplary Extracellular Antigen-Binding Domains In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD22. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises or consists of the amino acid sequence set forth in SEQ ID NO: 154 or SEQ ID NO: 155 and specifically binds to CD22, e.g., a human CD22 polypeptide. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95 or a conservative modification thereof, and a CDR3ACTIVE 509948342.269 072734.1771 PATENT comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96. SEQ ID NOs: 94-96 are provided in Table 5. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a light chain variable region (VL) comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99. SEQ ID NOs: 97-99 are provided in Table 5. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96, a conservative modification thereof; a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 94, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VHcomprising a CDR1, a CDR2, and a CDR3 of the VH having the amino acid sequence set forth in SEQ ID NO: 100. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VL comprising a CDR1, a CDR2, and a CDR3 of the VL having the amino acidACTIVE 509948342.270 072734.1771 PATENT sequence set forth in SEQ ID NO: 102. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1, a CDR2, and a CDR3 of the VH having the amino acid sequence set forth in SEQ ID NO: 100; and a VL comprising a CDR1, a CDR2, and a CDR3 of the VL having the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 100. For example, the extracellular antigen-binding domain of the first antigen-recognizing receptor comprises a VH comprising an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 100. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 100. SEQ ID NO: 100 is provided in Table 5. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 102. For example, the extracellular antigen-binding domain of the CAR comprises a VL comprising an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising the amino acid sequence set forth in SEQ ID NO: 102. SEQ ID NO: 102 is provided in Table 5. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 100, and a VLcomprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 100. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising the amino acidACTIVE 509948342.271 072734.1771 PATENT sequence set forth in SEQ ID NO: 102. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises VH comprising the amino acid sequence set forth in SEQ ID NO: 100 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the extracellular antigen-binding domain of the CAR is an scFv that comprises or consists of the amino acid sequence set forth in SEQ ID NO: 154 or SEQ ID NO: 155. SEQ ID NO: 154 and SEQ ID NO: 155 are provided below. In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6. MELGLSWIFLLAILKGVQCQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLG RTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVT VSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIYAAS SLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQGTKLEIK [SEQ ID NO: 154] MELGLSWIFLLAILKGVQCDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIYAA SSLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQGTKLEIKGGGGSQVQLQQSGP GLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSK NQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVTVSS [SEQ ID NO: 155] In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD22. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises or consists of the amino acid sequence set forth in SEQ ID NO: 198 and specifically binds to CD22, e.g., a human CD22 polypeptide. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 199, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 200, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 201. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a light chain variable region (VL) comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 202 or a conservative modification thereof, a CDR2 comprising the aminoACTIVE 509948342.272 072734.1771 PATENT acid sequence set forth in SEQ ID NO: 203 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 202, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 201, a conservative modification thereof; a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 202 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 199, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 200, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 201; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 202, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1, a CDR2, and a CDR3 of the VHhaving the amino acid sequence set forth in SEQ ID NO: 205. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VLcomprising a CDR1, a CDR2, and a CDR3 of the VLhaving the amino acid sequence set forth in SEQ ID NO: 206. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VHcomprising a CDR1, a CDR2, and a CDR3 of the VHhaving the amino acid sequence set forth in SEQ ID NO: 205; and a VLcomprising a CDR1, a CDR2, and a CDR3 of the VL having the amino acid sequence set forth in SEQ ID NO: 206. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 205. For example, the extracellular antigen-binding domain of the first antigen-recognizing receptor comprises a VHcomprising an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, aboutACTIVE 509948342.273 072734.1771 PATENT 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 205. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 205. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VLcomprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 206. For example, the extracellular antigen-binding domain of the CAR comprises a VL comprising an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 206. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising the amino acid sequence set forth in SEQ ID NO: 206. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 205, and a VL comprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 206. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 205. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VLcomprising the amino acid sequence set forth in SEQ ID NO: 206. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises VHcomprising the amino acid sequence set forth in SEQ ID NO: 205 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 206. In certain embodiments, the extracellular antigen-binding domain of the CAR is an scFv that comprises or consists of the amino acid sequence set forth in SEQ ID NO: 198 In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6. SEQ ID Nos: 198-206 are provided below. MELGLSWIFLLAILKGVQCQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLG RTYRRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVT VSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIYAASACTIVE 509948342.274 072734.1771 PATENT SLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQGTKLEIK [SEQ ID NO: 198] SNSAAWN [SEQ ID NO: 199] RTYRRSKWYNDYAVSVKS [SEQ ID NO: 200] EVTGDLEDAFDI [SEQ ID NO: 201] RASQTIWSYLN [SEQ ID NO: 202] AASSLQS [SEQ ID NO: 203] QQSYSIPQT [SEQ ID NO: 204] MELGLSWIFLLAILKGVQCQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLG RTYRRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVT VSS [SEQ ID NO: 205] DIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIYAASSLQSGVPSRFSGRGSGTD FTLTISSLQAEDFATYYCQQSYSIPQTFGQGTKLEIK [SEQ ID NO: 206] In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD19. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1; and a light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising the amino acid sequences disclosed in Section 2.2.1 and a light chain variable region (VL) comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD19. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises or consists of the amino acid sequence set forth in SEQ ID NO: 207 and specifically binds to CD19, e.g., a human CD19 polypeptide.ACTIVE 509948342.275 072734.1771 PATENT In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a light chain variable region (VL) comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 211 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 211, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210, a conservative modification thereof; a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 211 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213 or a conservative modification thereof. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 208, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 211, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VHcomprising a CDR1, a CDR2, and a CDR3 of the VH having the amino acid sequence set forth inACTIVE 509948342.276 072734.1771 PATENT SEQ ID NO: 214. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VL comprising a CDR1, a CDR2, and a CDR3 of the VL having the amino acid sequence set forth in SEQ ID NO: 215. In certain embodiments, extracellular antigen-binding domain of the CAR comprises a VH comprising a CDR1, a CDR2, and a CDR3 of the VH having the amino acid sequence set forth in SEQ ID NO: 214; and a VL comprising a CDR1, a CDR2, and a CDR3 of the VLhaving the amino acid sequence set forth in SEQ ID NO: 215. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 214. For example, the extracellular antigen-binding domain of the first antigen-recognizing receptor comprises a VH comprising an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 214. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 214. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 215. For example, the extracellular antigen-binding domain of the CAR comprises a VLcomprising an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 215. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VLcomprising the amino acid sequence set forth in SEQ ID NO: 215. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 214, and a VLcomprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 215. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 214. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VL comprising the amino acidACTIVE 509948342.277 072734.1771 PATENT sequence set forth in SEQ ID NO: 215. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises VH comprising the amino acid sequence set forth in SEQ ID NO: 214 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 215. In certain embodiments, the extracellular antigen-binding domain of the CAR is an scFv that comprises or consists of the amino acid sequence set forth in SEQ ID NO: 207. In certain embodiments, the VHand VLare linked via a linker. In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6. SEQ ID Nos: 207-215 are provided below. MALPVTALLLPLALLLHAEVKLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIY PGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYFCARKTISSVVDFYFDYWGQGTTVTVSS GGGGSGGGGSGGGGSDIELTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRN SGVPDRFTGSGSGTDFTLTITNVQSKDLADYFCQQYNRYPYTSGGGTKLEIKR [SEQ ID NO: 207] GYAFSSYW [SEQ ID NO: 208] IYPGDGDT [SEQ ID NO: 209] ARKTISSVVDFYFDY [SEQ ID NO: 210] QNVGTN [SEQ ID NO: 211] SA [SEQ ID NO: 212] QQYNRYPYT [SEQ ID NO: 213] MALPVTALLLPLALLLHAEVKLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIY PGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYFCARKTISSVVDFYFDYWGQGTTVTVSS [SEQ ID NO: 214] DIELTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTD FTLTITNVQSKDLADYFCQQYNRYPYTSGGGTKLEIKR [SEQ ID NO: 215] In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD70. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1; and a light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3ACTIVE 509948342.278 072734.1771 PATENT comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising the amino acid sequences disclosed in Section 2.2.1 and a light chain variable region (VL) comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD70. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises or consists of the amino acid sequence set forth in SEQ ID NO: 216 and specifically binds to CD70, e.g., a human CD70 polypeptide. In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD312. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1; and a light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising the amino acid sequences disclosed in Section 2.2.1 and a light chain variable region (VL) comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD312. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises or consists of the amino acid sequence set forth in SEQ ID NO: 217 and specifically binds to CD312, e.g., a human CD312 polypeptide. In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD276. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, theACTIVE 509948342.279 072734.1771 PATENT extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1; and a light chain variable region (VL) comprising a CDR1, a CDR2, and a CDR3 comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a heavy chain variable region (VH) comprising the amino acid sequences disclosed in Section 2.2.1 and a light chain variable region (VL) comprising the amino acid sequences disclosed in Section 2.2.1. In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD276. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises or consists of the amino acid sequence set forth in SEQ ID NO: 218 and specifically binds to CD276, e.g., a human CD276 polypeptide. The VH and / or VL amino acid sequences having at least about 80%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% (e.g., about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%) homology or identity to a specific sequence (e.g., SEQ ID NOs: 52, 53, 56, 57, 70, 72, 80, 82, 90, and 92) may contain substitutions (e.g., conservative substitutions), insertions, or deletions relative to the specified sequence(s), but retain the ability to bind to a target antigen (e.g., CD19, CD70, CD312, CD276, CD22). In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted and / or deleted in a specific sequence (e.g., SEQ ID NOs: 52, 53, 56, 57, 70, 72, 80, 82, 90, and 92). In certain embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (e.g., in the FRs) of the extracellular antigen-binding domain. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises VH and / or VL sequence selected from SEQ ID NOs: 52, 53, 56, 57, 70, 72, 80, 82, 90, and 92, including post- translational modifications of that sequence (SEQ ID NO: 52, 53, 56, 57, 70, 72, 80, 82, 90, and 92). 4.1.2.2. Transmembrane Domain and Hinge / Spacer Region In certain embodiments, the second antigen-recognizing receptor is a CAR that comprises a transmembrane domain. Different transmembrane domains result in different receptor stability. After antigen recognition, receptors cluster and a signal are transmitted to the cell. In accordance with the presently disclosed subject matter, the transmembrane domain of the first antigen- recognizing receptor can comprise a native or modified transmembrane domain of a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD40 polypeptide, a 4-1BB polypeptide,ACTIVE 509948342.280 072734.1771 PATENT an OX40 polypeptide, a CD84 polypeptide, a CD166 polypeptide, a CD8a polypeptide, a CD8b polypeptide, an ICOS polypeptide, an ICAM-1 polypeptide, a CTLA-4 polypeptide, a CD27 polypeptide, a CD40 polypeptide, a NKG2D polypeptide, a synthetic polypeptide (not based on a protein associated with the immune response), or a combination thereof. In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide (e.g., the transmembrane domain of CD28 or a portion thereof). In certain embodiments, the transmembrane domain of the CAR comprises a transmembrane domain of human CD28 or a portion thereof. In certain embodiments, the CD28 polypeptide comprises or consists of an amino acid sequence that is a consecutive portion of the amino acid sequence having a NCBI Reference No: NP_006130 (SEQ ID NO: 156), which is at least about 20, or at least about 25, or at least about 30, and / or up to about 220 amino acids in length. In certain embodiments, the CD28 polypeptide comprises or consists of an amino acid sequence of amino acids 1 to 220, 1 to 50, 50 to 100, 100 to 150, 114 to 220, 150 to 200, 153 to 179, or 200 to 220 of SEQ ID NO: 156. In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide that comprises or consists of amino acids 153 to 179 of SEQ ID NO: 156. SEQ ID NO: 156 is provided below. MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYG NYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPPPYLDNEKSNGTIIHVKGKHL CPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYA PPRDFAAYRS [SEQ ID NO: 156] In certain embodiments, the second antigen-recognizing receptor is a CAR that further comprises a hinge / spacer region that links the extracellular antigen-binding domain to the transmembrane domain. The hinge / spacer region can be flexible enough to allow the antigen binding domain to orient in different directions to facilitate antigen recognition. In certain embodiments, the hinge / spacer region of the CAR can comprise a native or modified hinge region of a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD40 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, a CD84 polypeptide, a CD166 polypeptide, a CD8a polypeptide, a CD8b polypeptide, an ICOS polypeptide, an ICAM-1 polypeptide, a CTLA-4 polypeptide, a CD27 polypeptide, a CD40 polypeptide, a NKG2D polypeptide, a synthetic polypeptide (not based on a protein associated with the immune response), or a combination thereof. The hinge / spacer region can be the hinge region from IgG1, or the CH2CH3 region of immunoglobulin and portions of CD3, a portion of a CD28 polypeptide (e.g., a portion of SEQ ID NO: 156), a portion of a CD8 polypeptide, or a synthetic spacer sequence. In certain embodiments, the second antigen-recognizing receptor is a CAR that further comprises a hinge / spacer region comprising a native or modified hinge region of a CD28ACTIVE 509948342.281 072734.1771 PATENT polypeptide. In certain embodiments, the hinge / spacer region of the first antigen-recognizing receptor (e.g., a CAR) comprises a CD28 polypeptide comprising or consisting of amino acids 114 to 152 of SEQ ID NO: 156. In certain embodiments, the hinge / spacer region is positioned between the extracellular antigen-binding domain and the transmembrane domain. In certain embodiments, the hinge / spacer region comprises a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, a CD166 polypeptide, a CD8a polypeptide, a CD8b polypeptide, an ICOS polypeptide, an ICAM-1 polypeptide, a CTLA-4 polypeptide, a CD27 polypeptide, a CD40 polypeptide, a NKG2D polypeptide, a synthetic polypeptide (not based on a protein associated with the immune response), or a combination thereof. In certain embodiments, the transmembrane domain comprises a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, a CD166 polypeptide, a CD8a polypeptide, a CD8b polypeptide, an ICOS polypeptide, an ICAM-1 polypeptide, a CTLA-4 polypeptide, a CD27 polypeptide, a CD40 polypeptide, a NKG2D polypeptide, a synthetic polypeptide (not based on a protein associated with the immune response), or a combination thereof. In certain embodiments, the transmembrane domain and the hinge / spacer region are derived from the same molecule. In certain embodiments, the transmembrane domain and the hinge / spacer region are derived from different molecules. In certain embodiments, the hinge / spacer region comprises a CD28 polypeptide and the transmembrane domain comprises a CD28 polypeptide. In certain embodiments, the hinge / spacer region comprises a CD28 polypeptide and the transmembrane domain comprises a CD28 polypeptide. In certain embodiments, the hinge / spacer region comprises a CD84 polypeptide and the transmembrane domain comprises a CD84 polypeptide. In certain embodiments, the hinge / spacer region comprises a CD166 polypeptide and the transmembrane domain comprises a CD166 polypeptide. In certain embodiments, the hinge / spacer region comprises a CD8a polypeptide and the transmembrane domain comprises a CD8a polypeptide. In certain embodiments, the hinge / spacer region comprises a CD8b polypeptide and the transmembrane domain comprises a CD8b polypeptide. In certain embodiments, the hinge / spacer region comprises a CD28 polypeptide and the transmembrane domain comprises an ICOS polypeptide. 4.1.2.3. Intracellular Signaling Domain In certain embodiments, the second antigen-recognizing receptor is a CAR that comprises an intracellular signaling domain. In certain embodiments, the intracellular signaling domain of the CAR comprises a CD3ζ polypeptide. CD3ζ can activate or stimulate a cell (e.g., a cell of theACTIVE 509948342.282 072734.1771 PATENT lymphoid lineage, e.g., a T-cell). Wild type (“native”) CD3ζ comprises three functional immunoreceptor tyrosine-based activation motifs (ITAMs), three functional basic-rich stretch (BRS) regions (BRS1, BRS2 and BRS3). CD3ζ transmits an activation signal to the cell (e.g., a cell of the lymphoid lineage, e.g., a T-cell) after antigen is bound. The intracellular signaling domain of the CD3ζ-chain is the primary transmitter of signals from endogenous TCRs. In certain embodiments, the intracellular signaling domain of the CAR comprises a native CD3ζ. In certain embodiments, the native CD3ζ comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical or homologous to the amino acid sequence having a NCBI Reference No: NP_932170 (SEQ ID NO: 8) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD3ζ polypeptide comprises or consists of an amino acid sequence that is a consecutive portion of SEQ ID NO: 12, which is at least about 20, or at least about 30, or at least about 40, or at least about 50, and up to about 164 amino acids in length. In certain embodiments, the native CD3ζ comprises or consists of the amino acid sequence of amino acids 1 to 164, 1 to 50, 50 to 100, 52 to 164, 100 to 150, or 150 to 164 of SEQ ID NO: 40. In certain embodiments, the intracellular signaling domain of the CAR comprises a native CD3ζ comprising or consisting of the amino acid sequence of amino acids 52 to 164 of SEQ ID NO: 40. In certain embodiments, the native CD3ζ comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 41. In certain embodiments, the intracellular signaling domain of the CAR comprises a modified CD3ζ polypeptide. In certain embodiments, the modified CD3ζ polypeptide comprises one, two or three ITAMs. In certain embodiments, the modified CD3ζ polypeptide comprises a native ITAM1. In certain embodiments, the native ITAM1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 157. QNQLYNELNLGRREEYDVLDKR [SEQ ID NO: 157] An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 157 is set forth in SEQ ID NO: 158, which is provided below. CAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGA [SEQ ID NO: 158] In certain embodiments, the modified CD3ζ polypeptide comprises an ITAM1 variant comprising one or more loss-of-function mutations. In certain embodiments, the ITAM1 variant comprises or consists of two loss-of-function mutations. In certain embodiments, each of the oneACTIVE 509948342.283 072734.1771 PATENT or more (e.g., two) loss of function mutations comprises a mutation of a tyrosine residue in ITAM1. In certain embodiments, the ITAM1 variant consists of two loss-of-function mutations. In certain embodiments, the ITAM1 variant comprises or consists of the amino acid sequence set forth in SEQ ID NO: 159, which is provided below. QNQLFNELNLGRREEFDVLDKR [SEQ ID NO: 159] An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 159 is set forth in SEQ ID NO: 160, which is provided below. CAGAACCAGCTCTTTAACGAGCTCAATCTAGGACGAAGAGAGGAGTTCGATGTTTTGGACAAGAGA [SEQ ID NO: 160] In certain embodiments, the modified CD3ζ polypeptide comprises a native ITAM2. In certain embodiments, the native ITAM2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 161, which is provided below. QEGLYNELQKDKMAEAYSEIGMK [SEQ ID NO: 161] An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 161 is set forth in SEQ ID NO: 162, which is provided below. CAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAA [SEQ ID NO: 162] In certain embodiments, the modified CD3ζ polypeptide comprises an ITAM2 variant. In certain embodiments, the ITAM2 variant comprises or consists of one or more loss-of-function mutations. In certain embodiments, the ITAM2 variant comprises or consists of two loss-of- function mutations. In certain embodiments, each of the one or more (e.g., two) the loss of function mutations comprises a mutation of a tyrosine residue in ITAM2. In certain embodiments, the ITAM1 variant consists of two loss-of-function mutations. In certain embodiments, the ITAM2 variant comprises or consists of the amino acid sequence set forth in SEQ ID NO: 163, which is provided below. QEGLFNELQKDKMAEAFSEIGMK [SEQ ID NO: 163] An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 163 is set forth in SEQ ID NO: 164, which is provided below. CAGGAAGGCCTGTTCAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTTCAGTGAGATTGGGATGAAA [SEQ ID NO: 164] In certain embodiments, the modified CD3ζ polypeptide comprises a native ITAM3. In certain embodiments, the native ITAM3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 165, which is provided below. HDGLYQGLSTATKDTYDALHMQ [SEQ ID NO: 165]ACTIVE 509948342.284 072734.1771 PATENT An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 165 is set forth in SEQ ID NO: 166, which is provided below. CACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAG [SEQ ID NO: 166] In certain embodiments, the modified CD3ζ polypeptide comprises an ITAM3 variant. In certain embodiments, the ITAM3 variant comprises or consists of two loss-of-function mutations. In certain embodiments, each of the one or more (e.g., two) the loss of function mutations comprises a mutation of a tyrosine residue in ITAM3. In certain embodiments, the ITAM3 variant comprises or consists of two loss-of-function mutations. In certain embodiments, the ITAM3 variant comprises or consists of the amino acid sequence set forth in SEQ ID NO: 167, which is provided below. HDGLFQGLSTATKDTFDALHMQ [SEQ ID NO: 167] An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 167 is set forth in SEQ ID NO: 168, which is provided below. CACGATGGCCTTTTCCAGGGGCTCAGTACAGCCACCAAGGACACCTTCGACGCCCTTCACATGCAG [SEQ ID NO: 168] Various modified CD3ζ polypeptides and CARs comprising modified CD3ζ polypeptides are disclosed in International Patent Application Publication No. WO2019 / 133969, which is incorporated by reference hereby in its entirety. In certain embodiments, the intracellular signaling domain of the CAR comprises a modified CD3ζ polypeptide comprising a native ITAM1, an ITAM2 variant comprising or consisting of one or more (e.g., two) loss-of-function mutations, and an ITAM3 variant comprising or consisting of one or more (e.g., two) loss-of-function mutations. In certain embodiments, the intracellular signaling domain of the CAR comprises a modified CD3ζ polypeptide comprising a native ITAM1, an ITAM2 variant consisting of two loss-of-function mutations, and an ITAM3 variant consisting of two loss-of-function mutations. In certain embodiments, the intracellular signaling domain of the CAR comprises a modified CD3ζ polypeptide comprising a native ITAM1 consisting of the amino acid sequence set forth in SEQ ID NO: 157, an ITAM2 variant consisting of the amino acid sequence set forth in SEQ ID NO: 163, and an ITAM3 variant consisting of the amino acid sequence set forth in SEQ ID NO: 167. In certain embodiments, the CAR is designated as “1XX”. In certain embodiments, the modified CD3ζ polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 169. SEQ ID NO: 169 is provided below:ACTIVE 509948342.285 072734.1771 PATENT RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLFNELQKDKMAEA FSEIGMKGERRRGKGHDGLFQGLSTATKDTFDALHMQALPPR [SEQ ID NO: 169] In certain embodiments, the intracellular signaling domain of the CAR comprises a modified CD3ζ polypeptide comprising or consisting of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% identical to SEQ ID NO: 169 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 169 is set forth in SEQ ID NO: 170, which is provided below. AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGC TCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGG AAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTTCAATGAACTGCAGAAAGATAAGATGGCGGAGGCC TTCAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTTCCAGGGGCTCAGTACAGCCACCAAGGACACCTTCGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC [SEQ ID NO:170] In certain embodiments, the intracellular signaling domain of the CAR further comprises at least one co-stimulatory signaling region. In certain embodiments, the at least one co- stimulatory region comprises a co-stimulatory molecule or a portion thereof. In certain embodiments, the at least one co-stimulatory region comprises at least an intracellular domain of at least one co-stimulatory molecule or a portion thereof. Non-limiting examples of costimulatory molecules include CD28, 4-1BB, OX40, CD27, CD40, CD154, CD97, CD11a / CD18, ICOS, DAP-10, CD2, CD150, CD226, and NKG2D. In certain embodiments, the intracellular signaling domain of the CAR comprises a co- stimulatory signaling region that comprises a CD28 polypeptide, e.g., an intracellular domain of CD28 or a portion thereof. In certain embodiments, the intracellular signaling domain of the CAR comprises a co-stimulatory signaling region that comprises an intracellular domain of human CD28 or a portion thereof. In certain embodiments, the CD28 polypeptide comprised in the co-stimulatory signaling region of the first antigen-recognizing receptor comprise or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 156 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD28 polypeptide comprised in the co-stimulatoryACTIVE 509948342.286 072734.1771 PATENT signaling region of the CAR comprises or consist of an amino acid sequence that is a consecutive portion of SEQ ID NO: 156, which is at least about 20, or at least about 30, or at least about 40, or at least about 50, and up to about 220 amino acids in length. Alternatively or additionally, in certain embodiments, the CD28 polypeptide comprised in the co-stimulatory signaling region of the CAR comprises or consists of amino acids 1 to 220, 1 to 50, 50 to 100, 100 to 150, 114 to 220, 150 to 200, 180 to 220, or 200 to 220 of SEQ ID NO: 156. In certain embodiments, the intracellular signaling domain of the CAR comprises a co-stimulatory signaling region that comprises a CD28 polypeptide comprising or consisting of amino acids 180 to 220 of SEQ ID NO: 156. An exemplary nucleic acid sequence encoding the amino acid sequence of amino acids 180 to 220 of SEQ ID NO: 156 is set forth in SEQ ID NO: 171, which is provided below. AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCC GCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC [SEQ ID NO: 171] In certain embodiments, the intracellular signaling domain of the first antigen-recognizing receptor comprises a co-stimulatory signaling region that comprises an intracellular domain of mouse CD28 or a portion thereof. In certain embodiments, the CD28 polypeptide comprised in the co-stimulatory signaling region comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% identical or homologous to the amino acid sequence having a NCBI Reference No: NP_031668.3 (or SEQ ID NO: 172) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD28 polypeptide comprised in the co-stimulatory signaling region of the CAR comprises or consists of an amino acid sequence that is a consecutive portion of SEQ ID NO: 172, which is at least about 20, or at least about 30, or at least about 40, or at least about 50, and up to 218 amino acids in length. In certain embodiments, the CD28 polypeptide comprised in the co-stimulatory signaling region of the CAR comprises or consists of the amino acid sequence of amino acids 1 to 218, 1 to 50, 50 to 100, 100 to 150, 150 to 218, 178 to 218, or 200 to 218 of SEQ ID NO: 172. In certain embodiments, the co-stimulatory signaling region of the CAR comprises a CD28 polypeptide that comprises or consists of amino acids 178 to 218 of SEQ ID NO: 172. SEQ ID NO: 172 is provided below. MTLRLLFLALNFFSVQVTENKILVKQSPLLVVDSNEVSLSCRYSYNLLAKEFRASLYKGVNSDVEVCVGN GNFTYQPQFRSNAEFNCDGDFDNETVTFRLWNLHVNHTDIYFCKIEFMYPPPYLDNERSNGTIIHIKEKH LCHTQSSPKLFWALVVVAGVLFCYGLLVTVALCVIWTNSRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPA RDFAAYRP [SEQ ID NO: 172]ACTIVE 509948342.287 072734.1771 PATENT In certain embodiments, the intracellular signaling domain of the CAR comprises a co- stimulatory signaling region that comprises a 4-1BB polypeptide, e.g., an intracellular domain of 4-1BB or a portion thereof. In certain embodiments, the co-stimulatory signaling region comprises an intracellular domain of human 4-1BB or a portion thereof. In certain embodiments, the 4-1BB comprised in the co-stimulatory signaling region of the CAR comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% identical or homologous to the sequence having a NCBI Ref. No.: NP_001552 (SEQ ID NO: 173) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the 4-1BB comprised in the co-stimulatory signaling region of the CAR comprises or consists of an amino acid sequence that is a consecutive portion of SEQ ID NO: 173, which is at least about 20, or at least about 30, or at least about 40, or at least about 50, and / or up to about 50, up to about 60, up to about 70, up to about 80, up to about 90, up to about 100, up to about 200, or up to about 255 amino acids in length. In certain embodiments, the co-stimulatory signaling region of the CAR comprises a 4-1BB polypeptide that comprises or consists of the amino acid sequence of amino acids 1 to 255, 1 to 50, 50 to 100, 100 to 150, 150 to 200, or 200 to 255 of SEQ ID NO: 173. In certain embodiments, the co-stimulatory signaling region of the CAR comprises a 4-1BB polypeptide comprising or consisting of the amino acid sequence of amino acids 214 to 255 of SEQ ID NO: 173. SEQ ID NO: 173 is provided below. MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKG VFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCS LDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRF SVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL [SEQ ID NO: 173] In certain embodiments, the intracellular signaling domain of the CAR comprises two co- stimulatory signaling regions, wherein the first co-stimulatory signaling region comprises an intracellular domain of a first co-stimulatory molecule or a portion thereof, and the second co- stimulatory signaling region comprises an intracellular domain of a second co-stimulatory molecule or a portion thereof. The first and second co-stimulatory molecules are independently selected from the group consisting of CD28, 4-1BB, OX40, CD27, CD40, CD154, CD97, CD11a / CD18, ICOS, DAP-10, CD2, CD150, CD226, and NKG2D. In certain embodiments, the intracellular signaling domain of the CAR comprises two co-stimulatory signaling regions, wherein the first co-stimulatory signaling region comprises an intracellular domain of CD28 or a portion thereof and the second co-stimulatory signaling region comprises an intracellular domain of 4-1BB or a portion thereof.ACTIVE 509948342.288 072734.1771 PATENT In certain embodiments, the second antigen-recognizing receptor is a CAR that comprises i) an extracellular antigen-binding domain, ii) a transmembrane domain comprising a CD28 polypeptide (e.g., human CD28 polypeptide, e.g., a transmembrane domain of CD28 (e.g., human CD28) or a portion thereof), iii) a hinge / spacer region derived from a CD28 polypeptide (e.g., a human CD28 polypeptide), iv) an intracellular signaling domain comprising a) a native CD3ζ polypeptide, and b) a co-stimulatory signaling region comprising a CD28 polypeptide (e.g., a human CD28 polypeptide, e.g., an intracellular domain of CD28 (e.g., human CD28) of a portion thereof). In certain embodiments, the transmembrane domain comprises a CD28 polypeptide comprising or consisting of amino acids 153 to 179 of SEQ ID NO: 156. In certain embodiments, the hinge / spacer region comprises a CD28 polypeptide comprising or consisting of amino acids 114 to 152 of SEQ ID NO: 156. In certain embodiments, the intracellular signaling domain comprises a native CD3ζ polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 41, and a co-stimulatory signaling region comprising a CD28 polypeptide that comprises or consists of 180 to 220 of SEQ ID NO: 156. In certain embodiments, the CAR is designated as “28z”. In certain embodiments, the CAR (e.g., 28z) is encoded by a nucleotide sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% identical to the nucleotide sequence set forth in SEQ ID NO: 174. In certain embodiments, the CAR (e.g., 28z) comprises the nucleotide sequence set forth in SEQ ID NO: 174. In certain embodiments, the second antigen-recognizing receptor is a CAR that comprises i) an extracellular antigen-binding domain, ii) a transmembrane domain comprising a CD28 polypeptide (e.g., human CD28 polypeptide, e.g., a transmembrane domain of CD28 (e.g., human CD28) or a portion thereof), iii) a hinge / spacer region derived from a CD28 polypeptide (e.g., a human CD28 polypeptide), iv) an intracellular signaling domain comprising a) a modified CD3ζ polypeptide (e.g., a modified human CD3ζ polypeptide) comprising a native ITAM1, an ITAM2 variant consisting of two loss-of-function mutations, and an ITAM3 variant consisting of two loss- of-function mutations, and b) a co-stimulatory signaling region comprising a CD28 polypeptide (e.g., a human CD28 polypeptide, e.g., an intracellular domain of CD28 (e.g., human CD28) of a portion thereof). In certain embodiments, the transmembrane domain comprises a CD28 polypeptide comprising or consisting of amino acids 153 to 179 of SEQ ID NO: 156. In certain embodiments, the hinge / spacer region comprises a CD28 polypeptide comprising or consisting of amino acids 114 to 152 of SEQ ID NO: 156. In certain embodiments, the intracellular signaling domain comprises a modified CD3ζ polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 169, and a co-stimulatory signaling region comprising a CD28 polypeptide that comprises or consists of 180 to 220 of SEQ ID NO: 156. In certain embodiments,ACTIVE 509948342.289 072734.1771 PATENT the CAR is designated as “28z1xx”. In certain embodiments, the CAR (e.g., 28z1xx) is encoded by a nucleotide sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% identical to the nucleotide sequence set forth in SEQ ID NO: 175 or SEQ ID NO: 176. In certain embodiments, the CAR (e.g., 28z1xx) comprises the nucleotide sequence set forth in SEQ ID NO: 175 or SEQ ID NO: 176. SEQ ID NO: 175 and SEQ ID NO: 176 are provided below. ATTGAAGTTATGTATCCTCCTCCTTACCTAGACAATGAGAAGAGCAATGGAACCATTATCCATGTGAAAG GGAAACACCTTTGTCCAAGTCCCCTATTTCCCGGACCTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTTGG TGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGG AGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACC AGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAGAGTGAAGTTCAGCAGGAGCGCAGACGC CCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGAT GTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAG GCCTGTTCAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTTCAGTGAGATTGGGATGAAAGGCGAGCG CCGGAGGGGCAAGGGGCACGATGGCCTTTTCCAGGGTCTCAGTACAGCCACCAAGGACACCTTCGACGCC CTTCACATGCAGGCCCTGCCCCCTCGC [SEQ ID NO: 175] ATTGAAGTTATGTATCCTCCTCCTTACCTAGACAATGAGAAGAGCAATGGAACCATTATCCATGTGAAAG GGAAACACCTTTGTCCAAGTCCCCTATTTCCCGGACCTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTTGG TGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGG AGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACC AGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCCAGAGTGAAGTTCAGCAGGAGCGCAGACGC CCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGAT GTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAG GCCTGTTCAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTTCAGTGAGATTGGGATGAAAGGCGAGCG CCGGAGGGGCAAGGGGCACGATGGCCTTTTCCAGGGTCTCAGTACAGCCACCAAGGACACCTTCGACGCC CTTCACATGCAGGCCCTGCCCCCTCGC [SEQ ID NO: 176] In certain embodiments, the second antigen-recognizing receptor is a CAR that comprises i) an extracellular antigen-binding domain, ii) a transmembrane domain, iii) a hinge / spacer region, iv) an intracellular signaling domain comprising a) a native CD3ζ polypeptide, and b) a co- stimulatory signaling region comprising a 4-1BB polypeptide (e.g., a human 4-1BB polypeptide, e.g., an intracellular domain of 4-1BB (e.g., human 4-1BB) of a portion thereof). In certain embodiments, the intracellular signaling domain comprises a native CD3ζ polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 41, and a co-stimulatory signaling region comprising a 4-1BB polypeptide that comprises or consists of 214 to 255 of SEQ ID NO: 173. In certain embodiments, the CAR is designated as “BBz”. In certain embodiments,ACTIVE 509948342.290 072734.1771 PATENT the CAR (e.g., BBz) is encoded by a nucleotide sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% identical to the nucleotide sequence set forth in SEQ ID NO: 177 or SEQ ID NO: 178. In certain embodiments, the CAR (e.g., BBz) comprises the nucleotide sequence set forth in SEQ ID NO: 177 or SEQ ID NO: 178. 4.1.2.4. Exemplary CARs In certain embodiments, the second antigen-recognizing receptor is a CAR comprising an extracellular antigen-binding domain that binds to CD22, a transmembrane domain, and an intracellular domain. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 94, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, the extracellular antigen-binding domain of the CAR is an scFv that comprises or consists of the amino acid sequence set forth in SEQ ID NO: 154 or SEQ ID NO: 155. In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide that comprises or consists of amino acids 153 to 179 of SEQ ID NO: 156. In certain embodiments, the CAR further comprises a hinge / spacer region that links the extracellular antigen-binding domain to the transmembrane domain comprising a CD28 polypeptide comprising or consisting of amino acids 114 to 152 of SEQ ID NO: 156. In certain embodiments, the intracellular signaling domain of the CAR comprises a modified CD3ζ polypeptide comprising a native ITAM1, an ITAM2 variant consisting of two loss-of-function mutations, and an ITAM3 variant consisting of two loss-of-function mutations. In certain embodiments, the modified CD3ζ polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 169. In certain embodiments, the intracellular signaling domain of the CAR further comprises a CD28 polypeptide that comprises or consists of amino acids 180 to 220 of SEQ ID NO: 156. In certain embodiments, the CAR is designated as “22C1XX”. In certain embodiments, the CAR comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 191. In certain embodiments, the HIT receptor comprises or consists of the amino acid sequence set forth in SEQ ID NO: 191. An exemplary nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 191 is set forth in SEQ ID NO: 192. SEQ ID NO: 191 and SEQ ID NO: 192 are provided below.ACTIVE 509948342.291 072734.1771 PATENT MELGLSWIFLLAILKGVQCQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLG RTYRRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREVTGDLEDAFDIWGQGTMVT VSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQTIWSYLNWYQQRPGKAPNLLIYAAS SLQSGVPSRFSGRGSGTDFTLTISSLQAEDFATYYCQQSYSIPQTFGQGTKLEIKAAAIEVMYPPPYLDN EKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMT PRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEM GGKPRRKNPQEGLFNELQKDKMAEAFSEIGMKGERRRGKGHDGLFQGLSTATKDTFDALHMQALPPR [SEQ ID NO: 191] ATGGAACTCGGTCTGTCCTGGATTTTTCTGCTTGCGATCTTGAAAGGAGTGCAGTGCCAAGTACAGCTTC AACAGTCAGGTCCGGGGCTGGTAAAGCCTTCTCAGACACTCAGCCTGACTTGTGCTATAAGTGGGGATAG TGTTTCATCCAACTCAGCGGCGTGGAACTGGATCCGGCAAAGTCCATCTCGGGGCCTGGAGTGGTTGGGG CGGACCTATCGCAGGTCTAAGTGGTACAATGATTACGCCGTCTCAGTGAAGTCACGGATCACAATCAATC CCGATACGAGTAAGAATCAGTTCTCACTTCAGCTTAACAGTGTGACACCTGAAGATACGGCAGTATATTA TTGCGCGAGAGAGGTTACTGGGGACCTCGAAGATGCCTTCGATATCTGGGGTCAAGGCACAATGGTTACA GTCAGCTCCGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGACATACAGATGACAC AATCTCCGAGTAGCCTTTCCGCATCCGTAGGTGATAGGGTTACCATAACTTGCCGCGCATCTCAAACGAT CTGGTCCTATCTGAACTGGTACCAGCAGAGACCAGGAAAAGCTCCTAATCTGCTTATCTACGCCGCAAGC TCACTGCAGTCTGGGGTTCCGAGTAGATTTTCTGGGCGAGGCAGCGGAACGGATTTTACTCTGACCATAA GCTCTCTGCAAGCAGAAGATTTTGCCACGTACTACTGCCAGCAATCTTACAGCATCCCACAAACATTTGG ACAAGGCACAAAGTTGGAGATCAAAGCGGCCGCCATTGAAGTTATGTATCCTCCTCCTTACCTAGACAAT GAGAAGAGCAATGGAACCATTATCCATGTGAAAGGGAAACACCTTTGTCCAAGTCCCCTATTTCCCGGAC CTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGT GGCCTTTATTATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACT CCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATC GCTCCAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAA CGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATG GGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTTCAATGAACTGCAGAAAGATAAGATGGCGG AGGCCTTCAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTTCCAGGG TCTCAGTACAGCCACCAAGGACACCTTCGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTAA [SEQ ID NO: 192] 4.1.3. Chimeric Ligand Receptors In certain embodiments, the second antigen-recognizing receptor is a chimeric ligand receptor that comprises a ligand or a portion thereof that binds to a second antigen. In certain embodiments, the chimeric ligand receptor further comprises a transmembrane domain and an intracellular signaling domain. In certain embodiments, the transmembrane domain is fused to the ligand or portion thereof. In certain embodiments, the transmembrane domain is fused to the intracellular signalingACTIVE 509948342.292 072734.1771 PATENT domain. In certain embodiments, the transmembrane domain is positioned between the ligand or portion thereof and the intracellular signaling domain. In certain embodiments the transmembrane domain of the chimeric ligand receptor is a transmembrane domain disclosed in Section 4.1.2.2. In certain embodiments, the intracellular signaling domain of the chimeric ligand receptor comprises a CD3ζ polypeptide (e.g., as disclosed in Section 4.1.2.3). Additional information on the presently disclosed chimeric ligand receptor can be found in Sauer et al., Blood (2021) 138 (4): 318–330, the content of which is incorporated by reference in its entirety. 4.2.3. Delivery of the Second Antigen-Recognizing Receptor In certain embodiments, the second antigen-recognizing receptor is delivered to the cell by a viral method. In certain embodiments, the viral method comprises a viral vector. In certain embodiments, the viral vector is a retroviral vector (e.g., a gamma­retroviral vector or a lentiviral vector). Other viral vectors include adenoviral vectors, adeno-associated viral vectors, vaccinia viruses, bovine papilloma viruses, and herpes viruses (e.g., such as Epstein-Barr Virus). In certain embodiments, the second antigen-recognizing receptor is delivered to the cell by a non-viral method. Any targeted genome editing methods can also be used to deliver the second antigen-recognizing receptor to the cell. 4.2. CCRs In certain embodiments, a presently disclosed cell can further comprise a CCR. The term “chimeric co-stimulating receptor” or “CCR” refers to a chimeric receptor that binds to an antigen and provides a co-stimulatory signal, but does not provide a T-cell activation signal to a cell comprising the CCR. Various CCRs are described in US20020018783 the contents of which are incorporated by reference in their entireties. CCRs mimic co-stimulatory signals, but unlike, CARs, do not provide a T-cell activation signal. In certain embodiments, the CCR lacks a CD3ζ polypeptide. CCRs provide co-stimulation signal (e.g., a CD28-like signal or 4-1BB-like signal), in the absence of the natural co-stimulatory ligand on the antigen-presenting cell. A combinatorial antigen recognition, i.e., use of a CCR in combination with a CAR, can augment T-cell reactivity against the dual-antigen expressing T cells, thereby improving selective tumor targeting. Kloss et al., describe a strategy that integrates combinatorial antigen recognition, split signaling, and, critically, balanced strength of T-cell activation and co-stimulation to generate T cells that eliminate target cells that express a combination of antigens while sparing cells that express each antigen individually (Kloss et al., Nature Biotechnology (2013);31(1):71-75, the content of which is incorporated by reference in its entirety). With this approach, T-cell activation requires CAR-ACTIVE 509948342.293 072734.1771 PATENT mediated recognition of one antigen, whereas co-stimulation is independently mediated by a CCR specific for a second antigen. To achieve tumor selectivity, the combinatorial antigen recognition approach diminishes the efficiency of T-cell activation to a level where it is ineffective without rescue provided by simultaneous CCR recognition of the second antigen. In certain embodiments, the CCR comprises an extracellular antigen-binding domain that binds to a third antigen and an intracellular domain that is capable of delivering a costimulatory signal to the cell but does not alone deliver an activation signal to the cell. In certain embodiments, the CCR further comprises a transmembrane domain. In certain embodiments, the intracellular domain of the CCR comprises at least an intracellular domain of a co-stimulatory molecule or a portion thereof. In certain embodiments, the co-stimulatory molecule is selected from the group consisting of CD28, 4-1BB, OX40, CD27, CD40, CD154, CD97, CD11a / CD18, ICOS, DAP-10, CD2, CD150, CD226, and NKG2D. In certain embodiments, the CCR comprises an intracellular domain of CD28 or a portion thereof. In certain embodiments, the CCR comprises an intracellular domain of 4-1BB or a portion thereof. In certain embodiments, the CCR comprises an intracellular domain of CD28 or a portion thereof, and an intracellular domain of 4-1BB or a portion thereof. In certain embodiments, the third antigen is selected so that expression of both of the first / second antigen and the third antigen is restricted to the targeted cells (e.g., cancerous tissue or cancerous cells, or LSCs, or AML HSPCs). Similar to a CAR, the extracellular antigen-binding domain can be an scFv, a Fab, a F(ab)2, or a fusion protein with a heterologous sequence to form the extracellular antigen-binding domain. In certain embodiments, the cell comprising the first antigen-recognizing receptor, the inhibitory polynucleotide, the second antigen-recognizing receptor, and the CCR exhibits a greater degree of cytolytic activity against cells that are positive for both the first / second antigen and the third antigen as compared to against cells that are singly positive for the first / second antigen. In certain embodiments, the cell comprising the first antigen-recognizing receptor, the inhibitory polynucleotide, the second antigen-recognizing receptor, and the CCR exhibits substantially no or negligible cytolytic activity against cells that are singly positive for the first / second antigen. In certain embodiments, the first antigen recognizing receptor and / or the second antigen recognizing receptor binds to the first antigen and the second antigen with a low binding affinity, e.g., a dissociation constant (KD) of about 1 × 10-8M or more, about 5 × 10-8M or more, about 1 × 10-7M or more, about 5 × 10-7M or more, or about 1 × 10-6M or more, or from about 1 × 10-8M to about 1 × 10-6M. In certain embodiments, the first antigen recognizing receptor (e.g., a CAR, a TCR, or a TCR-like fusion molecule) binds to the first antigen with a low binding avidity. In certain embodiments, the first antigen recognizing receptor (e.g., a CAR, a TCR, or a TCR-likeACTIVE 509948342.294 072734.1771 PATENT fusion molecule) binds to the first antigen at an epitope of low accessibility. In certain embodiments, the first antigen recognizing receptor (e.g., a CAR, a TCR, or a TCR-like fusion molecule) binds to the first antigen with a binding affinity that is lower compared to the binding affinity with which the second antigen-recognizing receptor (e.g., a CCR) binds to the second antigen. In certain embodiments, the CCR binds to the third antigen with a binding affinity KD of from about 1 × 10-9M to about 1 × 10-7M, e.g., about 1 × 10-7M or less, about 1 × 10-8M or less, or about 1 × 10-9M or less. 4.5. Co-stimulatory Ligands In certain embodiments, a presently disclosed cell can further comprise at least one recombinant or exogenous co-stimulatory ligand. For example, a presently disclosed cell can be further transduced with at least one co-stimulatory ligand, such that the cell expresses or is induced to express the first antigen-recognizing receptor, the second antigen-recognizing receptor, and the at least one co-stimulatory ligand. The at least one co-stimulatory ligand provides a co-stimulation signal to the cell. Non-limiting examples of co­stimulatory ligands include, but are not limited to, members of the tumor necrosis factor (TNF) superfamily, and immunoglobulin (Ig) superfamily ligands. TNF is a cytokine involved in systemic inflammation and stimulates the acute phase reaction. Its primary role is in the regulation of immune cells. Members of TNF superfamily share a number of common features. The majority of TNF superfamily members are synthesized as type II transmembrane proteins (extracellular C-terminus) containing a short cytoplasmic segment and a relatively long extracellular region. Non-limiting examples of TNF superfamily members include nerve growth factor (NGF), CD40L (also known as “CD154”), 4-1BBL, TNF-^, OX40L, CD70, Fas ligand (FasL), CD30L, tumor necrosis factor beta (TNFβ) / lymphotoxin-alpha (LT^), lymphotoxin-beta (LTβ), CD257 / B cell-activating factor (BAFF) / Blys / THANK / Tall-1, glucocorticoid-induced TNF Receptor ligand (GITRL), TNF-related apoptosis-inducing ligand (TRAIL), and LIGHT (TNFSF14). The immunoglobulin (Ig) superfamily is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. These proteins share structural features with immunoglobulins – they possess an immunoglobulin domain (fold). Non-limiting examples of immunoglobulin superfamily ligands include CD80, CD86, and ICOSLG. In certain embodiments, the at least one co-stimulatory ligand is selected from the group consisting of 4-1BBL, CD80, CD86, CD70, GITRL, CD40L, OX40L, CD30L, TNFRSF14, ICOSLG, TRAIL, and combinations thereof. In certain embodiments, the cell further comprises one exogenous co-stimulatory ligand that is 4-1BBL. In certain embodiments, the co-stimulatory ligand is human 4-1BBL. In certainACTIVE 509948342.295 072734.1771 PATENT embodiments, the 4-1BBL comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% homologous or identical to the amino acid sequence having a Uniprot Reference No: P41273-1 (SEQ ID NO: 181) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the 4-1BBL comprises or consists of an amino acid sequence that is a consecutive portion of the amino acid sequence of SEQ ID NO: 181. SEQ ID NO: 181 is provided below. MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRL REGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGV YYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQ RLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE [SEQ ID NO: 181] An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 181 is set forth in SEQ ID NO: 182. In certain embodiments, the cell further comprises one exogenous co-stimulatory ligand that is CD80. In certain embodiments, the co-stimulatory ligand is human CD80. In certain embodiments, the CD80 comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% homologous or identical to the amino acid sequence having a NCBI Reference No: NP_005182 (SEQ ID NO: 183) or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD80 comprises or consists of an amino acid sequence that is a consecutive portion of the amino acid sequence of SEQ ID NO: 183. SEQ ID NO: 183 is provided below. MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEVATLSCGHNVSVEELAQTRIYWQKEK KMVLTMMSGDMNIWPEYKNRTIFDITNNLSIVILALRPSDEGTYECVVLKYEKDAFKREHLAEVTLSVKA DFPTPSISDFEIPTSNIRRIICSTSGGFPEPHLSWLENGEELNAINTTVSQDPETELYAVSSKLDFNMTT NHSFMCLIKYGHLRVNQTFNWNTTKQEHFPDNLLPSWAITLISVNGIFVICCLTYCFAPRCRERRRNERL RRESVRPV [SEQ ID NO: 183] An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 183 is set forth in SEQ ID NO: 184. SEQ ID NO: 184 is provided below. In certain embodiments, the cell further comprises two exogenous co-stimulatory ligands that are 4-1BBL and CD80. In certain embodiments, the cell further comprises two exogenous co-stimulatory ligands that are 4-1BBL and CD80, wherein the 4-1BBL comprises or consists ofACTIVE 509948342.296 072734.1771 PATENT the amino acid sequence set forth in SEQ ID NO: 181, and the CD80 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 183. Receptor-comprising cells comprising at least one exogenous co-stimulatory ligand are described in U.S. Patent No.8,389,282, which is incorporated by reference in its entirety. 4.6. Fusion Polypeptides In certain embodiments, a presently disclosed cell comprising a first antigen-recognizing receptor and a second antigen-recognizing receptor further comprises a fusion polypeptide. For example, a presently disclosed cell can be further transduced with the fusion polypeptide, such that the cell expresses or is induced to express the first antigen-recognizing receptor, the second antigen-recognizing receptor, and the fusion polypeptide. The fusion polypeptide provides a co- stimulation signal to the cell. The fusion polypeptides are capable of enhancing the activity and / or efficacy of a cell comprising the first antigen-recognizing receptor (e.g., a CAR or a TCR-like fusion molecule). In certain embodiments, the fusion polypeptide comprises a) an extracellular domain and a transmembrane domain of a co-stimulatory ligand, and b) an intracellular domain of a first co-stimulatory molecule. Non-limiting examples of the co-stimulatory ligand include tumor necrosis factor (TNF) family members, immunoglobulin (Ig) superfamily members, and combinations thereof. The TNF family member can be selected from the group consisting of 4-1BBL, OX40L, CD70, GITRL, CD40L, and combinations thereof. The Ig superfamily member can be selected from the group consisting of CD80, CD86, ICOS ligand (ICOSLG (also known as “CD275”), and combinations thereof. In certain embodiments, the co-stimulatory ligand is selected from the group consisting of 4-1BBL, OX40L, CD70, GITRL, CD40L, CD80, CD86, ICOSLG, and combinations thereof. In certain embodiments, the fusion polypeptide comprises an extracellular domain and a transmembrane domain of a co-stimulatory ligand that is CD80. In certain embodiments, the co- stimulatory ligand is human CD80. In certain embodiments, the CD80 comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD80 comprises or consists of an amino acid sequence that is a consecutive portion of the amino acid sequence of SEQ ID NO: 183. In certain embodiments, the extracellular domain of CD80 comprises or consists of an amino acid sequence that is at least about 80%, at least about 81%, at least about 82%, at leastACTIVE 509948342.297 072734.1771 PATENT about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to amino acids 1- 242 of SEQ ID NO: 183. In certain embodiments, the extracellular domain of CD80 comprises or consists of amino acids 1-242 of SEQ ID NO: 183 or a functional fragment thereof. A functional fragment can be a consecutive portion of amino acids 1-242 of SEQ ID NO: 183, which is at least about 50, at least about 75, at least about 100, at least about 125, at least about 150, at least about 175, or at least about 200, or at least about 220 amino acids in length. In certain embodiments, the functional fragment retains at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% of the primary function of the extracellular domain of CD80. Non-limiting examples of the primary functions of the extracellular domain of CD80 include binding to / interacting with CD28, binding to / interacting with CTLA-4, binding to / interacting with PD-L1, and contributing to CD80 homodimerization. In certain embodiments, an extracellular domain of CD80 comprises or consists of amino acids 1-242 of SEQ ID NO: 183. In certain embodiments, the transmembrane domain of CD80 comprises or consists of an amino acid sequence that is at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to amino acids 243-263 of SEQ ID NO: 183. In certain embodiments, the transmembrane domain of CD80 comprises or consists of amino acids 243-263 of SEQ ID NO: 183 or a fragment thereof. Such fragment can be at least about 5, at least about 10, at least about 15, or at least about 20 amino acids in length. In certain embodiments, the transmembrane domain of CD80 comprises or consists of amino acids 243-263 of SEQ ID NO: 183. Non-limiting examples of co-stimulatory molecules include CD28, 4-1BB, OX40, ICOS, DAP-10, CD27, CD40, NKG2D, CD2, and combinations thereof. In certain embodiments, the fusion polypeptide comprises an extracellular domain and a transmembrane domain of a co-stimulatory molecule that is 4-1BB. In certain embodiments, the co-stimulatory molecule is human 4-1BB. In certain embodiments, the 4-1BB comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 173 or a fragment thereof, and / or may optionally comprise up to one or up to two orACTIVE 509948342.298 072734.1771 PATENT up to three conservative amino acid substitutions. In certain embodiments, the 4-1BB comprises or consists of an amino acid sequence that is a consecutive portion of the amino acid sequence of SEQ ID NO: 173. In certain embodiments, the intracellular domain of 4-1BB comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% homologous or identical to amino acids 214-255 of SEQ ID NO: 173 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the intracellular domain of 4-1BB comprises or consists of amino acids 214-255 of SEQ ID NO: 173 or a functional fragment thereof. Such functional fragment can be a consecutive portion of amino acids 214-255 of SEQ ID NO: 173, which is at least about 20, at least about 25, at least about 30, at least about 35, or at least about 40 amino acids in length. In certain embodiments, the functional fragment of amino acids 214-255 of SEQ ID NO: 173 retains at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% of the primary functions of the intracellular domain of 4- 1BB. Non-limiting examples of the primary functions of the intracellular domain of 4-1BB include providing co-stimulatory signaling for the activation and proliferation of an immunoresponsive cell (e.g., a T cell), and interacting and activating downstream adaptors (e.g., TRAFs). In certain embodiments, the intracellular domain of 4-1BB comprises or consists of amino acids 214-255 of SEQ ID NO: 173. In certain embodiments, the co-stimulatory molecule is CD28. In certain embodiments, the co-stimulatory molecule is human CD28. In certain embodiments, the CD28 comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 156 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD28 comprises or consists of an amino acid sequence that is a consecutive portion of the amino acid sequence of SEQ ID NO: 156. In certain embodiments, the intracellular domain of CD28 comprises or consists of an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, at least about 100% homologous or identical to amino acids 180 to 219 of SEQ ID NO: 156 or a fragment thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the intracellular domain of CD28 comprises or consists of amino acids 180 to 219 of SEQ ID NO: 156 or a functional fragment thereof. A functional fragment of amino acids 180 to 219 of SEQ ID NO: 156 can be a consecutiveACTIVE 509948342.299 072734.1771 PATENT portion of amino acids 180 to 219 of SEQ ID NO: 156, which is at least about 20, at least about 25, at least about 30, or at least about 35 amino acids in length. In certain embodiments, such functional fragment retains at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% of the primary function of the intracellular domain of CD28. Non-limiting examples of the primary functions of the intracellular domain of CD28 include providing co-stimulatory signaling for the activation and proliferation of an immunoresponsive cell (e.g., a T cell), and interacting with protein adaptors (e.g., PI3K, GRB2, and LCK). In certain embodiments, the intracellular domain of CD28 comprises or consists of amino acids 180 to 219 of SEQ ID NO: 156. In certain embodiments, the fusion polypeptide comprises an intracellular domain of a second co-stimulatory molecule. In certain embodiments, the fusion polypeptide comprises an intracellular domain of a third co-stimulatory molecule. In certain embodiments, the fusion polypeptide comprises an intracellular domain of a fourth co-stimulatory molecule. In certain embodiments, the fusion polypeptide comprises an intracellular domain of a fifth co-stimulatory molecule. In certain embodiments, the first, second, third, fourth, and fifth co-stimulatory molecule can be the same or different among each other. In certain embodiments, the fusion polypeptide comprises an extracellular domain and a transmembrane domain of a co-stimulatory ligand that is CD80, and an intracellular domain of a co-stimulatory molecule that is 4-1BB. In certain embodiments, the fusion polypeptide comprises or consists of an amino acid sequence that is at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 185. In certain embodiments, the fusion polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 185. SEQ ID NO: 185 is provided below. MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEVATLSCGHNVSVEELAQTRIYWQKEK KMVLTMMSGDMNIWPEYKNRTIFDITNNLSIVILALRPSDEGTYECVVLKYEKDAFKREHLAEVTLSVKA DFPTPSISDFEIPTSNIRRIICSTSGGFPEPHLSWLENGEELNAINTTVSQDPETELYAVSSKLDFNMTT NHSFMCLIKYGHLRVNQTFNWNTTKQEHFPDNLLPSWAITLISVNGIFVICCLTYCFKRGRKKLLYIFKQ PFMRPVQTTQEEDGCSCRFPEEEEGGCEL [SEQ ID NO: 185] In certain embodiments, the fusion polypeptide comprises an extracellular domain and a transmembrane domain of a co-stimulatory ligand that is CD80, an intracellular domain of a firstACTIVE 509948342.2100 072734.1771 PATENT co-stimulatory molecule that is 4-1BB, and an intracellular domain of a second co-stimulatory molecule that is CD28. In certain embodiments, the fusion polypeptide comprises an amino acid sequence that is at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 72. In certain embodiments, the fusion polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 72. SEQ ID NO: 72 is provided below. MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEVATLSCGHNVSVEELAQTRIYWQKEK KMVLTMMSGDMNIWPEYKNRTIFDITNNLSIVILALRPSDEGTYECVVLKYEKDAFKREHLAEVTLSVKA DFPTPSISDFEIPTSNIRRIICSTSGGFPEPHLSWLENGEELNAINTTVSQDPETELYAVSSKLDFNMTT NHSFMCLIKYGHLRVNQTFNWNTTKQEHFPDNLLPSWAITLISVNGIFVICCLTYCFRSKRSRLLHSDYM NMTPRRPGPTRKHYQPYAPPRDFAAYRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL [SEQ ID NO: 186] Various modified fusion polypeptides are disclosed in International Patent Application No. PCT / US20 / 42753, which is incorporated by reference hereby in its entirety. 4.6. Exemplary Cells In certain embodiments, the presently disclosed cell is a T cell comprising (a) a HIT receptor that targets CD19 comprising a first antigen binding chain and a second antigen binding chain; and (b) an inhibitory polynucleotide. In certain embodiments, the first antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a heavy chain variable region (VH) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and (ii) a TRAC polypeptide. In certain embodiments, the second antigen binding chain of the HIT comprises (i) an antigen- binding fragment of a light chain variable region (VL) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and (b) a TRBC polypeptide. In certain embodiments, the inhibitory polynucleotide comprises an shRNA targeting TRAC. In certain embodiments, the shRNA comprises the nucleotide sequence set forth in SEQ ID NO: 110 or SEQ ID NO: 122. In certain embodiments, the HIT and the inhibitory polynucleotide are expressed by an exogenous nucleic acid integrated in the genome of the T cell. In certain embodiments, the HIT and the inhibitoryACTIVE 509948342.2101 072734.1771 PATENT polynucleotide are expressed by an exogenous nucleic acid that is not integrated in the TRAC locus or TRBC locus. In certain embodiments, the presently disclosed cell is a T cell comprising (a) a HIT receptor that targets CD19 comprising a first antigen binding chain and a second antigen binding chain; and (b) an inhibitory polynucleotide. In certain embodiments, the first antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a heavy chain variable region (VH) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and (ii) a TRAC polypeptide. In certain embodiments, the second antigen binding chain of the HIT comprises (i) an antigen- binding fragment of a light chain variable region (VL) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and (b) a TRBC polypeptide. In certain embodiments, the inhibitory polynucleotide comprises (i) an shRNA targeting TRAC, and (ii) an shRNA targeting TRBC. In certain embodiments, the shRNA targeting TRAC comprises the nucleotide sequence set forth in SEQ ID NO: 110 or SEQ ID NO: 122. In certain embodiments, the shRNA targeting TRBC comprises the nucleotide sequence set forth in SEQ ID NO: 131 or SEQ ID NO: 137. In certain embodiments, the HIT and the inhibitory polynucleotide are expressed by an exogenous nucleic acid integrated in the genome of the T cell. In certain embodiments, the HIT and the inhibitory polynucleotide are expressed by an exogenous nucleic acid that is not integrated in the TRAC locus or TRBC locus. In certain embodiments, the presently disclosed cell is a T cell comprising (a) a HIT receptor that targets CD19 comprising a first antigen binding chain and a second antigen binding chain; and (b) an inhibitory polynucleotide. In certain embodiments, the first antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a heavy chain variable region (VH) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and (ii) a TRAC polypeptide. In certain embodiments, the second antigen binding chain of the HIT comprises (i) an antigen- binding fragment of a light chain variable region (VL) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and (b) a TRBC polypeptide. In certain embodiments, the inhibitory polynucleotide comprises (i) an shRNA targeting TRAC, (ii) an shRNA targeting TRBC, and (iii)ACTIVE 509948342.2102 072734.1771 PATENT an shRNA targeting CD70. In certain embodiments, the shRNA targeting TRAC comprises the nucleotide sequence set forth in SEQ ID NO: 110 or SEQ ID NO: 122. In certain embodiments, the shRNA targeting TRBC comprises the nucleotide sequence set forth in SEQ ID NO: 131 or SEQ ID NO: 137. In certain embodiments, the shRNA targeting CD70 comprises the nucleotide sequence set forth in SEQ ID NO: 145 or SEQ ID NO: 150. In certain embodiments, the HIT and the inhibitory polynucleotide are expressed by an exogenous nucleic acid integrated in the genome of the T cell. In certain embodiments, the HIT and the inhibitory polynucleotide are expressed by an exogenous nucleic acid that is not integrated in the TRAC locus or TRBC locus. In certain embodiments, the presently disclosed cell is a T cell comprising (a) a HIT receptor that targets CD19 comprising a first antigen binding chain and a second antigen binding chain; (b) an inhibitory polynucleotide; and (c) a chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain that targets CD22, a transmembrane domain, and an intracellular domain. In certain embodiments, the first antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a heavy chain variable region (VH) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and (ii) a TRAC polypeptide. In certain embodiments, the second antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a light chain variable region (VL) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and (b) a TRBC polypeptide. In certain embodiments, the inhibitory polynucleotide comprises an shRNA targeting TRAC. In certain embodiments, the shRNA comprises the nucleotide sequence set forth in SEQ ID NO: 110 or SEQ ID NO: 122. In certain embodiments, the extracellular antigen- binding domain of the CAR comprises a VHcomprising a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 94, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide that comprises or consists of amino acids 153 to 179 of SEQ ID NO: 156. In certain embodiments, the intracellular domain of the CAR comprises a CD28 polypeptide and a modified CD3ζ polypeptide. In certain embodiments, the CD28 polypeptide comprises amino acids 180 to 220 of SEQ ID NO: 156, and the modified CD3ζ polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 169. In certainACTIVE 509948342.2103 072734.1771 PATENT embodiments, the HIT, the inhibitory polynucleotide, and the CAR are expressed by an exogenous nucleic acid integrated in the genome of the T cell. In certain embodiments, the HIT, the inhibitory polynucleotide, and the CAR are expressed by an exogenous nucleic acid that is not integrated in the TRAC locus or TRBC locus. In certain embodiments, the presently disclosed cell is a T cell comprising (a) a HIT receptor that targets CD19 comprising a first antigen binding chain and a second antigen binding chain; (b) an inhibitory polynucleotide; and (c) a chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain that targets CD22, a transmembrane domain, and an intracellular domain. In certain embodiments, the first antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a heavy chain variable region (VH) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and (ii) a TRAC polypeptide. In certain embodiments, the second antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a light chain variable region (VL) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and (b) a TRBC polypeptide. In certain embodiments, the inhibitory polynucleotide comprises (i) an shRNA targeting TRAC, and (ii) an shRNA targeting TRBC. In certain embodiments, the shRNA targeting TRAC comprises the nucleotide sequence set forth in SEQ ID NO: 110 or SEQ ID NO: 122. In certain embodiments, the shRNA targeting TRBC comprises the nucleotide sequence set forth in SEQ ID NO: 131 or SEQ ID NO: 137. In certain embodiments, the extracellular antigen- binding domain of the CAR comprises a VHcomprising a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 94, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide that comprises or consists of amino acids 153 to 179 of SEQ ID NO: 156. In certain embodiments, the intracellular domain of the CAR comprises a CD28 polypeptide and a modified CD3ζ polypeptide. In certain embodiments, the CD28 polypeptide comprises amino acids 180 to 220 of SEQ ID NO: 156, and the modified CD3ζ polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 169. In certain embodiments, the HIT, the inhibitory polynucleotide, and the CAR are expressed by an exogenous nucleic acid integrated in the genome of the T cell. In certain embodiments, the HIT, the inhibitoryACTIVE 509948342.2104 072734.1771 PATENT polynucleotide, and the CAR are expressed by an exogenous nucleic acid that is not integrated in the TRAC locus or TRBC locus. In certain embodiments, the presently disclosed cell is a T cell comprising (a) a HIT receptor that targets CD19 comprising a first antigen binding chain and a second antigen binding chain; (b) an inhibitory polynucleotide; and (c) a chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain that targets CD22, a transmembrane domain, and an intracellular domain. In certain embodiments, the first antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a heavy chain variable region (VH) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and (ii) a TRAC polypeptide. In certain embodiments, the second antigen binding chain of the HIT comprises (i) an antigen-binding fragment of a light chain variable region (VL) of an antibody comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, and (b) a TRBC polypeptide. In certain embodiments, the inhibitory polynucleotide comprises (i) an shRNA targeting TRAC, (ii) an shRNA targeting TRBC, and (iii) an shRNA targeting CD70. In certain embodiments, the shRNA targeting TRAC comprises the nucleotide sequence set forth in SEQ ID NO: 110 or SEQ ID NO: 122. In certain embodiments, the shRNA targeting TRBC comprises the nucleotide sequence set forth in SEQ ID NO: 131 or SEQ ID NO: 137. In certain embodiments, the shRNA targeting CD70 comprises the nucleotide sequence set forth in SEQ ID NO: 145 or SEQ ID NO: 150. In certain embodiments, the extracellular antigen-binding domain of the CAR comprises a VHcomprising a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 94, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide that comprises or consists of amino acids 153 to 179 of SEQ ID NO: 156. In certain embodiments, the intracellular domain of the CAR comprises a CD28 polypeptide and a modified CD3ζ polypeptide. In certain embodiments, the CD28 polypeptide comprises amino acids 180 to 220 of SEQ ID NO: 156, and the modified CD3ζ polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 169. In certain embodiments, the HIT, the inhibitory polynucleotide, and the CAR are expressed by an exogenous nucleic acid integrated in the genome of the T cell. In certain embodiments, the HIT, the inhibitoryACTIVE 509948342.2105 072734.1771 PATENT polynucleotide, and the CAR are expressed by an exogenous nucleic acid that is not integrated in the TRAC locus or TRBC locus. 5. Nucleic Acid Molecules and Vectors The presently disclosed subject matter provides nucleic acid molecules comprising a first polynucleotide encoding an antigen-recognizing receptor disclosed herein (e.g., disclosed in Section 2) and a second polynucleotide encoding an inhibitory polynucleotide disclosed herein (e.g., disclosed in Section 3). Additionally or alternatively, the presently disclosed subject matter provides nucleic acid compositions comprising a first polynucleotide encoding an antigen- recognizing receptor disclosed herein (e.g., disclosed in Section 2) and a second polynucleotide encoding an inhibitory polynucleotide disclosed herein (e.g., disclosed in Section 3). Also provided are cells comprising such nucleic acid molecules and nucleic acid compositions. In certain embodiments, the first polynucleotide further comprises a first promoter that is operably linked to the antigen-recognizing receptor. In certain embodiments, the second polynucleotide further comprises a second promoter that is operably linked to the inhibitory polynucleotide. In addition, the presently disclosed subject matter provides nucleic acid molecules comprising a first polynucleotide encoding a first antigen-recognizing receptor disclosed herein (e.g., disclosed in Section 2), a second polynucleotide encoding an inhibitory polynucleotide disclosed herein (e.g., disclosed in Section 3), and a third polynucleotide encoding a second antigen-recognizing receptor disclosed herein (e.g., disclosed in Section 4.1). Further, the presently disclosed subject matter provides nucleic acid compositions comprising a first polynucleotide encoding a first antigen-recognizing receptor disclosed herein (e.g., disclosed in Section 2), a second polynucleotide encoding an inhibitory polynucleotide disclosed herein (e.g., disclosed in Section 3), and a third polynucleotide encoding a second antigen-recognizing receptor disclosed herein (e.g., disclosed in Section 4.1). Also provided are cells comprising such nucleic acid molecules or nucleic acid compositions. In certain embodiments, the first polynucleotide further comprises a first promoter that is operably linked to the antigen-recognizing receptor. In certain embodiments, the second polynucleotide further comprises a second promoter that is operably linked to the inhibitory polynucleotide. In certain embodiments, the third polynucleotide further comprises a third promoter that is operably linked to the second antigen-recognizing receptor. In certain embodiments, one or both of the first promoter and second promoter are endogenous or exogenous. In certain embodiments, one of the first promoter, the second promoter, and the third promoter are endogenous or exogenous.ACTIVE 509948342.2106 072734.1771 PATENT In certain embodiments, the exogenous promoter is selected from an elongation factor (EF)-1 promoter, a CMV promoter, a SV40 promoter, a PGK promoter, and a metallothionein promoter. In certain embodiments, one or both of the first and second promoters are inducible promoters. In certain embodiment, the inducible promoter is selected from a NFAT transcriptional response element (TRE) promoter, a CD69 promoter, a CD25 promoter, and an IL- 2 promoter. In certain embodiments, the first polynucleotide and the second polynucleotide are integrated at a locus within the genome of the T cell, e.g., a TRAC locus, a TRBC locus, a TRDC locus, or a TRGC locus. In certain embodiments, the first polynucleotide, the second polynucleotide, and the third polynucleotide are integrated at a locus within the genome of the T cell. In certain embodiments, the locus is a TRAC locus. In certain embodiments, the expression of the antigen-recognizing receptors and the inhibitory polynucleotides are under the control of an endogenous promoter. Non-limiting examples of endogenous promoters include an endogenous TRAC promoter, an endogenous TRBC promoter, an endogenous TRDC promoter, and an endogenous TRGC promoter. In certain embodiments, the endogenous promoter is an endogenous TRAC promoter. In certain embodiments, the nucleic acid molecule or the nucleic acid composition is a vector. In certain embodiments, the vector is a retroviral vector (e.g., a gamma­retroviral vector or a lentiviral vector). In certain embodiments, the vector is viral vectors selected from the group consisting of adenoviral vectors, adena-associated viral vectors, vaccinia viruses, bovine papilloma viruses, and herpes viruses (e.g., such as Epstein-Barr Virus). In certain embodiments, the vector is a retroviral vector. Retroviral vectors encompassed by the presently disclosed subject matter include, for example and without any limitation, murine leukemia virus (MLV), human T-cell leukemia virus (HTLV), mouse mammary tumour virus (MMTV), Rous sarcoma virus (RSV), Fujinami sarcoma virus (FuSV), Moloney murine leukemia virus (Mo MLV), FBR murine osteosarcoma virus (FBR MSV), Moloney murine sarcoma virus (Mo-MSV), Abelson murine leukemia virus (A-MLV), Avian myelocytomatosis virus-29 (MC29) and Avian erythroblastosis virus (AEV). In certain embodiments, the retroviral vector includes an intron. In certain embodiments, the intron of the retroviral vector includes an inhibitory polynucleotide disclosed herein. In certain embodiments, the vector is a lentiviral vector. Lentiviral vectors encompassed by the presently disclosed subject matter include vectors selected from or derived from, for example and without any limitation, human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), visna / maedi virus (VMV), caprine arthritis-encephalitis virus (CAEV), equine infectious anaemia virus (EIAV), feline immunodeficiency virus (FIV), MaediACTIVE 509948342.2107 072734.1771 PATENT visna virus (MVV), or bovine immunodeficiency virus (BIV). Additional details on lentiviruses encompassed by the presently disclosed subject matter can be found in Coffin et al. (1997) “Retroviruses” Cold Spring Harbor Laboratory Press Eds: JM Coffin, SM Hughes, HE Varmus pp 758-763). In certain embodiments, the lentiviral vector includes an intron. In certain embodiments, the intron of the lentiviral vector includes an inhibitory polynucleotide disclosed herein. In certain embodiments, the vector is an adenoviral vector. Adenoviral vectors encompassed by the presently disclosed subject matter include, for example and without any limitation, adenovirus derived from Ad2, Ad5, Ad12, and Ad40. In certain embodiments, the adenoviral vector includes an intron. In certain embodiments, the intron of the adenoviral vector includes an inhibitory polynucleotide disclosed herein. In certain embodiments, the vector is an adeno-associated viral vector (AAV). AAVs encompassed by the presently disclosed subject matter include, for example and without any limitation, vectors derived from an adeno-associated virus serotype, including without limitation, AAV-1 , AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7 and AAV-8. In certain embodiments, the AAV includes an intron. In certain embodiments, the intron of the AAV includes an inhibitory polynucleotide disclosed herein.Additionally, the nucleic acid compositions can be administered to subjects or and / delivered into cells by art-known methods or as described herein. Genetic modification of a cell (e.g., a T cell or a NK cell) can be accomplished by transducing a substantially homogeneous cell composition with a recombinant DNA construct. In certain embodiments, a retroviral vector (either gamma­retroviral or lentiviral) is employed for the introduction of the nucleic acid compositions into the cell. For example, the first polynucleotide and the second polynucleotide can be cloned into a retroviral vector and expression can be driven from its endogenous promoter, from the retroviral long terminal repeat, or from a promoter specific for a target cell type of interest. Non-viral vectors may be used as well. The first polynucleotide and the second polynucleotide can be constructed in a single, multicistronic expression cassette, in multiple expression cassettes of a single vector, or in multiple vectors. Additionally or alternatively, the first polynucleotide, the second polynucleotide, and the third polynucleotide can be constructed in a single, multicistronic expression cassette, in multiple expression cassettes of a single vector, or in multiple vectors. Examples of elements that create polycistronic expression cassette include, but is not limited to, various viral and non-viral Internal Ribosome Entry Sites (IRES, e.g., FGF-1 IRES, FGF-2 IRES, VEGF IRES, IGF-II IRES, NF-κB IRES, RUNX1 IRES, p53 IRES, hepatitis A IRES, hepatitis C IRES, pestivirus IRES, aphthovirus IRES, picornavirus IRES, poliovirus IRES andACTIVE 509948342.2108 072734.1771 PATENT encephalomyocarditis virus IRES) and cleavable linkers (e.g., 2A peptides , e.g., P2A, T2A, E2A and F2A peptides). In certain embodiments, the nucleic acid molecules or the nucleic acid compositions comprise a cleavable linker. In certain embodiments, the cleavable linker is a P2A peptide. In certain embodiments, the P2A peptide comprises the amino acid sequence set forth in SEQ ID NO: 187. An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 187 is set forth in SEQ ID NO: 188. SEQ ID NO: 187 and SEQ ID NO: 188 are provided below. GSGATNFSLLKQAGDVEENPGP [SEQ ID NO: 187] GGCTCTGGCGCTACCAATTTTTCCCTCCTCAAACAGGCTGGAGATGTCGAAGAGAACCCCGGACCT [SEQ ID NO: 188] As illustrated in Figures 4A-4H, vectors encompassed by the presently disclosed subject matter include an intron including a splice donor sequence at its 5’ end and a splice acceptor sequence at its 3’ end. In certain embodiments, the intron includes the inhibitory polynucleotides disclosed herein (e.g., disclosed in Section 3). In certain embodiments, the vectors encompassed by the presently disclosed subject matter are based on a SFG vector. In certain embodiments, the vector comprises a splice donor sequence in the gag region and a splice acceptor sequence in the pol region. Additional information of vectors encompassed by the presently disclosed subject matter can be found in International Patent Publication No. WO 2007 / 044627, which is incorporated by reference in its entirety. Combinations of retroviral vector and an appropriate packaging line are also suitable, where the capsid proteins will be functional for infecting human cells. Various amphotropic virus- producing cell lines are known, including, but not limited to, PA12 (Miller, et al. (1985) Mol. Cell. Biol. 5:431-437); PA317 (Miller, et al. (1986) Mol. Cell. Biol. 6:2895-2902); and CRIP (Danos, et al. (1988) Proc. Natl. Acad. Sci. USA 85:6460-6464). Non-amphotropic particles are suitable too, e.g., particles pseudotyped with VSVG, RD114 or GALV envelope and any other known in the art. Possible methods of transduction also include direct co-culture of the cells with producer cells, e.g., by the method of Bregni, et al. (1992) Blood 80:1418-1422, or culturing with viral supernatant alone or concentrated vector stocks with or without appropriate growth factors and polycations, e.g., by the method of Xu, et al. (1994) Exp. Hemat.22:223-230; and Hughes, et al. (1992) J. Clin. Invest.89:1817. Other transducing viral vectors can be used to modify a cell. In certain embodiments, the chosen vector exhibits high efficiency of infection and stable integration and expression (see, e.g., Cayouette et al., Human Gene Therapy 8:423-430, 1997; Kido et al., Current Eye ResearchACTIVE 509948342.2109 072734.1771 PATENT 15:833-844, 1996; Bloomer et al., Journal of Virology 71:6641-6649, 1997; Naldini et al., Science 272:263-267, 1996; and Miyoshi et al., Proc. Natl. Acad. Sci. U.S.A.94:10319, 1997). Other viral vectors that can be used include, for example, adenoviral, lentiviral, and adena-associated viral vectors, vaccinia virus, a bovine papilloma virus, or a herpes virus, such as Epstein-Barr Virus (also see, for example, the vectors of Miller, Human Gene Therapy 15-14, 1990; Friedman, Science 244:1275-1281, 1989; Eglitis et al., BioTechniques 6:608-614, 1988; Tolstoshev et al., Current Opinion in Biotechnology 1:55-61, 1990; Sharp, The Lancet 337:1277-1278, 1991; Cornetta et al., Nucleic Acid Research and Molecular Biology 36:311-322, 1987; Anderson, Science 226:401-409, 1984; Moen, Blood Cells 17:407-416, 1991; Miller et al., Biotechnology 7:980-990, 1989; LeGal La Salle et al., Science 259:988-990, 1993; and Johnson, Chest 107:77S- 83S, 1995). Retroviral vectors are particularly well developed and have been used in clinical settings (Rosenberg et al., N. Engl. J. Med 323:370, 1990; Anderson et al., U.S. Pat. No. 5,399,346). Non-viral approaches can also be employed for genetic modification of a cell. For example, a nucleic acid molecule can be delivered into a cell by administering the nucleic acid in the presence of lipofection (Feigner et al., Proc. Natl. Acad. Sci. U.S.A. 84:7413, 1987; Ono et al., Neuroscience Letters 17:259, 1990; Brigham et al., Am. J. Med. Sci. 298:278, 1989; Staubinger et al., Methods in Enzymology 101:512, 1983), asialoorosomucoid-polylysine conjugation (Wu et al., Journal of Biological Chemistry 263:14621, 1988; Wu et al., Journal of Biological Chemistry 264:16985, 1989), or by micro-injection under surgical conditions (Wolff et al., Science 247:1465, 1990). Other non-viral means for gene transfer include transfection in vitro using calcium phosphate, DEAE dextran, electroporation, and protoplast fusion. Liposomes can also be potentially beneficial for delivery of DNA into a cell. Transplantation of normal genes into the affected tissues of a subject can also be accomplished by transferring a normal nucleic acid into a cultivatable cell type ex vivo (e.g., an autologous or heterologous primary cell or progeny thereof), after which the cell (or its descendants) are injected into a targeted tissue or are injected systemically. Transient expression may be obtained by RNA electroporation. In certain embodiments, the presently disclosed nucleic acid molecules or nucleic acid compositions (e.g., vectors) can be integrated by a method comprising homologous recombination, a Zinc finger nuclease, a meganuclease, a Transcription activator-like effector nuclease (TALEN), a Clustered regularly-interspaced short palindromic repeats (CRISPR) system, or a combination thereof. Clustered regularly-interspaced short palindromic repeats (CRISPR) system is a genome editing tool discovered in prokaryotic cells. When utilized for genome editing, the system includes Cas9 (a protein able to modify DNA utilizing crRNA as its guide), CRISPR RNA (crRNA,ACTIVE 509948342.2110 072734.1771 PATENT contains the RNA used by Cas9 to guide it to the correct section of host DNA along with a region that binds to tracrRNA (generally in a hairpin loop form) forming an active complex with Cas9), trans-activating crRNA (tracrRNA, binds to crRNA and forms an active complex with Cas9), and an optional section of DNA repair template (DNA that guides the cellular repair process allowing insertion of a specific DNA sequence). CRISPR / Cas9 often employs a plasmid to transfect the target cells. The crRNA needs to be designed for each application as this is the sequence that Cas9 uses to identify and directly bind to the target DNA in a cell. The repair template carrying CAR expression cassette need also be designed for each application, as it must overlap with the sequences on either side of the cut and code for the insertion sequence. Multiple crRNA's and the tracrRNA can be packaged together to form a single-guide RNA (sgRNA). This sgRNA can be joined together with the Cas9 gene and made into a plasmid in order to be transfected into cells. In certain embodiments, the CRISPR system comprises base editors. In certain embodiments, the CRISPR system comprises transposases / recombinases. In certain embodiments, the CRISPR system comprises prime editors. In certain embodiments, the CRISPR system comprises an epigenetic modulator. In certain embodiments, the CRISPR system comprises is a CRISPRoff system. Additional details on the CRISPR systems of the presentl...

Claims

1. 072734.1771 PATENT WHAT IS CLAIMED IS:

1. A cell comprising:(a) a polynucleotide encoding an antigen-recognizing receptor, wherein the antigen- recognizing receptor is a HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and (b) an inhibitory polynucleotide targeting one or more genes.

2. The cell of claim 1, wherein the inhibitory polynucleotide is positioned between a splicedonor sequence and a splice acceptor sequence.

3. The cell of claim 1, wherein the polynucleotide encoding the antigen-recognizingreceptor and the inhibitory polynucleotide are operably linked.

4. The cell of claim 3, wherein the polynucleotide encoding the antigen-recognizingreceptor and the inhibitory polynucleotide are operably linked to a promoter.

5. The cell of claim 4 comprising, from 5’ end to 3’ end, the promoter, the intron, and thepolynucleotide encoding the antigen-recognizing receptor.

6. The cell of claim 5, wherein the promoter is a constitutive promoter or an induciblepromoter.

7. The cell of claim 6, wherein the inhibitory polynucleotide comprises one or more shorthairpin RNA (shRNA), small interfering RNA (siRNA), double stranded RNA (dsRNA), antisense oligonucleotide, or a combination thereof.

8. The cell of claim 7, wherein the inhibitory polynucleotide comprises one or moreshRNAs.

9. The cell of claim 8, wherein the one or more genes are selected from TRAC, TRBC1,TRBC2, CD70, or a combination thereof.

10. The cell of claim 9, wherein the one or more genes are TRAC, TRBC1, TRBC2, andCD70.

11. The cell of claim 9, wherein the one or more genes are TRAC, TRBC1, and TRBC2.

12. The cell of claim 9, wherein the inhibitory polynucleotide targeting TRAC comprises thenucleotide sequence set forth in SEQ ID NO.105, SEQ ID NO.106, SEQ ID NO.107, SEQ ID NO.108, SEQ ID NO.109, SEQ ID NO.110, SEQ ID NO.111, SEQ ID NO.112, SEQ ID NO. 113, SEQ ID NO.114, SEQ ID NO.115, or SEQ ID NO.116.

13. The cell of claim 12, wherein the inhibitory polynucleotide targeting TRAC comprisesthe nucleotide sequence set forth in SEQ ID NO.110.

14. The cell of claim 9, wherein the inhibitory polynucleotide targeting TRAC comprises thenucleotide sequence set forth in SEQ ID NO.117, SEQ ID NO.118, SEQ ID NO.119, SEQ IDACTIVE 509948342.2159072734.1771 PATENT NO.120, SEQ ID NO.121, SEQ ID NO.122, SEQ ID NO.123, SEQ ID NO.124, SEQ ID NO. 125, SEQ ID NO.126, SEQ ID NO.127, or SEQ ID NO.128.

15. The cell of claim 14, wherein the inhibitory polynucleotide targeting TRAC comprisesthe nucleotide sequence set forth in SEQ ID NO.122.

16. The cell of claim 9, wherein the inhibitory polynucleotide targeting TRBC1 and TRBC2comprises the nucleotide sequence set forth in SEQ ID NO.131, SEQ ID NO.132, SEQ ID NO. 133, SEQ ID NO.134, SEQ ID NO.135, or SEQ ID NO.136.

17. The cell of claim 16, wherein the inhibitory polynucleotide targeting TRBC1 andTRBC2 comprises the nucleotide sequence set forth in SEQ ID NO.131.

18. The cell of claim 9, wherein the inhibitory polynucleotide targeting TRBC1 and TRBC2comprises the nucleotide sequence set forth in SEQ ID NO.137, SEQ ID NO.138, SEQ ID NO. 139, SEQ ID NO.140, SEQ ID NO.141, or SEQ ID NO.142.

19. The cell of claim 18, wherein the inhibitory polynucleotide targeting TRBC1 andTRBC2 comprises the nucleotide sequence set forth in SEQ ID NO.137.

20. The cell of claim 9, wherein the inhibitory polynucleotide targeting CD70 comprises thenucleotide sequence set forth in SEQ ID NO.144, SEQ ID NO.145, SEQ ID NO.146, SEQ ID NO.147, or SEQ ID NO.148.

21. The cell of claim 20, wherein the inhibitory polynucleotide targeting CD70 comprisesthe nucleotide sequence set forth in SEQ ID NO.145.

22. The cell of claim 9, wherein the inhibitory polynucleotide targeting CD70 comprises thenucleotide sequence set forth in SEQ ID NO.149, SEQ ID NO.150, SEQ ID NO.151, SEQ ID NO.152, or SEQ ID NO.153.

23. The cell of claim 22, wherein the inhibitory polynucleotide targeting CD70 comprisesthe nucleotide sequence set forth in SEQ ID NO.150.

24. The cell of claim 1, wherein the inhibitory polynucleotide comprises a microRNA.

25. The cell of claim 1, wherein the polynucleotide encoding the antigen-recognizingreceptor and the inhibitory polynucleotide are integrated in a genome of the cell.

26. The cell of claim 1, wherein the polynucleotide encoding the antigen-recognizingreceptor and the inhibitory polynucleotide are not integrated in a TRAC locus and / or a TRBC locus.

27. The cell of claim 1, wherein the antigen-recognizing receptor is a HIT receptor.

28. The cell of claim 27, wherein(a) the HIT receptor comprises a first antigen-binding chain comprising an antigen- binding fragment of a heavy chain variable region (VH) of an antibody and a TRAC polypeptide and a second antigen-binding chain comprising an antigen-binding fragment of a light chainACTIVE 509948342.2160072734.1771 PATENT variable region (VL) of an antibody and a TRBC polypeptide, wherein the HIT receptor binds to an antigen in an HLA-independent manner; or (b) the HIT receptor comprises a first antigen-binding chain comprising an antigen- binding fragment of a heavy chain variable region (VH) of an antibody and a TRBC polypeptide and a second antigen-binding chain comprising an antigen-binding fragment of a light chain variable region (VL) of an antibody and a TRAC polypeptide, wherein the HIT receptor binds to an antigen in an HLA-independent manner.

29. The cell of claim 28, wherein(a) the TRAC polypeptide comprises an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to the amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 11; and (b) the TRBC polypeptide comprises an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 19.

30. The cell of claim 28, wherein(a) the TRAC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 11; and (b) the TRBC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 19.

31. The cell of claim 28, wherein(a) the TRAC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7; (b) the TRBC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14.

32. The cell of claim 27, wherein the HIT receptor binds to an antigen with a dissociationconstant (KD) of about 1 × 10-8M or less.

33. The cell of claim 32, wherein the HIT receptor binds to the antigen with a dissociationconstant (KD) of about 5 × 10-9M or less.

34. The cell of claim 27, wherein the HIT receptor is capable of associating with a CD3ζpolypeptide.

35. The cell of claim 34, wherein the HIT receptor, upon binding to an antigen, is capable ofactivating the CD3ζ polypeptide.ACTIVE 509948342.2161072734.1771 PATENT36. The cell of claim 35, wherein the activation of the CD3ζ polypeptide is capable ofactivating the cell.

37. The cell of claim 27, further comprising a polynucleotide encoding a chimeric antigen-recognizing receptor (CAR).

38. The cell of claim 37, wherein the polynucleotide encoding the CAR is integrated in thegenome of the cell.

39. The cell of claim 38, wherein the polynucleotide encoding the CAR is not integrated in aTRAC locus and / or a TRBC locus.

40. The cell of claim 37, wherein the polynucleotide encoding the HIT receptor, theinhibitory polynucleotide, and the polynucleotide encoding the CAR are operably linked.

41. The cell of claim 37, wherein the CAR comprises an extracellular antigen-bindingdomain that binds to a second antigen, and an intracellular signaling domain that is capable of delivering an activation signal to the cell.

42. The cell of claim 41, wherein the intracellular signaling domain of the CAR comprises aCD3ζ polypeptide.

43. The cell of claim 42, wherein the CD3ζ polypeptide is a native CD3ζ polypeptide or amodified CD3ζ polypeptide.

44. The cell of claim 43, wherein the modified CD3ζ polypeptide comprises a nativeITAM1, an ITAM2 variant consisting of two loss-of-function mutations, and an ITAM3 variant consisting of two loss-of-function mutations.

45. The cell of claim 44, wherein the modified CD3ζ polypeptide comprises the amino acidsequence set forth in SEQ ID NO: 169.

46. The cell of claim 41, wherein the intracellular signaling domain of the CAR furthercomprises at least one costimulatory signaling region.

47. The cell of claim 46, wherein the at least one costimulatory signaling region comprises atleast an intracellular domain of a co-stimulatory molecule or a portion thereof.

48. The cell of claim 47, wherein the costimulatory molecule is selected from the groupconsisting of CD28, 4-1BB, OX40, CD27, CD40, CD154, CD97, CD11a / CD18, ICOS, DAP-10, CD2, CD150, CD226, and NKG2D.

49. The cell of claim 48, wherein the CAR comprises a transmembrane domain.

50. The cell of claim 1, wherein the cell is a cell of the lymphoid lineage or a cell of themyeloid lineage.

51. The cell of claim 50, wherein the cell of the lymphoid lineage is selected from the groupconsisting of a T cell, a B cell, a Natural Killer (NK) cell, and a dendritic cell.

52. The cell of claim 1, wherein the cell is a T cell.ACTIVE 509948342.2162072734.1771 PATENT53. The cell of claim 52, wherein the T cell is derived from an induced pluripotent stem cell.

54. The cell of claim 53, wherein the T cell is a CD8+ T cell.

55. The cell of claim 54, wherein the CD8+ T cell is CD4 independent.

56. The cell of claim 52, wherein the T cell is selected from the group consisting of acytotoxic T lymphocyte (CTL), a γδ T cell, a tumor-infiltrating lymphocyte (TIL), a regulatory T cell, and a Natural Killer T (NKT) cell.

57. The cell of claim 52, wherein the T cell is CD62L+, CD45RA+, or CD45RA+ CD62L+.

58. The cell of claim 1, wherein the antigen-recognizing receptor binds to a tumor antigen ora pathogen antigen.

59. The cell of claim 58, wherein the tumor antigen is selected from the group consisting ofCD19, CD70, IL1RAP, ABCG2, AChR, ACKR6, ADAMTS13, ADGRE2, ADGRE2 (EMR2), ADORA3, ADRA1D, AGER, ALS2, an antigen of a cytomegalovirus (CMV) infected cell (e.g. a cell surface antigen), ANO9, AQP2, ASIC3, ASPRV1, ATP6V0A4, B3GNT4, B7-H3, BCMA, BEST4, C3orf35, CADM3, CAIX, CAPN3, CCDC155, CCR1, CD10, CD117, CD123, CD133, CD135 (FLT3), CD138, CD20, CD22, CD244 (2B4), CD25, CD26 , CD30, CD300LF, CD312, CD32, CD321, CD33, CD34, CD36, CD38, CD41, CD44, CD44V6, CD47, CD49f, CD56, CD7, CD71, CD74, CD8, CD82, CD96, CD98, CD99, CDH13, CDHR1, CEA, CEACAM6, CHST3, CLEC12A, CLEC1A, CLL1, CNIH2, COL15A1, COLEC12, CPM, CR1, CX3CR1, CXCR4, CYP4F11, DAGLB, DARC, DFNB31, DGKI, EGF1R, EGFR-VIII, EGP-2, EGP-40, ELOVL6, EMB, EMC10, EMR2, ENG, EpCAM, EphA2, EPHA4, ERBB, ERBB2, Erb-B3, Erb-B4, E-selectin, EXOC3L4, EXTL3, FAM186B, FBP, FCGR1A, FCRL5, FKBP1B, FLRT1, folate receptor-α, FOLR2, FRMD5, GABRB2, GAS2, GD2, GD3, GDPD3, GNA14, GNAZ, GPC2, GPC3, GPR153, GPR56, GYPA, HEPHL1, HER-2, hERT, HILPDA, HLA-DR, HOOK1, hTERT, HTR2A, ICAM1, IGFBP3, IL10RB, IL20RB, IL23R, ILDR1, Interleukin-13 receptor subunit alpha-2 (IL-13Rα2), ITFG3, ITGA4, ITGA5, ITGA8, ITGAX, ITGB5, ITGB8, JAM3, KCND1, KCNJ5, KCNK13, KCNN4, KCNV2, KDR, KIF19, KIF26B, κ-light chain, L1CAM, LAX1, LEPR, Lewis Y (CD174), Lewis Y (LeY), LILRA2, LILRA6, LILRB2, LILRB3, LILRB4, LOXL4, LPAR2, LRRC37A3, LRRC8E, LRRN2, LRRTM2, LTB4R, MAGE-A1, MAGEA3, MANSC1, MART1,GP100, MBOAT1, MBOAT7, melanoma antigen family A, Mesothelin (MSLN), MFAP3L, MMP25, MRP1, MT-ND1, Mucin 1 (MUC1), Mucin 16 (MUC16), MYADM, MYADML2, NGFR, NKCS1, NKG2D ligands, NLGN3, NPAS2, NY- ESO-1, oncofetal antigen (h5T4), OTOA, P2RY13, p53, PDE3A, PEAR1, PIEZO1, PLXNA4, PLXNC1, PNPLA3, PPFIA4, PPP2R5B, PRAME, PRAME, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), Proteinase3 (PR1), PSD2, PTPRJ, RDH16, receptor tyrosine-protein kinase Erb-B2, RHBDL3, RNF173, RNF183, ROR1, RYR2, SCIN,ACTIVE 509948342.2163072734.1771 PATENT SCN11A, SCN2A, SCNN1D, SEC31B, SEMA4A, SH3PXD2A, SIGLEC6, SIGLEC11, SIRPB1, SLC16A6, SLC19A1, SLC22A5, SLC25A36, SLC25A41, SLC30A1, SLC34A3, SLC43A3, SLC44A1, SLC44A3, SLC45A3, SLC6A16, SLC6A6, SLC8A3, SLC9A1, SLCO2B1, SPAG17, STC1, STON2, SUN3, Survivin, SUSD2, SYNC, TACSTD2, TAS1R3, TEX29, TFR2, TIM-3 (HAVCR2), TLR2, TMEFF2, TMEM145, TMEM27, TMEM40, TMEM59L, TMEM89, TMPRSS5, TNFRSF14, TNFRSF1B, TRIM55, TSPEAR, TTYH3, tumor-associated glycoprotein 72 (TAG-72), Tyrosinase, vascular endothelial growth factor R2 (VEGF-R2), VLA-4, Wilms tumor protein (WT-1), WNT4, WT1, and ZDHHC11.

60. The cell of claim 1, wherein the cell comprises a HIT receptor that binds to CD19 andcomprises a first antigen binding chain comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a second antigen binding chain comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51.

61. The cell of claim 60, wherein the cell further comprises a CAR that binds to CD22 andcomprises an extracellular antigen-binding domain comprising a VH comprising a CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 94, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 99.

62. The cell of claim 1, further comprising a polynucleotide encoding a chimeric co-stimulating receptor (CCR).

63. The cell of claim 1, further comprising a polynucleotide encoding at least one exogenouscostimulatory ligand.

64. The cell of claim 1, further comprising a polynucleotide encoding a fusion polypeptidecomprising: a) an extracellular domain and a transmembrane domain of a co-stimulatory ligand, and b) an intracellular domain of a first co-stimulatory molecule.

65. The cell of claim 64, wherein the co-stimulatory ligand is selected from the groupconsisting of a tumor necrosis factor (TNF) family member, an immunoglobulin (Ig) superfamily member, and combinations thereof.

66. The cell of claim 64, wherein (a) the TNF family member is selected from the groupconsisting of 4-1BBL, OX40L, CD70, GITRL, CD40L, and combinations thereof, and / or (b) theACTIVE 509948342.2164072734.1771 PATENT Ig superfamily member is selected from the group consisting of CD80, CD86, ICOSLG, and combinations thereof.

67. The cell of claim 64, wherein the co-stimulatory ligand is CD80.

68. The cell of claim 64, wherein the first co-stimulatory molecule is selected from the groupconsisting of CD28, 4-1BB, OX40, ICOS, DAP-10, CD27, CD40, NKG2D, CD2, and combinations thereof.

69. The cell of claim 68, wherein the first co-stimulatory molecule is 4-1BB.

70. The cell of claim 64, wherein the co-stimulatory ligand is CD80 and the first co-stimulatory molecule is 4-1BB.

71. The cell of claim 70, wherein the fusion polypeptide comprises the amino acid sequenceset forth in SEQ ID NO: 185.

72. The cell of claim 64, wherein the fusion polypeptide further comprises an intracellulardomain of a second co-stimulatory molecule.

73. The cell of claim 72, wherein the second co-stimulatory molecule is selected from thegroup consisting of CD28, 4-1BB, OX40, ICOS, DAP-10, CD27, CD40, NKG2D, CD2, and combinations thereof.

74. The cell of claim 73, wherein the second co-stimulatory molecule is CD28.

75. The cell of claim 73, wherein the co-stimulatory ligand is CD80, the first co-stimulatorymolecule is 4-1BB, and the second co-stimulatory molecule is CD28.

76. The cell of claim 75, wherein the fusion polypeptide comprises the amino acid sequenceset forth in SEQ ID NO: 186.

77. The cell of claim 1, wherein the cell is autologous or allogeneic.

78. A cell comprising:(a) a polynucleotide encoding an antigen-recognizing receptor that binds a tumor antigen, wherein the antigen-recognizing receptor is an HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and (b) an inhibitory polynucleotide targeting TRAC.

79. The cell of claim 78, wherein the tumor antigen is selected from the group consisting ofCD19, IL1RAP, ABCG2, AChR, ACKR6, ADAMTS13, ADGRE2, ADGRE2 (EMR2), ADORA3, ADRA1D, AGER, ALS2, an antigen of a cytomegalovirus (CMV) infected cell (e.g. a cell surface antigen), ANO9, AQP2, ASIC3, ASPRV1, ATP6V0A4, B3GNT4, B7-H3, BCMA, BEST4, C3orf35, CADM3, CAIX, CAPN3, CCDC155, CCR1, CD10, CD117, CD123, CD133, CD135 (FLT3), CD138, CD20, CD22, CD244 (2B4), CD25, CD26 , CD30, CD300LF, CD312, CD32, CD321, CD33, CD34, CD36, CD38, CD41, CD44, CD44V6, CD47, CD49f, CD56, CD7, CD71, CD74, CD8, CD82, CD96, CD98, CD99, CDH13, CDHR1, CEA,ACTIVE 509948342.2165072734.1771 PATENT CEACAM6, CHST3, CLEC12A, CLEC1A, CLL1, CNIH2, COL15A1, COLEC12, CPM, CR1, CX3CR1, CXCR4, CYP4F11, DAGLB, DARC, DFNB31, DGKI, EGF1R, EGFR-VIII, EGP-2, EGP-40, ELOVL6, EMB, EMC10, EMR2, ENG, EpCAM, EphA2, EPHA4, ERBB, ERBB2, Erb-B3, Erb-B4, E-selectin, EXOC3L4, EXTL3, FAM186B, FBP, FCGR1A, FCRL5, FKBP1B, FLRT1, folate receptor-α, FOLR2, FRMD5, GABRB2, GAS2, GD2, GD3, GDPD3, GNA14, GNAZ, GPC2, GPC3, GPR153, GPR56, GYPA, HEPHL1, HER-2, hERT, HILPDA, HLA-DR, HOOK1, hTERT, HTR2A, ICAM1, IGFBP3, IL10RB, IL20RB, IL23R, ILDR1, Interleukin-13 receptor subunit alpha-2 (IL-13Rα2), ITFG3, ITGA4, ITGA5, ITGA8, ITGAX, ITGB5, ITGB8, JAM3, KCND1, KCNJ5, KCNK13, KCNN4, KCNV2, KDR, KIF19, KIF26B, κ-light chain, L1CAM, LAX1, LEPR, Lewis Y (CD174), Lewis Y (LeY), LILRA2, LILRA6, LILRB2, LILRB3, LILRB4, LOXL4, LPAR2, LRRC37A3, LRRC8E, LRRN2, LRRTM2, LTB4R, MAGE-A1, MAGEA3, MANSC1, MART1,GP100, MBOAT1, MBOAT7, melanoma antigen family A, Mesothelin (MSLN), MFAP3L, MMP25, MRP1, MT-ND1, Mucin 1 (MUC1), Mucin 16 (MUC16), MYADM, MYADML2, NGFR, NKCS1, NKG2D ligands, NLGN3, NPAS2, NY- ESO-1, oncofetal antigen (h5T4), OTOA, P2RY13, p53, PDE3A, PEAR1, PIEZO1, PLXNA4, PLXNC1, PNPLA3, PPFIA4, PPP2R5B, PRAME, PRAME, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), Proteinase3 (PR1), PSD2, PTPRJ, RDH16, receptor tyrosine-protein kinase Erb-B2, RHBDL3, RNF173, RNF183, ROR1, RYR2, SCIN, SCN11A, SCN2A, SCNN1D, SEC31B, SEMA4A, SH3PXD2A, SIGLEC6, SIGLEC11, SIRPB1, SLC16A6, SLC19A1, SLC22A5, SLC25A36, SLC25A41, SLC30A1, SLC34A3, SLC43A3, SLC44A1, SLC44A3, SLC45A3, SLC6A16, SLC6A6, SLC8A3, SLC9A1, SLCO2B1, SPAG17, STC1, STON2, SUN3, Survivin, SUSD2, SYNC, TACSTD2, TAS1R3, TEX29, TFR2, TIM-3 (HAVCR2), TLR2, TMEFF2, TMEM145, TMEM27, TMEM40, TMEM59L, TMEM89, TMPRSS5, TNFRSF14, TNFRSF1B, TRIM55, TSPEAR, TTYH3, tumor-associated glycoprotein 72 (TAG-72), Tyrosinase, vascular endothelial growth factor R2 (VEGF-R2), VLA-4, Wilms tumor protein (WT-1), WNT4, WT1, and ZDHHC11.

80. A cell comprising:(a) a polynucleotide encoding an antigen-recognizing receptor that binds CD70, wherein the antigen-recognizing receptor is an HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and (b) an inhibitory polynucleotide targeting CD70.

81. The cell of claim 80, wherein the HIT receptor comprises a first antigen binding chaincomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66, and a second antigen binding chainACTIVE 509948342.2166072734.1771 PATENT comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 67, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 68, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 69.

82. A cell comprising:(a) a polynucleotide encoding an antigen-recognizing receptor that binds CD70, wherein the antigen-recognizing receptor is an HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and (b) an inhibitory polynucleotide targeting TRAC and CD70.

83. The cell of claim 82, wherein the HIT receptor comprises a first antigen binding chaincomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66, and a second antigen binding chain comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 67, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 68, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 69.

84. The cell of any one of claims 78-83, wherein the inhibitory polynucleotide targetingTRAC comprises the nucleotide sequence set forth in SEQ ID NO.105, SEQ ID NO.106, SEQ ID NO.107, SEQ ID NO.108, SEQ ID NO.109, SEQ ID NO.110, SEQ ID NO.111, SEQ ID NO.112, SEQ ID NO.113, SEQ ID NO.114, SEQ ID NO.115, SEQ ID NO.116, SEQ ID NO. 117, SEQ ID NO.118, SEQ ID NO.119, SEQ ID NO.120, SEQ ID NO.121, SEQ ID NO.122, SEQ ID NO.123, SEQ ID NO.124, SEQ ID NO.125, SEQ ID NO.126, SEQ ID NO.127, or SEQ ID NO.128.

85. The cell of any one of claims 80-84, wherein the inhibitory polynucleotide targetingCD70 comprises the nucleotide sequence set forth in SEQ ID NO.144, SEQ ID NO.145, SEQ ID NO.146, SEQ ID NO.147, SEQ ID NO.148, SEQ ID NO.149, SEQ ID NO.150, SEQ ID NO.151, SEQ ID NO.152, or SEQ ID NO.153.

86. A composition comprising the cell of any one of claims 1-85.

87. The composition of claim 86, which is a pharmaceutical composition further comprisinga pharmaceutically acceptable excipient.

88. A nucleic acid molecule comprising:(a) a polynucleotide encoding an antigen-recognizing receptor, wherein the antigen- recognizing receptor is a HLA-independent T cell receptor (HIT receptor) or a chimeric antigen receptor (CAR); and (b) an intron comprising an inhibitory polynucleotide targeting one or more genes.ACTIVE 509948342.2167072734.1771 PATENT89. The nucleic acid molecule of claim 88, wherein the inhibitory polynucleotide ispositioned between a splice donor sequence and a splice acceptor sequence of the intron.

90. The nucleic acid molecule of claim 89, wherein the polynucleotide encoding the antigen-recognizing receptor and the intron are operably linked to each other.

91. The nucleic acid molecule of claim 90, wherein the polynucleotide encoding the antigen-recognizing receptor and the inhibitory polynucleotide are operably linked to a promoter.

92. The nucleic acid molecule of claim 91 comprising, from 5’ end to 3’ end, the promoter,the intron, and the polynucleotide encoding the antigen-recognizing receptor.

93. The nucleic acid molecule of claim 91 , wherein the promoter is a constitutive promoteror an inducible promoter.

94. The nucleic acid molecule of claim 88, wherein the antigen-recognizing receptor is aHIT receptor.

95. The nucleic acid molecule of claim 94, wherein(a) the HIT receptor comprises a first antigen-binding chain comprising an antigen- binding fragment of a heavy chain variable region (VH) of an antibody and a TRAC polypeptide and a second antigen-binding chain comprising an antigen-binding fragment of a light chain variable region (VL) of an antibody and a TRBC polypeptide, wherein the HIT receptor binds to an antigen in an HLA-independent manner; or (b) the HIT receptor comprises a first antigen-binding chain comprising an antigen- binding fragment of a heavy chain variable region (VH) of an antibody and a TRBC polypeptide and a second antigen-binding chain comprising an antigen-binding fragment of a light chain variable region (VL) of an antibody and a TRAC polypeptide, wherein the HIT receptor binds to an antigen in an HLA-independent manner.

96. The nucleic acid molecule of claim 95, wherein(a) the TRAC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 11; and (b) the TRBC polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, or SEQ ID NO: 19.

97. The nucleic acid molecule of claim 88, wherein the inhibitory polynucleotide comprisesone or more short hairpin RNA (shRNA), small interfering RNA (siRNA), double stranded RNA (dsRNA), antisense oligonucleotide, or a combination thereof.

98. The nucleic acid molecule of claim 97, wherein the inhibitory polynucleotide comprisesone or more shRNAs.

99. The nucleic acid molecule of claim 97, wherein the one or more genes are selected fromTRAC, TRBC1, TRBC2, CD70, or a combination thereof.ACTIVE 509948342.2168072734.1771 PATENT100. The nucleic acid molecule of claim 99, wherein(a) the inhibitory polynucleotide targeting TRAC comprises the nucleotide sequence set forth in SEQ ID NO.105, SEQ ID NO.106, SEQ ID NO.107, SEQ ID NO.108, SEQ ID NO. 109, SEQ ID NO.110, SEQ ID NO.111, SEQ ID NO.112, SEQ ID NO.113, SEQ ID NO.114, SEQ ID NO.115, SEQ ID NO.116, SEQ ID NO.117, SEQ ID NO.118, SEQ ID NO.119, SEQ ID NO.120, SEQ ID NO.121, SEQ ID NO.122, SEQ ID NO.123, SEQ ID NO.124, SEQ ID NO.125, SEQ ID NO.126, SEQ ID NO.127, or SEQ ID NO.128; (b) the inhibitory polynucleotide targeting TRBC1 and TRBC2 comprises the nucleotide sequence set forth in SEQ ID NO.131, SEQ ID NO.132, SEQ ID NO.133, SEQ ID NO.134, SEQ ID NO.135, SEQ ID NO.136, SEQ ID NO.137, SEQ ID NO.138, SEQ ID NO.139, SEQ ID NO.140, SEQ ID NO.141, or SEQ ID NO.142; and / or (c) the inhibitory polynucleotide targeting CD70 comprises the nucleotide sequence set forth in SEQ ID NO.144, SEQ ID NO.145, SEQ ID NO.146, SEQ ID NO.147, SEQ ID NO. 148, SEQ ID NO.149, SEQ ID NO.150, SEQ ID NO.151, SEQ ID NO.152, or SEQ ID NO. 153.

101. The nucleic acid molecule of claim 88, wherein the inhibitory polynucleotide comprisesa microRNA.

102. The nucleic acid molecule of claim 94, further comprising (a) a polynucleotide encodinga chimeric antigen-recognizing receptor (CAR); (b) a polynucleotide encoding a chimeric co- stimulating receptor (CCR); (c) a polynucleotide encoding at least one exogenous costimulatory ligand; and / or (d) a polynucleotide encoding a fusion polypeptide comprising an extracellular domain of a co-stimulatory ligand, a transmembrane domain of the co-stimulatory ligand, and an intracellular domain of a co-stimulatory molecule.

103. A vector comprising the nucleic acid molecule of any one of claims 88-102.

104. The vector of claim 103, wherein the vector is a lentiviral vector.

105. The vector of claim 103, wherein the vector is a γ-retroviral vector.

106. A lipid nanoparticle comprising the nucleic acid molecule of any one of claims 88-102.

107. A composition comprising the nucleic acid molecule of any one of claims 88-102, thevector of any one of claims 103-105, or the lipid nanoparticle of claim 106.

108. The composition of claim 107, which is a pharmaceutical composition furthercomprising a pharmaceutically acceptable excipient.

109. A cell comprising the nucleic acid molecule of any one of claims 88-102, the vector ofany one of claims 103-105, or the lipid nanoparticle of claim 106.ACTIVE 509948342.2169072734.1771 PATENT110. A method for producing a cell, the method comprising introducing into the cell thenucleic acid molecule of any one of claims 88-102, the vector of any one of claims 103-15, or the lipid nanoparticle of claim 106.

111. A cell produced by the method of claim 110.

112. A method of reducing tumor burden in a subject, the method comprising administering tothe subject an effective amount of the cells of any one of claims 1-85, 109, and 111, the nucleic acid molecule of any one of claims 88-102, the vector of any one of claims 103-105, the lipid nanoparticle of claim 106, or the composition of claim 86, 87, 107, and 108.

113. The method of claim 112, wherein the method reduces the number of tumor cells,reduces tumor size, and / or eradicates the tumor in the subject.

114. A method of preventing and / or treating a neoplasm or a tumor in the subject,administering to the subject an effective amount of the cells of any one of claims 1-85, 109, and 111, the nucleic acid molecule of any one of claims 88-102, the vector of any one of claims 103- 105, the lipid nanoparticle of claim 106, or the composition of claim 86, 87, 107, and 108.

115. The method of any one of claims 112-114, wherein the neoplasm or tumor is cancer.

116. The method of any one of claims 112-115, wherein the neoplasm or tumor is a solidtumor.

117. The method of claim 116, wherein the solid tumor is selected from the group consistingof melanoma, renal cell carcinoma, non-small-cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, lung neuroendocrine carcinoma, small-cell lung cancer, pancreatic cancer, breast cancer, astrocytoma, glioblastoma, laryngeal / pharyngeal carcinoma, EBV- associated nasopharyngeal carcinoma, and ovarian carcinoma.

118. The method of any one of claims 112-115, wherein the neoplasm or tumor is a bloodcancer.

119. The method of claim 118, wherein the neoplasm or tumor is a myeloid disorder, a B-cellmalignancy, a leukemia, or a lymphoma.

120. The method of claim 119, wherein the myeloid disorder is selected from the groupconsisting of myelodysplastic syndromes, myeloproliferative neoplasms, chronic myelomonocytic leukemia, or acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, chronic myelocytic leukemia, and polycythemia vera.

121. The method of claim 119 or 120, wherein the myeloid disorder is acute myeloidleukemia (AML).

122. The method of claim 119, wherein the B-cell malignancy is selected from the groupconsisting of B cell non-Hodgkin lymphoma (NHL), B cell Hodgkin's lymphoma, B cell acuteACTIVE 509948342.2170072734.1771 PATENT lymphocytic leukemia (ALL), B cell chronic lymphocytic leukemia (CLL), multiple myeloma (MM), CLL with Richter’s transformation, and CNS lymphoma.

123. The method of claim 119 or 122, wherein the B-cell malignancy is B cell acutelymphocytic leukemia.

124. The method of claim 119, wherein the leukemia is selected from the group consisting ofacute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), mixed- phenotype acute leukemia (MLL), hairy cell leukemia, B cell prolymphocytic leukemia, B-cell precursor acute lymphoblastic leukemia, and T-cell precursor acute lymphoblastic leukemia.

125. The method of claim 119, wherein the lymphoma is selected from the group consistingof Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, B-cell non-Hodgkin’s lymphoma, T-cell non-Hodgkin’s lymphoma, and T-cell precursor acute lymphoblastic lymphoma.

126. The method of any one of claims 112-125, wherein the subject has a relapse of theneoplasm or tumor.

127. The method of any one of claims 112-126, wherein the subject received treatment whichleads to residual tumor cells.

128. A method of preventing and / or treating a pathogen infection in a subject, the methodcomprising administering to the subject an effective amount of the cells of any one of claims 1- 85, 109, and 111, the nucleic acid molecule of any one of claims 88-102, the vector of any one of claims 103-105, the lipid nanoparticle of claim 106, or the composition of claim 86, 87, 107, and 108.

129. A method of preventing and / or treating an autoimmune disease in a subject, the methodcomprising administering to the subject an effective amount of the cells of any one of claims 1- 85, 109, and 111, the nucleic acid molecule of any one of claims 88-102, the vector of any one of claims 103-105, the lipid nanoparticle of claim 106, or the composition of claim 86, 87, 107, and 108.

130. A method of preventing and / or treating an infectious disease in a subject, the methodcomprising administering to the subject an effective amount of the cells of any one of claims 1- 85, 109, and 111, the nucleic acid molecule of any one of claims 88-102, the vector of any one of claims 103-105, the lipid nanoparticle of claim 106, or the composition of claim 86, 87, 107, and 108.

131. A kit comprising the cells of any one of claims 1-85, 109, and 111, the nucleic acidmolecule of any one of claims 88-102, the vector of any one of claims 103-105, the lipid nanoparticle of claim 106, or the composition of claim 86, 87, 107, and 108.ACTIVE 509948342.2171072734.1771 PATENT132. The kit of claim 131, wherein the kit further comprises written instructions for reducingtumor burden, treating and / or preventing a neoplasm or a tumor, preventing and / or treating a pathogen infection, preventing and / or treating an autoimmune disease, and / or preventing and / or treating an infectious disease.ACTIVE 509948342.2172

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