Anti-TCR antibody molecules and uses thereof

Abstract

To provide additional methods of administering genetically engineered T cells not posing significant risks to the patients.SOLUTION: Disclosed is a method for reducing or altering an immune response induced by an adoptive T cell therapy in a subject, the method comprising the steps of: (a) administering an adoptive T cell therapy to the subject where the adoptive T cell therapy comprises a plurality of T cells expressing an αβ T cell receptor (TCR) comprising T cell receptor beta variable chain (TCRβV) region; and (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor β variable (TCRβV) region and activates the T cells.SELECTED DRAWING: Figure 14

Description

[Technical Field]

[0001] cross reference

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 935,172, filed November 14, 2019, and U.S. Provisional Patent Application No. 62 / 956,969, filed January 3, 2020, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Current molecules designed to activate and expand ex vivo T cells encoding exogenous receptors (e.g., CAR T cells, T cells expressing exogenous TCRs) for cancer immunotherapy typically target the CD3 epsilon (CD3ε) subunit of the T cell receptor (TCR), either alone or in combination with targeting the costimulatory receptor CD28. However, this approach has limitations. Previous studies have shown that the use of these anti-CD3ε targeting molecules, when infused into a subject, can result in the production of other cells that produce or stimulate proinflammatory cytokines (e.g., IL-1, IL-6, and TNFα) associated with inflammatory conditions, such as cytokine release syndrome (CRS), macrophage activation syndrome, neurotoxicity, and tumor lysis syndrome. Therefore, there is an ongoing need to develop additional methods for administering the types of genetically engineered T cells described above that do not pose these significant risks to patients. Summary of the Invention [Means for solving the problem]

[0003]

[0003] In one aspect, provided herein is a method for reducing or altering an immune response induced by adoptive T cell therapy in a subject, the method comprising: (a) administering to the subject an adoptive T cell therapy, wherein the adoptive T cell therapy comprises a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; and (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cells.

[0004]

[0004] In some embodiments, a first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered in an amount sufficient to reduce or alter the immune response induced by the adoptive T cell therapy in the subject.

[0005]

[0005] In some embodiments, the reduction is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region, and the reduction is in comparison to the level of the cytokine or chemokine in a sample from the subject before administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region to the subject and after administration of the adoptive T cell therapy.

[0006]

[0006] In some embodiments, a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject before, simultaneously with, or after the adoptive T cell therapy is administered to the subject.

[0007] In some embodiments, the first agent is a T cell receptor beta variable chain (TCRβV) the TCRβ V region comprises a domain that specifically binds to a TCRβ V region, wherein the TCRβ V region belongs to the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily; and the second agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ and a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0008] In some embodiments, the plurality of T cells expresses an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily; and the second agent belongs to the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ and a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβTCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβTCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0009] In some embodiments, the subject has cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a solid tumor.

[0010] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma, stomach cancer, thyroid cancer, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, Hodgkin's lymphoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.

[0010]

[0011] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, stomach cancer, thyroid cancer, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, neck cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, nasopharyngeal cancer, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, or testicular cancer.

[0011]

[0012] In some embodiments, the cancer is leukemia, myeloma, or lymphoma, hi some embodiments, the cancer is acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiple myeloma.

[0012]

[0013] In some embodiments, the adoptive T cell therapy comprises an exogenous receptor.

[0014] In some embodiments, the exogenous cell receptor is a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR).

[0013]

[0015] In some embodiments, the chimeric antigen receptor (CAR) or chimeric T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen.In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) is selected from the group consisting of CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, CISH, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen (Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-like tyrosine kinase 3 (FLT3), tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), interleukin-13 receptor subunit alpha -2, mesothelin, interleukin-11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA), protease serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis (Y) antigen, CD24, platelet-derived growth factor receptor beta (PDGFR-beta), stage-specific embryonic antigen-4 (SSEA-4), CD20, folate receptor alpha, receptor tyrosine-protein kinase ERBB2 (Her2 / neu), mucin 1, cell surface-associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), proteasome (prosome, macropain) subunit, beta, 9 (LMP2) ), glycoprotein 100 (gp100), oncogene fusion protein (bcr-abl) consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl), tyrosinase, ephrin type A receptor 2 (EphA2), fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight melanoma-associated antigen (HMWMAA), and o-acetylglucosamine. Chil-GD2 ganglioside (OAcGD2), folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid-stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide moiety of globoglycoceramide (GloboH), mammary differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), hepatitis A virus cellular receptor 1 (HAVCR1), adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K9 (LY6K), olfactory receptor 51E2 (OR51E2), TCR gamma alternative reading frame protein (TARP), Wilms tumor protein (WT1), cancer / testis antigen 1 (NY-ESO-1), cancer / testis antigen 2 (LAGE-1a), melanoma-associated antigen 1 (MAGE-A1), chromosome ETS translocation variant gene 6 (ETV6-AML) located on 12p, sperm protein 17 (SPA17), X antigen family, member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen 2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, survivin, telomerase, prostate cancer tumor antigen-1, melanoma antigen 1 recognized by T cells, rat sarcoma (Ras) mutant, human te human teratoma reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-acetylglucosaminyltransferase V (NA17), synaptic box protein Pax-3 (PAX3), androgen receptor, cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN), Ras homolog family member C (RhoC), tyrosinase-related protein 2 (TRP-2), cytochrome P4501B1 (CYP1B1), CCCTC-binding factor (zinc finger protein)-like, T-cell-recognized squamous cell carcinoma antigen 3 (SART3), paired box protein Pax-5 (PAX5), proacrosin-binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A-kinase anchor protein 4 (AKAP-4), synovial sarcoma, X-breakpoint 2 (SSX2), receptor for advanced glycation end products (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papillomavirus E6 (HPV E6), human papillomavirus E7 (HPV E7), intestinal carboxylesterase, heat shock protein 70-2 mutant (mutated) hsp70-2), CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), glypican 3 (GPC3), Fc receptor-like 5 (FCRL5), or immunoglobulin lambda-like polypeptide 1 (IGLL1) antigen-binding region.

[0014]

[0016] In some embodiments, the adoptive T cell therapy (ACT) comprises a plurality of cells that are allogeneic or autologous to the subject.

[0017] In some embodiments, the subject has or is at risk of developing cytokine release syndrome.

[0015]

[0018] In some embodiments, the cytokine or chemokine is IL-6, IFNγ, TNFα, IFNα, IL-1β, IL-8, IL-10, IL-2, IL-4, IL-5, IL-7, IL-10, IL-13, IL-15, IL-1RA, sIL1RI, sIL1RI, sIL1R ... IL1RII, sIL2Rα, sgp130, sIL6R, MCP1, MIP1α, MIP1β, MIG, GCSF, IP10, sTNFRI, sTNFRII, HGF, VEGF, sCD30, or GM-CSF.

[0016]

[0019] In some embodiments, the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

[0017]

[0020] In some embodiments, the antibody comprises a full-length antibody, a Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

[0018]

[0021] In some embodiments, the antibody binds to at least one Fc receptor. In some embodiments, the antibody exhibits at least one effector function. In some embodiments, the antibody is a variant that does not bind to at least one Fc receptor to which a corresponding wild-type antibody binds. In some embodiments, the antibody lacks at least one effector function. In some embodiments, the sample is a blood sample or a serum sample.

[0019]

[0022] In some embodiments, said administering said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region results in an increased proliferation rate of said plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region.

[0020]

[0023] In some embodiments, the rate of proliferation is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold compared to the rate of proliferation of a comparable plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region administered in the absence of said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region.

[0021]

[0024] In one aspect, provided herein is a method of mitigating an excessive immune response induced by adoptive T cell therapy in a subject, the method comprising: (a) administering to the subject an adoptive T cell therapy, wherein the adoptive T cell therapy comprises a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; and (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell.

[0022]

[0025] In some embodiments, a first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered in an amount sufficient to mitigate an excessive immune response induced by the adoptive T cell therapy in the subject.

[0023]

[0026] In some embodiments, the alleviation is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region, and the alleviation is in comparison to the level of the cytokine or chemokine in a control sample from the subject before administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region to the subject and before administration of the adoptive T cell therapy, The level of cytokine or chemokine from a sample from the subject after administration of the first agent is within 1000-fold, 500-fold, 400-fold, 300-fold, 200-fold, 100-fold, 50-fold, 25-fold, 10-fold, 5-fold, or 2-fold of the level in the control sample.

[0024]

[0027] In some embodiments, a first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is administered to the subject before, simultaneously with, or after the adoptive T cell therapy is administered to the subject.

[0025]

[0028] In some embodiments, the first agent comprises a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ and the second agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ The first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0026]

[0029] In some embodiments, the plurality of T cells expresses an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily; and the second agent belongs to the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, T and a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the TCRβV27 subfamily, the TCRβV28 subfamily, the TCRβV24 subfamily, the TCRβV20 subfamily, the TCRβV25 subfamily, or the TCRβV29 subfamily, wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0027]

[0030] In some embodiments, the subject has cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a solid tumor.

[0031] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma, stomach cancer, thyroid cancer, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, Hodgkin's lymphoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.

[0028]

[0032] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, stomach cancer, thyroid cancer, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, neck cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, nasopharyngeal cancer, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, or testicular cancer.

[0029]

[0033] In some embodiments, the cancer is leukemia, myeloma, or lymphoma, hi some embodiments, the cancer is acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiple myeloma.

[0030]

[0034] In some embodiments, the adoptive T cell therapy comprises an exogenous receptor.

[0035] In some embodiments, the exogenous cell receptor is a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR).

[0031]

[0036] In some embodiments, the chimeric antigen receptor (CAR) or chimeric T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen. In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen. In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen, such as CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, CISH, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B-cell maturation (BCMA), Tn antigen (Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-like tyrosine kinase 3 (FLT3), tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), interleukin-13 receptor subunit alpha-2, mesothelin, interleukin Interleukin-11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA), protease serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis (Y) antigen, CD24, platelet-derived growth factor receptor beta (PDGFR-beta), stage-specific embryonic antigen-4 (SSEA-4), CD20, folate receptor alpha, receptor tyrosine-protein kinase ERBB2 (Her2 / neu), mucin 1, cell surface-associated (MUC1), epidermal growth factor receptor (EGFR) ), neural cell adhesion molecule (NCAM), prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), proteasome (prosome, macropain) subunit, beta, 9 (LMP2), glycoprotein 100 (gp100), oncogene fusion protein (b) consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl). cr-abl), tyrosinase, ephrin type A receptor 2 (EphA2), fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid-stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), Chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide moiety of globo-H glycoceramide (GloboH), mammary differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), hepatitis A virus cellular receptor 1 (HAVCR1), adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K9 (LY6K), olfactory receptor 51E2 (O R51E2), TCR gamma alternative reading frame protein (TARP), Wilms tumor protein (WT1), cancer / testis antigen 1 (NY-ESO-1), cancer / testis antigen 2 (LAGE-1a), melanoma-associated antigen 1 (MAGE-A1), ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X antigen family, member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen 2 (MAD-CT-2),Fos-related antigen 1, tumor protein p53 (p53), p53 mutants, prostein, survivin, telomerase, prostate cancer tumor antigen-1, melanoma antigen 1 recognized by T cells, rat sarcoma (Ras) mutants, human telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-acetylglucosaminyltransferase V (NA17), association box protein Pax-3 (PAX3), androgen receptor, cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN), Ras homolog family member C (RhoC), tyrosinase-related protein 2 (TRP-2), cytochrome P450 1B1 (CYP1B1), CCCTC-binding factor (zinc finger protein)-like, T-cell-recognized squamous cell carcinoma antigen 3 (SART3), paired box protein Pax-5 (PAX5), proacrosin-binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A-kinase anchor protein 4 (AKAP-4), synovial sarcoma, X-breakpoint 2 (SSX2), receptor for advanced glycation end products (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papillomavirus E6 (HPV E6), human papillomavirus E7 (HPV E7), intestinal carboxylesterase, heat shock protein 70-2 mutant (mutated) hsp70-2), CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), glypican 3 (GPC3), Fc receptor-like 5 (FCRL5), or immunoglobulin lambda-like polypeptide 1 (IGLL1) antigen.

[0032]

[0037] In some embodiments, the adoptive T cell therapy (ACT) comprises a plurality of cells that are allogeneic or autologous to the subject.

[0038] In some embodiments, the subject has or is at risk of developing cytokine release syndrome.

[0033]

[0039] In some embodiments, the cytokine or chemokine is IL-6, IFNγ, TNFα, IFNα, IL-1β, IL-8, IL-10, IL-2, IL-4, IL-5, IL-7, IL-10, IL-13, IL-15, IL-1RA, sIL1RI, sIL1RII, sIL2Rα, sgp130, sIL6R, MCP1, MIP1α, MIP1β, MIG, GCSF, IP10, sTNFRI, sTNFRII, HGF, VEGF, sCD30, or GM-CSF.

[0034]

[0040] In some embodiments, the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

[0035]

[0041] In some embodiments, the antibody comprises a full-length antibody, a Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

[0036]

[0042] In some embodiments, the antibody binds to at least one Fc receptor. In some embodiments, the antibody exhibits at least one effector function. In some embodiments, the antibody is a variant that does not bind to at least one Fc receptor to which a corresponding wild-type antibody binds. In some embodiments, the antibody lacks at least one effector function. In some embodiments, the sample is a blood sample or a serum sample.

[0037]

[0043] In some embodiments, said administering said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region results in an increased proliferation rate of said plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region.

[0038]

[0044] In some embodiments, the rate of proliferation is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold compared to the rate of proliferation of a comparable plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region administered in the absence of said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region.

[0039]

[0045] In one aspect, provided herein is a method of treating cancer in a subject, the method comprising: (a) administering to the subject an adoptive T cell therapy, wherein the adoptive T cell therapy comprises a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; and (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell.

[0040]

[0046] In some embodiments, a first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered in an amount sufficient to reduce or alter the immune response induced by the adoptive T cell therapy in the subject.

[0041]

[0047] In some embodiments, the reduction is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the first agent, wherein the reduction is in comparison to the level of the cytokine or chemokine in a control sample from a subject administered the adoptive T cell therapy in the absence of the first agent.

[0042]

[0048] In some embodiments, a first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to ameliorate symptoms induced by the adoptive T cell therapy.

[0043]

[0049] In some embodiments, the symptom-ameliorating reduction is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the first agent, wherein the reduction is compared to the level of the cytokine or chemokine in a sample from the subject before administration of the first agent to the subject and after administration of the adoptive T cell therapy.

[0044]

[0050] In some embodiments, a first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is administered to the subject before, simultaneously with, or after the adoptive T cell therapy is administered to the subject.

[0045]

[0051] In some embodiments, the first agent comprises a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ and the second agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ The first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0046]

[0052] In some embodiments, the plurality of T cells expresses an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, and the second agent belongs to the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ and a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V15 subfamily, the TCRβ V30 subfamily, the TCRβ V19 subfamily, the TCRβ V27 subfamily, the TCRβ TCRβ V28 subfamily, the TCRβ V24 subfamily, the TCRβ V20 subfamily, the TCRβ V25 subfamily, or the TCRβ V29 subfamily, wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0047]

[0053] In some embodiments, the subject has cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a solid tumor.

[0054] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma, stomach cancer, thyroid cancer, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, Hodgkin's lymphoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.

[0048]

[0055] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, stomach cancer, thyroid cancer, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, neck cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, nasopharyngeal cancer, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, or testicular cancer.

[0049]

[0056] In some embodiments, the cancer is leukemia, myeloma, or lymphoma, hi some embodiments, the cancer is acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiple myeloma.

[0050]

[0057] In some embodiments, the adoptive T cell therapy comprises an exogenous receptor.

[0058] In some embodiments, the exogenous cell receptor is a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR).

[0051]

[0059] In some embodiments, the chimeric antigen receptor (CAR) or chimeric T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen. In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen, such as CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, CISH, epidermal growth factor receptor variant III (EGFRvIII), gangliosides, or gliomas. Ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-like tyrosine kinase 3 (FLT3), tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), interleukin-13 receptor subunit alpha-2, mesothelin, interleukin-11 receptor alpha (IL-11Ra) ), prostate stem cell antigen (PSCA), protease serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis (Y) antigen, CD24, platelet-derived growth factor receptor beta (PDGFR-beta), stage-specific embryonic antigen-4 (SSEA-4), CD20, folate receptor alpha, receptor tyrosine-protein kinase ERBB2 (Her2 / neu), mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), prostase, prostatic acid phosphatase (PA) P), elongation factor 2 mutant (ELF2M), ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), proteasome (prosome, macropain) subunit, beta, 9 (LMP2), glycoprotein 100 (gp100), oncogene fusion protein (bcr-abl) consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl), tyrosinase, ephrin EphA2 type receptor 2 (EphA2), fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid-stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D),Chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide moiety of globo-H glycoceramide (GloboH), mammary differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), hepatitis A virus cellular receptor 1 (HAVCR1), adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR2) 0), lymphocyte antigen 6 complex, locus K9 (LY6K), olfactory receptor 51E2 (OR51E2), TCR gamma alternative reading frame protein (TARP), Wilms tumor protein (WT1), cancer / testis antigen 1 (NY-ESO-1), cancer / testis antigen 2 (LAGE-1a), melanoma-associated antigen 1 (MAGE-A1), ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X antigen family, member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen 2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, survivin, telomerase, prostate cancer tumor antigen-1, melanoma antigen 1 recognized by T cells, rat sarcoma (Ras) mutant, human telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoint, melanoma inhibitor of apoptosis Inhibitor (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-acetylglucosaminyltransferase V (NA17), synaptic box protein Pax-3 (PAX3), androgen receptor, cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN), Ras homolog family member C (RhoC), tyrosinase-related protein 2 (TRP-2), cytochrome P450 1B1 (CYP1B1), CCCTC-binding factor (zinc finger protein)-like, T cell-recognized squamous cell carcinoma antigen 3 (SART3), synaptic box protein Pax-5 (PAX5), proacrosin-binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK),A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (S, SX2), receptor for advanced glycation end products (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papillomavirus E6 (HPV E6), human papillomavirus E7 (HPV E7), intestinal carboxylesterase, heat shock protein 70-2 mutant (mut hsp70-2), CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), glypican 3 (GPC3), Fc receptor-like 5 (FCRL5), or immunoglobulin lambda-like polypeptide 1 (IGLL1) antigen-binding region.

[0052]

[0060] In some embodiments, the adoptive T cell therapy (ACT) comprises a plurality of cells that are allogeneic or autologous to the subject.

[0061] In some embodiments, the subject has or is at risk of developing cytokine release syndrome.

[0053]

[0062] In some embodiments, the cytokine or chemokine is IL-6, IFNγ, TNFα, IFNα, IL-1β, IL-8, IL-10, IL-2, IL-4, IL-5, IL-7, IL-10, IL-13, IL-15, IL-1RA, sIL1RI, sIL1RII, sIL2Rα, sgp130, sIL6R, MCP1, MIP1α, MIP1β, MIG, GCSF, IP10, sTNFRI, sTNFRII, HGF, VEGF, sCD30, or GM-CSF.

[0054]

[0063] In some embodiments, the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

[0055]

[0064] In some embodiments, the antibody comprises a full-length antibody, a Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

[0056]

[0065] In some embodiments, the antibody binds to at least one Fc receptor. In some embodiments, the antibody exhibits at least one effector function. In some embodiments, the antibody is a variant that does not bind to at least one Fc receptor to which a corresponding wild-type antibody binds. In some embodiments, the antibody lacks at least one effector function. In some embodiments, the sample is a blood sample or a serum sample.

[0057]

[0066] In some embodiments, said administering said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region results in an increased proliferation rate of said plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region.

[0058]

[0067] In some embodiments, the rate of proliferation is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, or greater than the rate of proliferation of a comparable plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region administered in the absence of said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region. It increases by 8, 9, 10, 20, 50, 100 times.

[0059]

[0068] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising: (a) administering to the subject a first pharmaceutical composition comprising an adoptive T cell therapy that induces an immune response against cancer cells in the subject, wherein the adoptive T cell therapy comprises a plurality of T cells that express an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; and (b) administering to the subject a second pharmaceutical composition comprising a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell.

[0060]

[0069] In some embodiments, a second pharmaceutical composition comprising the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to reduce the immune response induced by the adoptive T cell therapy in the subject.

[0061]

[0070] In some embodiments, the reduction is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the second pharmaceutical composition, wherein the reduction is in comparison to the level of the cytokine or chemokine in a control sample from a subject administered the first pharmaceutical composition in the absence of the second pharmaceutical composition.

[0062]

[0071] In some embodiments, the second pharmaceutical composition comprising the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to ameliorate symptoms induced by the adoptive T cell therapy.

[0063]

[0072] In some embodiments, the reduction is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the second pharmaceutical composition, wherein the reduction is in comparison to the level of the cytokine or chemokine in a sample from the subject before administration of the second pharmaceutical composition and after administration of the first pharmaceutical composition to the subject.

[0064]

[0073] In some embodiments, the first pharmaceutical composition is administered in an amount of 0.1 to 10.0 x 10 per kg of the subject's body weight. 6 0.1 to 9.0 x 10 cells per kg of the subject's body weight 6 0.1 to 8.0 x 10 cells per kg of the subject's body weight 6 0.1 to 7.0 x 10 cells per kg of the subject's body weight 6 0.1 to 6.0 x 10 cells per kg of the subject's body weight 6 0.1 to 5.0 x 10 cells per kg of the subject's body weight 6 0.1 to 4.0 x 10 cells per kg of the subject's body weight 6 0.1 to 3.0 x 10 cells per kg of the subject's body weight 6 0.1 to 2.0 x 10 cells per kg of the subject's body weight 6 cells, or 0.1 to 1.0 x 10 cells per kg of the subject's body weight 6 Contains cells.

[0065]

[0074] In some embodiments, the first pharmaceutical composition is administered in an amount of 0.2 to 5.0 x 10 per kg of the subject's body weight. 6 Contains cells.

[0075] In some embodiments, the first pharmaceutical composition is administered at a dose of 2.0×10 per kg of the subject's body weight. 6 Contains cells.

[0066]

[0076] In some embodiments, the first pharmaceutical composition contains 0.1 to 10 x 10 8 cells, 0.1-9×10 8 cells, 0.1–8×10 8 cells, 0.1–7×108 cells, 0.1–6×10 8 cells, 0.1-5×10 8 cells, 0.1-4 x 10 8 pieces cells, 0.1~3×10 8 cells, 0.1-2 x 10 8 cells, or 0.1–1×10 8 Contains cells.

[0067]

[0077] In some embodiments, the first pharmaceutical composition contains 0.1 to 2.5 x 10 8 Contains cells.

[0078] In some embodiments, the first pharmaceutical composition contains 0.6 to 6.0 x 10 8 Contains cells.

[0068]

[0079] In some embodiments, the first pharmaceutical composition is administered at a dose of 2×10 per kg of body weight. 6 In some embodiments, the first pharmaceutical composition comprises 2 x 10 cells. 8 Contains cells.

[0080] In some embodiments, a first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is administered to the subject before, simultaneously with, or after the adoptive T cell therapy is administered to the subject.

[0069]

[0081] In some embodiments, the first agent comprises a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ and the second agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ The first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0070]

[0082] In some embodiments, the plurality of T cells expresses an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily; and the second agent belongs to the TCRβ V6 subfamily, TCRβ V10 subfamily, , TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, wherein the first agent and the second agent each specifically bind to TCRβVs belonging to different subfamilies or different members of the same TCRβV subfamily.

[0071]

[0083] In some embodiments, the subject has cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a solid tumor.

[0084] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma, stomach cancer, thyroid cancer, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, Hodgkin's lymphoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.

[0072]

[0085] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, stomach cancer, thyroid cancer, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, neck cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, nasopharyngeal cancer, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, or testicular cancer.

[0073]

[0086] In some embodiments, the cancer is leukemia, myeloma, or lymphoma, hi some embodiments, the cancer is acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiple myeloma.

[0074]

[0087] In some embodiments, the adoptive T cell therapy comprises an exogenous receptor.

[0088] In some embodiments, the exogenous cell receptor is a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR).

[0075]

[0089] In some embodiments, the chimeric antigen receptor (CAR) or chimeric T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen. In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) is selected from the group consisting of CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, CISH, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-like tyrosine kinase 3 (FLT3), tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), interleukin-13 Receptor subunit alpha-2, mesothelin, interleukin-11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA), protease serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis (Y) antigen, CD24, platelet-derived growth factor receptor beta (PDGFR-beta), stage-specific embryonic antigen-4 (SSEA-4), CD20, folate receptor alpha, receptor tyrosine-protein kinase ERBB2 (Her2 / neu), mucin 1, cell surface-associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule These proteins include NCAM, prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), proteasome (prosome, macropain) subunit, beta-type 9 (LMP2), glycoprotein 100 (gp100), oncogene fusion protein (bcr-abl) consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl), and thymidine kinase inhibitor (THK). Rosinase, ephrin type A receptor 2 (EphA2), fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid-stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), open chromosome X Reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide moiety of globo-H glycoceramide (GloboH), mammary differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), hepatitis A virus cellular receptor 1 (HAVCR1), adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K9 (LY6K), olfactory receptor 51E2 (OR51E2),TCR gamma alternative reading frame protein (TARP), Wilms tumor protein (WT1), cancer / testis antigen 1 (NY-ESO-1), cancer / testis antigen 2 (LAGE-1a), melanoma-associated antigen 1 (MAGE-A1), ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X antigen family, member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen 2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, survivin, telomerase, pre Prostate carcinoma tumor antigen-1, melanoma antigen 1 recognized by T cells, rat sarcoma (Ras) mutant, human telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoint, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-acetylglucosaminyltransferase V (NA17), association box protein Pax-3 (PAX3), androgen receptor, cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN), Ras homolog family member C (RhoC), tyrosinase-related protein 2 (TRP-2), cytochrome P450 1B1 (CYP1B1), CCCTC-binding factor (zinc finger protein)-like, T-cell-recognized squamous cell carcinoma antigen 3 (SART3), paired box protein Pax-5 (PAX5), proacrosin-binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A-kinase anchor protein 4 (AKAP-4), synovial sarcoma, X-breakpoint 2 (SSX2), receptor for advanced glycation end products (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papillomavirus E6 (HPV E6), human papillomavirus E7 (HPV E7), intestinal carboxylesterase, heat shock protein 70-2 mutant (mutated) hsp70-2), CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89),Leukocyte immunoglobulin-like receptor subfamily A member 2, (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), glypican 3 (GPC3), Fc receptor-like 5 (FCRL5), or immunoglobulin lambda-like polypeptide 1 (IGLL1) antigens.

[0076]

[0090] In some embodiments, the adoptive T cell therapy (ACT) comprises a plurality of cells that are allogeneic or autologous to the subject.

[0091] In some embodiments, the subject has or is at risk of developing cytokine release syndrome.

[0077]

[0092] In some embodiments, the cytokine or chemokine is IL-6, IFNγ, TNFα, IFNα, IL-1β, IL-8, IL-10, IL-2, IL-4, IL-5, IL-7, IL-10, IL-13, IL-15, IL-1RA, sIL1RI, sIL1RII, sIL2Rα, sgp130, sIL6R, MCP1, MIP1α, MIP1β, MIG, GCSF, IP10, sTNFRI, sTNFRII, HGF, VEGF, sCD30, or GM-CSF.

[0078]

[0093] In some embodiments, the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

[0079]

[0094] In some embodiments, the antibody comprises a full-length antibody, a Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

[0080]

[0095] In some embodiments, the antibody binds to at least one Fc receptor. In some embodiments, the antibody exhibits at least one effector function. In some embodiments, the antibody is a variant that does not bind to at least one Fc receptor to which a corresponding wild-type antibody binds. In some embodiments, the antibody lacks at least one effector function. In some embodiments, the sample is a blood sample or a serum sample.

[0081]

[0096] In some embodiments, said administering said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region results in an increased proliferation rate of said plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region.

[0082]

[0097] In some embodiments, the rate of proliferation is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold compared to the rate of proliferation of a comparable plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region administered in the absence of said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region.

[0083]

[0098] In one aspect, provided herein is a method of reducing an immune response induced by adoptive T cell therapy in a subject, the method comprising: (a) administering an adoptive T cell therapy to said subject, said adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; and (b). and administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell when the level of the cytokine or chemokine in the sample from the subject is at least 1000-fold higher than the baseline level.

[0084]

[0099] In some embodiments, a first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered in an amount sufficient to reduce an immune response induced by the adoptive T cell therapy.

[0085]

[0100] In some embodiments, the subject is administered a first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region when the level of the cytokine or chemokine in a sample from the subject is at least 2000-fold, 3000-fold, 4000-fold, 5000-fold, 6000-fold, 7000-fold, 8000-fold, 9000-fold, or 100,000-fold greater than the baseline level.

[0086]

[0101] In some embodiments, a first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is administered to the subject before, simultaneously with, or after the adoptive T cell therapy is administered to the subject.

[0087]

[0102] In some embodiments, the first agent comprises a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ and the second agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ The first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0088]

[0103] In some embodiments, the plurality of T cells expresses an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TC and the second agent belongs to the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, and and a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V19 subfamily, the TCRβ V27 subfamily, the TCRβ TCRβ V28 subfamily, the TCRβ V24 subfamily, the TCRβ V20 subfamily, the TCRβ V25 subfamily, or the TCRβ V29 subfamily, wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0089]

[0104] In some embodiments, the subject has cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a solid tumor.

[0105] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma, stomach cancer, thyroid cancer, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, Hodgkin's lymphoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.

[0090]

[0106] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, stomach cancer, thyroid cancer, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, neck cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, nasopharyngeal cancer, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, or testicular cancer.

[0091]

[0107] In some embodiments, the cancer is leukemia, myeloma, or lymphoma, hi some embodiments, the cancer is acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiple myeloma.

[0092]

[0108] In some embodiments, the adoptive T cell therapy comprises an exogenous receptor.

[0109] In some embodiments, the exogenous cell receptor is a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR).

[0093]

[0110] In some embodiments, the chimeric antigen receptor (CAR) or chimeric T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen. In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) binds to any of the following antigens: CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, CISH, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family members, B cell proliferation, and the like. mature (BCMA), Tn antigen ((Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-like tyrosine kinase 3 (FLT3), tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), interleukin-13 receptor subunit alpha-2, mesothelin, interleukin-11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA) ), protease serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis (Y) antigen, CD24, platelet-derived growth factor receptor beta (PDGFR-beta), stage-specific embryonic antigen-4 (SSEA-4), CD20, folate receptor alpha, receptor tyrosine-protein kinase ERBB2 (Her2 / neu), mucin 1, cell surface-associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), ephrin B2, fibroblast growth factor receptor alpha (EGFR), prostate cancer cell adhesion molecule (NCA), prostate cancer cell adhesion molecule 2 (PAC ... Cell activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), proteasome (prosome, macropain) subunit, beta-type 9 (LMP2), glycoprotein 100 (gp100), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type A receptor 2 (EphA2), fucosyl-GM1, sialyl Lewis adhesion molecule (sLe), gangliosides Side GM3, transglutaminase 5 (TGS5), high molecular weight melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid-stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK),Polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide moiety of globo-H glycoceramide (GloboH), mammary differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), hepatitis A virus cellular receptor 1 (HAVCR1), adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K9 (LY6K), olfactory receptor 51E2 (OR51E2) , TCR gamma alternative reading frame protein (TARP), Wilms tumor protein (WT1), cancer / testis antigen 1 (NY-ESO-1), cancer / testis antigen 2 (LAGE-1a), melanoma-associated antigen 1 (MAGE-A1), ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X antigen family, member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (T ie2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen 2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, survivin, telomerase, prostate cancer tumor antigen-1, melanoma antigen 1 recognized by T cells, rat sarcoma (Ras) mutant, human telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoint, melanoma inhibitor of apoptosis (ML-IAP), ERG ( Transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-acetylglucosaminyltransferase V (NA17), paired box protein Pax-3 (PAX3), androgen receptor, cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN), Ras homolog family member C (RhoC), tyrosinase-related protein 2 (TRP-2), cytochrome P450 1B1 (CYP1B1), CCCTC-binding factor (zinc finger protein)-like, T cell-recognized squamous cell carcinoma antigen 3 (SART3), paired box protein Pax-5 (PAX5), proacrosin-binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (SSX2), receptor for advanced glycation end products (RAGE-1), kidney ubiquitous 1 (RU1),Kidney Yu, Viquitus 2 (RU2), legumain, human papillomavirus E6 (HPV E6), human papillomavirus E7 (HPV E7), intestinal carboxylesterase, heat shock protein 70-2 mutant (mut hsp70-2), CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), glypican 3 (GPC3), Fc receptor-like 5 (FCRL5), or immunoglobulin lambda-like polypeptide 1 (IGLL1) antigen-binding region.

[0094]

[0111] In some embodiments, the adoptive T cell therapy (ACT) comprises a plurality of cells that are allogeneic or autologous to the subject.

[0112] In some embodiments, the subject has or is at risk of developing cytokine release syndrome.

[0095]

[0113] In some embodiments, the cytokine or chemokine is IL-6, IFNγ, TNFα, IFNα, IL-1β, IL-8, IL-10, IL-2, IL-4, IL-5, IL-7, IL-10, IL-13, IL-15, IL-1RA, sIL1RI, sIL1RII, sIL2Rα, sgp130, sIL6R, MCP1, MIP1α, MIP1β, MIG, GCSF, IP10, sTNFRI, sTNFRII, HGF, VEGF, sCD30, or GM-CSF.

[0096]

[0114] In some embodiments, the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

[0097]

[0115] In some embodiments, the antibody comprises a full-length antibody, a Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

[0098]

[0116] In some embodiments, the antibody binds to at least one Fc receptor. In some embodiments, the antibody exhibits at least one effector function. In some embodiments, the antibody is a variant that does not bind to at least one Fc receptor to which a corresponding wild-type antibody binds. In some embodiments, the antibody lacks at least one effector function. In some embodiments, the sample is a blood sample or a serum sample.

[0099]

[0117] In some embodiments, said administering said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region results in an increased proliferation rate of said plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region.

[0100]

[0118] In some embodiments, the rate of proliferation is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold compared to the rate of proliferation of a comparable plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region administered in the absence of said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region.

[0101]

[0119]

[0013] In one aspect, provided herein is a method of reducing an immune response in a subject administered an adoptive T cell therapy, comprising: (a) administering an adoptive T cell therapy to said subject, wherein said adoptive T cell therapy comprises an αβ variable chain comprising a T cell receptor beta variable chain (TCRβV) region. and (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell, in an amount sufficient to reduce an excessive immune response induced by the adoptive cell therapy, wherein the reduction is determined by measuring the presence or severity of at least one symptom associated with the excessive immune response in the subject after administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region, wherein the reduction is in comparison to the presence or severity of the at least one symptom in the subject before administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region to the subject and after administration of the adoptive cell therapy.

[0102]

[0120] In some embodiments, a first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to reduce an excessive immune response induced by the adoptive T cell therapy in the subject.

[0103]

[0121] In some embodiments, a first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is administered to the subject before, simultaneously with, or after the adoptive T cell therapy is administered to the subject.

[0104]

[0122] In some embodiments, the first agent comprises a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ and the second agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ The first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0105]

[0123] In some embodiments, the plurality of T cells expresses an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily; and the second agent belongs to the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ and a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβTCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβTCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0106]

[0124] In some embodiments, the subject has cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a solid tumor.

[0125] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma, stomach cancer, thyroid cancer, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, Hodgkin's lymphoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.

[0107]

[0126] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, stomach cancer, thyroid cancer, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, neck cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, nasopharyngeal cancer, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, or testicular cancer.

[0108]

[0127] In some embodiments, the cancer is leukemia, myeloma, or lymphoma, hi some embodiments, the cancer is acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiple myeloma.

[0109]

[0128] In some embodiments, the adoptive T cell therapy comprises an exogenous receptor.

[0129] In some embodiments, the exogenous cell receptor is a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR).

[0110]

[0130] In some embodiments, chimeric antigen receptors (CARs) or chimeric T cell receptors (The TCR comprises an antigen-binding region that specifically binds to a tumor-associated antigen. In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) binds to any of CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, CISH, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B-cell maturation (BCMA), Tn antigen (Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-like tyrosine kinase 3 (FLT3), tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), interleukin-13 receptor subunit alpha-2, mesothelin, interleukin-11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA), protease serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis (Y) antigen, CD24, platelet-derived growth factor receptor beta (PDGFR-beta), stage-specific embryonic antigen-4 (SSEA-4), CD20, folate receptor alpha, receptor tyrosine-protein kinase ERBB2 (Her2 / neu), Mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), proteasome (prosome, macropain) subunit, beta type 9 ( LMP2), glycoprotein 100 (gp100), oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl), tyrosinase, ephrin type A receptor 2 (EphA2), fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight melanoma-associated antigen (HMWMAA),o-Acetyl-GD2 ganglioside (OAcGD2), folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid-stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide moiety of globoglycerin (GloboH) ), mammary differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), hepatitis A virus cellular receptor 1 (HAVCR1), adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K9 (LY6K), olfactory receptor 51E2 (OR51E2), TCR gamma alternative reading frame protein (TARP), Wilms tumor protein (WT1), cancer / testis antigen 1 (NY-ESO-1), cancer / testis antigen 2 (LAGE-1a), melanoma-associated antigen 1 ( MAGE-A1), ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X antigen family, member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen 2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, survivin, telomerase, prostate cancer tumor antigen-1, melanoma antigen 1 recognized by T cells, rat sarcoma (Ras) mutant corpus callosum, human telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-acetylglucosaminyltransferase V (NA17), synaptic box protein Pax-3 (PAX3), androgen receptor, cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN), Ras homolog family member C (RhoC), tyrosinase-related protein 2 (TRP-2),Cytochrome P450 1B1 (CYP1B1), , CCCTC-binding factor (zinc finger protein)-like, T cell-recognized squamous cell carcinoma antigen 3 (SART3), paired box protein Pax-5 (PAX5), proacrosin-binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A-kinase anchor protein 4 (AKAP-4), synovial sarcoma, X-breakpoint 2 (SSX2), receptor for advanced glycation end products (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papillomavirus E6 (HPV E6), human papillomavirus E7 (HPV E7), intestinal carboxylesterase, heat shock protein 70-2 mutant (mutated) hsp70-2), CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), glypican 3 (GPC3), Fc receptor-like 5 (FCRL5), or immunoglobulin lambda-like polypeptide 1 (IGLL1) antigen-binding region.

[0111]

[0131] In some embodiments, the adoptive T cell therapy (ACT) comprises a plurality of cells that are allogeneic or autologous to the subject.

[0132] In some embodiments, the subject has or is at risk of developing cytokine release syndrome.

[0112]

[0133] In some embodiments, the cytokine or chemokine is IL-6, IFNγ, TNFα, IFNα, IL-1β, IL-8, IL-10, IL-2, IL-4, IL-5, IL-7, IL-10, IL-13, IL-15, IL-1RA, sIL1RI, sIL1RII, sIL2Rα, sgp130, sIL6R, MCP1, MIP1α, MIP1β, MIG, GCSF, IP10, sTNFRI, sTNFRII, HGF, VEGF, sCD30, or GM-CSF.

[0113]

[0134] In some embodiments, the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

[0114]

[0135] In some embodiments, the antibody comprises a full-length antibody, a Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

[0115]

[0136] In some embodiments, the antibody binds to at least one Fc receptor. In some embodiments, the antibody exhibits at least one effector function. In some embodiments, the antibody is a variant that does not bind to at least one Fc receptor to which a corresponding wild-type antibody binds. In some embodiments, the antibody lacks at least one effector function. In some embodiments, the sample is a blood sample or a serum sample.

[0116]

[0137] In some embodiments, said administering said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region results in an increased proliferation rate of said plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region.

[0117]

[0138] In some embodiments, the rate of proliferation is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold compared to the rate of proliferation of a comparable plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region administered in the absence of said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region.

[0118]

[0139] In one aspect, provided herein is a method of alleviating an excessive immune response in a subject administered an immunotherapeutic agent, comprising: (a) administering an adoptive T cell therapy to the subject, wherein the adoptive T cell therapy comprises a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; and (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell, in an amount sufficient to reduce an excessive immune response induced by the adoptive cell therapy, wherein the alleviation is determined by measuring the severity of at least one symptom associated with the excessive immune response in the subject following administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region; and comparing the severity of at least one symptom associated with the excessive immune response in the subject before administration of the first agent comprising the domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region and before administration of the adoptive T cell therapy, wherein the at least one symptom associated with the excessive immune response in the subject after administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is less severe compared to the at least one symptom before administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and before administration of the adoptive T cell therapy to the subject.

[0119]

[0140] In some embodiments, a first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to mitigate the excessive immune response induced by adoptive T cell therapy in the subject.

[0120]

[0141] In some embodiments, the at least one symptom is associated with cytokine release syndrome, macrophage activation syndrome, neurotoxicity, or tumor lysis syndrome. In some embodiments, the at least one symptom is associated with cytokine release syndrome. In some embodiments, the at least one symptom comprises hemophagocytic lymphohistiocytosis (HLH), fever, nausea, vomiting, chills, hypotension, tachycardia, arrhythmia, cardiomyopathy, acute heart failure, asthenia, headache, rash, dyspnea, encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, hallucinations, cerebral edema, hepatomegaly, hypofibrinogenemia, liver failure, diarrhea, edema, stiffness, arthralgia, myalgia, acute renal failure, splenomegaly, respiratory failure, pulmonary edema, hypoxia, capillary leak syndrome, macrophage activation syndrome, or tachypnea.

[0121]

[0142] In some embodiments, the at least one symptom is associated with neurotoxicity, ie, at least one symptom comprises encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, or cerebral edema.

[0122]

[0143] In some embodiments, the at least one symptom is associated with macrophage activation syndrome. In some embodiments, the at least one symptom comprises fever, headache, lymphadenopathy, hepatosplenomegaly, coagulopathy, rash, tachycardia, arrhythmia, cardiomyopathy, lethargy, pancytopenia, liver dysfunction, disseminated intravascular coagulation, hypofibrinogenemia, hyperferritinemia, or hypertriglyceridemia.

[0123]

[0144] In some embodiments, the at least one symptom is associated with tumor lysis syndrome. In some embodiments, the at least one symptom comprises nausea, vomiting, diarrhea, muscle cramps, muscle spasms, weakness, numbness, tingling, fatigue, lethargy, decreased urination, encephalopathy, aphasia, tremors, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, cerebral edema, or hallucinations.

[0124]

[0145] In one aspect, provided herein is a method of treating or alleviating adoptive T cell therapy-induced syndrome in a subject, the method comprising: (a) administering an adoptive T cell therapy to the subject, wherein the adoptive T cell therapy comprises a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; and (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell, in an amount sufficient to prevent, treat, or reduce the severity of at least one symptom associated with the adoptive T cell therapy-induced syndrome.

[0125]

[0146] In some embodiments, the syndrome is cytokine release syndrome, macrophage activation syndrome, neurotoxicity, or tumor lysis syndrome.

[0147] In some embodiments, the syndrome is cytokine release syndrome. In some embodiments, the at least one symptom comprises hemophagocytic lymphohistiocytosis, fever, nausea, vomiting, chills, hypotension, tachycardia, arrhythmia, cardiomyopathy, acute heart failure, asthenia, headache, rash, dyspnea, encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, cerebral edema, hepatomegaly, hypofibrinogenemia, liver failure, diarrhea, edema, stiffness, arthralgia, myalgia, acute renal failure, splenomegaly, respiratory failure, pulmonary edema, hypoxia, capillary leak syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis (HLH), or tachypnea.

[0126]

[0148] In some embodiments, the syndrome is neurotoxicity. In some embodiments, at least one symptom comprises encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, or cerebral edema.

[0127]

[0149] In some embodiments, the syndrome is macrophage activation syndrome. In some embodiments, the at least one symptom comprises fever, headache, lymphadenopathy, hepatosplenomegaly, coagulopathy, rash, tachycardia, arrhythmia, cardiomyopathy, lethargy, pancytopenia, liver dysfunction, disseminated intravascular coagulation, hypofibrinogenemia, hyperferritinemia, or hypertriglyceridemia.

[0128]

[0150] In some embodiments, the syndrome is tumor lysis syndrome. In some embodiments, at least one symptom comprises nausea, vomiting, diarrhea, muscle cramps, muscle spasms, weakness, numbness, tingling, fatigue, lethargy, decreased urination, encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, cerebral edema, or hallucinations.

[0129]

[0151] In some embodiments, said administering said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region results in an increased proliferation rate of said plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region.

[0130]

[0152] In some embodiments, the rate of proliferation is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold compared to the rate of proliferation of a comparable plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region administered in the absence of said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region.

[0131]

[0153] In some embodiments, a first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is administered to the subject prior to administering the adoptive T cell therapy to the subject: Simultaneously therewith, or thereafter, it is administered to the subject.

[0132]

[0154] In some embodiments, the first agent comprises a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ and the second agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ The first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0133]

[0155] In some embodiments, the plurality of T cells expresses an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region, wherein the TCRβV region is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily; and the second agent belongs to the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ and a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβTCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβTCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0134]

[0156] In some embodiments, the subject has cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the cancer is a solid tumor.

[0157] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma, stomach cancer, thyroid cancer, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, Hodgkin's lymphoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.

[0135]

[0158] In some embodiments, the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, stomach cancer, thyroid cancer, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, neck cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, nasopharyngeal cancer, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, or testicular cancer.

[0136]

[0159] In some embodiments, the cancer is leukemia, myeloma, or lymphoma, hi some embodiments, the cancer is acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiple myeloma.

[0137]

[0160] In some embodiments, the adoptive T cell therapy comprises an exogenous receptor.

[0161] In some embodiments, the exogenous cell receptor is a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR).

[0138]

[0162] In some embodiments, the chimeric antigen receptor (CAR) or chimeric T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen. In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen. In some embodiments, the chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen, such as CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, CISH, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B-cell maturation (BCMA), Tn antigen (Tn Ag) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-like tyrosine kinase 3 (FLT3), tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), interleukin-13 receptor subunit alpha-2, mesothelin, interleukin-11 receptor alpha (IL-11Ra), prostate stem cell antigen (PSCA), protease serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis (Y) antigen, CD24, platelet-derived growth factor receptor beta (PDGFR-beta), stage-specific embryonic antigen -4 (SSEA-4), CD20, folate receptor alpha, receptor tyrosine-protein kinase ERBB2 (Her2 / neu), mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), ephrin B2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), proteasome (prosome, macropain) subunit, beta, 9 (LMP2), glycoprotein 100 (gp100), breakpoint cluster region (BCR), and oncogene consisting of Abelson murine leukemia viral oncogene homolog 1 (Abl). Fusion protein (bcr-abl), tyrosinase, ephrin type A receptor 2 (EphA2), fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid-stimulating hormone receptor (TSHR), G protein-coupled receptor class C group 5, members D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), polysialic acid, placenta-specific 1 (PLAC1), hexasaccharide moiety of globo-H glycoceramide (GloboH), mammary differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), hepatitis A virus cellular receptor 1 (HAVCR1), adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3), G protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K9 (LY6K), Olfactory receptor 51E2 (OR51E2), TCR gamma alternative reading frame protein (TARP), Wilms tumor protein (WT1), cancer / testis antigen 1 (NY-ESO-1), cancer / testis antigen 2 (LAGE-1a), melanoma-associated antigen 1 (MAGE-A1), ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X antigen family, member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen 2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, survivin, telomerase, prostate cancer tumor antigen-1, melanoma antigen 1 recognized by T cells, rat sarcoma (Ras) mutant, human telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoint, melanoma inhibitor of apoptosis (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-acetylglucosaminyltransferase V (NA17), paired box protein Pax-3 (PAX3),Androgen receptor, cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN), Ras homolog family member C (RhoC), tyrosinase-related protein 2 (TRP-2), cytochrome P450 1B1 (CYP1B1), CCCTC-binding factor (zinc finger protein)-like, T cell-recognized squamous cell carcinoma antigen 3 (SART3), association box protein Pax-5 (PAX5), proacrosin-binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A kinase anchor protein 4 (AKAP-4), synovial sarcoma, X breakpoint 2 (SSX2), receptor for advanced glycation end products (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papillomavirus E6 (HPV E6), human papillomavirus E7 (HPV E7) E7), intestinal carboxylesterase, heat shock protein 70-2 mutant (mut hsp70-2), CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of IgA receptor (FCAR or CD89), leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), glypican 3 (GPC3), Fc receptor-like 5 (FCRL5), or immunoglobulin lambda-like polypeptide 1 (IGLL1) antigen.

[0139]

[0163] In some embodiments, the adoptive T cell therapy (ACT) comprises a plurality of cells that are allogeneic or autologous to the subject.

[0164] In some embodiments, the subject has or is at risk of developing cytokine release syndrome.

[0140]

[0165] In some embodiments, the cytokine or chemokine is IL-6, IFNγ, TNFα, IFNα, IL-1β, IL-8, IL-10, IL-2, IL-4, IL-5, IL-7, IL-10, IL-13, IL-15, IL-1RA, sIL1RI, sIL1RII, sIL2Rα, sgp130, sIL6R, MCP1, MIP1α, MIP1β, MIG, GCSF, IP10, sTNFRI, sTNFRII, HGF, VEGF, sCD30, or GM-CSF.

[0141]

[0166] In some embodiments, the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

[0142]

[0167] In some embodiments, the antibody comprises a full-length antibody, a Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

[0143]

[0168]

[0013] In one aspect, provided herein is a method of reducing cytokine or chemokine release induced by adoptive T cell therapy in a subject in need thereof, comprising: (a) measuring a first level of cytokine or chemokine in a first sample from the subject prior to administering the adoptive T cell therapy to the subject; and (b) administering an adoptive T cell therapy to the subject, wherein the adoptive T cell therapy comprises an αβ variable chain (TCRβV) comprising a T cell receptor beta variable chain (TCRβV) region. (c) measuring a second level of a cytokine or chemokine in a second sample from the subject after administering the adoptive T cell therapy to the subject; (d) comparing the first level with the second level to determine whether the subject has or is at risk of developing at least one symptom associated with an excessive immune response induced by the adoptive T cell therapy; and (e) if the subject is determined to have or be at risk of developing the at least one symptom, administering to the subject a first agent comprising an agonist comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, wherein the agonist ameliorates the at least one symptom.

[0144]

[0169] In some embodiments, the at least one symptom is associated with cytokine release syndrome, macrophage activation syndrome, neurotoxicity, or tumor lysis syndrome.

[0170] In some embodiments, the at least one symptom comprises hemophagocytic lymphohistiocytosis, fever, nausea, vomiting, chills, hypotension, tachycardia, arrhythmia, cardiomyopathy, acute heart failure, asthenia, headache, rash, dyspnea, encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, cerebral edema, hepatomegaly, hypofibrinogenemia, liver failure, diarrhea, edema, stiffness, arthralgia, myalgia, acute renal failure, splenomegaly, respiratory failure, pulmonary edema, hypoxia, capillary leak syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis (HLH), or tachypnea.

[0145]

[0171] In some embodiments, the plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region of the adoptive cell therapy are expanded ex vivo by contacting the plurality of T cells with an agent comprising a first domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region, thereby generating a first population of T cells.

[0146]

[0172] In some embodiments, the first agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily the second agent comprises a domain that specifically binds to a TCRβV region of a first TCRβV belonging to the TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily; and the second agent comprises a domain that specifically binds to a TCRβV region of a first TCRβV belonging to the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ and a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

[0147]

[0173] In some embodiments, the contacting comprises incubating or culturing the plurality of T cells with the first agent.

[0174] In some embodiments, the contacting comprises incubating or culturing the plurality of T cells with the first agent for at least about 10 minutes, 20 minutes, 30 minutes, 1 hour, 6 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 5 days, 7 days, 10 days, 14 days, 15 days, or 30 days.

[0148]

[0175] In some embodiments, the contacting comprises incubating or culturing the plurality of T cells with the first agent for up to about 10 minutes, 20 minutes, 30 minutes, 1 hour, 6 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 5 days, 7 days, 10 days, 12 days, 14 days, 15 days, 21 days, 30 days, 45 days, or 60 days.

[0149]

[0176] In some embodiments, the contacting comprises incubating or culturing the plurality of T cells with the first agent for about 10-90 minutes, 10-60 minutes, 10-30 minutes, 1-30 days, 1-21 days, 1-14 days, 1-7 days, 1-5 days, 1-3 days, 21-30 days, 14-30 days, 7-30 days, 5-30 days, or 3-30 days.

[0150]

[0177] In some embodiments, the agent is bound to a solid surface (eg, a bead).

[0178] In some embodiments, the agent is an antibody, a functional fragment thereof, or a functional variant thereof.

[0151]

[0179] In some embodiments, the antibody or functional fragment thereof comprises a full-length antibody, Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

[0152]

[0180] In some embodiments, the antibody, functional fragment thereof, or functional variant thereof is an anti-idiotype antibody domain.

[0181] In some embodiments, the antibody binds to at least one Fc receptor. In some embodiments, the antibody exhibits at least one effector function. In some embodiments, the antibody is a variant that does not bind to at least one Fc receptor to which a corresponding wild-type antibody binds. In some embodiments, the antibody lacks at least one effector function. In some embodiments, the sample is a blood sample or a serum sample.

[0153]

[0182] Further aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature and not restrictive. [Brief explanation of the drawings]

[0154] [Figure 1]

[0183] Figure 1 shows a phylogenetic tree of the TCRβV gene family and subfamilies to which the corresponding antibodies were mapped. The subfamily identifications are as follows: Subfamily A: TCRβ V6; Subfamily B: TCRβ V10; Subfamily C: TCRβ V12; Subfamily D: TCRβ V5; Subfamily E: TCRβ V7; Subfamily F: TCRβ V11; Subfamily G: TCRβ V14; Subfamily H: TCRβ V16; Subfamily I: TCRβ V18; Subfamily J: TCRβ V9; Subfamily K: TCRβ V13; Subfamily L: TCRβ V4; Subfamily M: TCRβ V3; Subfamily N: TCRβ V2; Subfamily O: TCRβ V15; Subfamily P: TCRβ V30; Subfamily Q: TCRβ V19; Subfamily R: TCRβ V27; Subfamily S: TCRβ V28; Subfamily T: TCRβ V24; Subfamily U: TCRβ V20; Subfamily V: TCRβ V25; and Subfamily W: TCRβ V29 Subfamily. Subfamily members are described in detail herein in the section entitled "TCR beta V (TCRβV)." [Figure 2A]

[0184] Figures 2A-2C show human CD3+ T cells activated with anti-TCRVβ13.1 antibody (BHM1709) for 6 days. Human CD3+ T cells were isolated using magnetic bead separation (negative selection) and activated with 100 nM immobilized (plate-coated) anti-TCRVβ13.1 (BHM1709) or anti-CD3ε (OKT3) antibody for 6 days. Figure 2A shows two scatter plots (left: activated with OKT3; right: activated with BHM1709) of expanded T cells assessed for TRVβ13.1 surface expression using anti-TCRVβ13.1 (BHM1709) followed by a secondary fluorochrome-conjugated antibody for flow cytometry analysis. [Figure 2B]Figures 2A-2C show human CD3+ T cells activated with anti-TCRVβ13.1 antibody (BHM1709) for 6 days. Human CD3+ T cells were isolated using magnetic bead separation (negative selection) and activated with 100 nM immobilized (plate-coated) anti-TCRVβ13.1 (BHM1709) or anti-CD3ε (OKT3) antibody for 6 days. Figure 2B shows the percentage (%) of TCR Vβ13.1-positive T cells activated by anti-TCRVβ13.1 (BHM1709) or anti-CD3ε (OKT3) plotted against total T cells (CD3+). [Figure 2C] Figures 2A-2C show human CD3+ T cells activated with anti-TCRVβ13.1 antibody (BHM1709) for 6 days. Human CD3+ T cells were isolated using magnetic bead separation (negative selection) and activated with 100 nM immobilized (plate-coated) anti-TCRVβ13.1 (BHM1709) or anti-CD3ε (OKT3) antibody for 6 days. Figure 2C shows relative cell counts obtained by counting the number of events in each T cell subset gate (CD3 or TCRVβ13.1) at a constant speed of 60 μl / min for 20 s. Data represent average values ​​from three donors. [Figure 3A]

[0185] Figures 3A-3B show the cytolytic activity of human CD3+ T cells activated with anti-TCRVβ13.1 antibody (BHM1709) against the transformed cell line RPMI8226. Figure 3A shows target cell lysis of human CD3+ T cells activated with BHM1709 or OKT3. Human CD3+ T cells were isolated using magnetic bead separation (negative selection) and activated with immobilized (plate-coated) BHM1709 or OKT3 at the indicated concentrations for 4 days, followed by coculture with RPMI8226 cells at a 5:1 (E:T) ratio for 2 days. Samples were then analyzed for cytolysis of RPMI8226 cells using flow cytometry analysis by FACS staining for CFSE / CD138 labeling and a membrane-impermeable DNA dye (DRAQ7). [Figure 3B]Figures 3A-3B show the cytolytic activity of human CD3+ T cells activated with anti-TCRVβ13.1 antibody (BHM1709) against the transformed cell line RPMI8226. Figure 3B shows target cell lysis of human CD3+ T cells activated with BHM1709 or OKT3 as described above, incubated with RPMI8226 cells at a 5:1 (E:T) ratio for 6 days, and then subjected to RPMI8226 cell lysis analysis. The percentage (%) of target cell lysis was determined by normalizing to basal target cell lysis (i.e., without antibody treatment) using the following formula: ((x - basal) / (100% - basal), where x is the sample lysis. Data shown are representative of n = 1 donor. [Figure 4A]

[0186] Figures 4A-4B show IFNγ production by human PBMCs activated with the indicated antibodies. Human PBMCs were isolated from whole blood of the indicated number of donors and subsequently solid-phase (plate-coated) stimulated with 100 μM of the indicated antibodies. Supernatants were collected on days 1, 2, 3, 5, or 6. Figure 4A is a graph comparing IFNγ production in human PBMCs activated with the indicated antibodies to those activated with anti-TCRVβ13.1 antibodies (BHM1709 or BHM1710) or anti-CD3e antibodies (OKT3 or SP34-2) on days 1, 2, 3, 5, or 6 after activation. [Figure 4B] Figures 4A-4B show IFNγ production by human PBMCs activated with the indicated antibodies. Human PBMCs were isolated from whole blood of the indicated number of donors, followed by solid-phase (plate-coated) stimulation with 100 Nm of the indicated antibodies. Supernatants were collected on days 1, 2, 3, 5, or 6. Figure 4B shows IFNγ production in human PBMCs activated with the indicated anti-TCRVβ13.1 antibodies or anti-CD3e antibody (OKT3) on days 1, 2, 3, 5, or 6 after activation. [Figure 5A]

[0187] Figure 5A shows IL-2 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 4A-4B was used. [Figure 5B] Figure 5B shows IL-2 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 4A-4B was used. [Figure 6A]

[0188] Figure 6A shows IL-6 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 4A-4B was used. [Figure 6B] Figure 6B shows IL-6 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 4A-4B was used. [Figure 7A]

[0189] Figure 7A shows TNF-alpha production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 4A-4B was used. [Figure 7B] Figure 7B shows TNF-alpha production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 4A-4B was used. [Figure 8A]

[0190] FIG. 8A shows IL-1β production by human PBMCs activated with the indicated antibodies. [Figure 8B] Figure 8B shows IL-1β production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described in Figures 4A-4B was used. [Figure 9A]

[0191] FIG. 9A is a graph showing the delayed kinetics of IFNγ secretion in human PBMCs from four donors activated with the anti-TCRVβ13.1 antibody BHM1709 compared to PBMCs activated with the anti-CD3e antibody OKT3. [Figure 9B]Figure 9B is a graph showing the delayed kinetics of IFNγ secretion in human PBMCs from four donors activated with the anti-TCRVβ13.1 antibody BHM1709 compared to PBMCs activated with the anti-CD3e antibody OKT3. Data shown are representative of n=8 donors. [Figure 10]

[0192] Figure 10 shows an increase in CD8+ TSCM and TEMRA T cell subsets in human PBMCs activated with anti-TCRVβ13.1 antibodies (BHM1709 or BHM1710) compared to PBMCs activated with anti-CD3e antibodies (OKT3 or SP34-2). [Figure 11A]

[0193] FIG. 11A shows an exemplary T cell stimulation method. [Figure 11B] FIG. 11B shows a graph of IFNγ production by human PBMCs activated with the indicated antibodies. [Figure 11C] FIG. 11C shows a graph of IFNγ production by human PBMCs activated with the indicated antibodies using the method shown in FIG. 11A. [Figure 12A]

[0194] FIG. 12A shows an exemplary T cell stimulation method. [Figure 12B] FIG. 12B shows a graph of IL-6 production by human PBMCs activated with the indicated antibodies using the method shown in FIG. 12A. [Figure 12C] FIG. 12C shows a graph of IL-1β production by human PBMCs activated with the indicated antibodies using the method shown in FIG. 12A. [Figure 12D] FIG. 12D shows a graph of IFNγ production by human PBMCs activated with the indicated antibodies using the method shown in FIG. 12A. [Figure 13]

[0195] 13 shows an exemplary T cell receptor (TCR) described herein. The TCR comprises a TCR alpha polypeptide chain comprising an immunoglobulin variable heavy chain or immunoglobulin variable light chain, a TCR alpha constant domain, a TCR alpha transmembrane domain, a TCR alpha intracellular domain, and optionally one or more (e.g., two or three) costimulatory domains, and a TCR beta polypeptide chain comprising an immunoglobulin variable heavy chain or immunoglobulin variable light chain, a TCR beta constant domain (a TCR beta constant 1 domain or a TCR beta constant 2 domain), a TCR alpha transmembrane domain, a TCR beta intracellular domain, and optionally one or more (e.g., two or three) costimulatory domains, wherein the immunoglobulin domains form the antigen-binding domain. [Figure 14]

[0196] Figure 14 shows an exemplary chimeric antigen receptor (CAR) described herein. The CAR comprises an antigen-binding domain (e.g., scFv), a TCR β constant domain (TCR β constant 1 domain or TCR β constant 2 domain), a TCR α transmembrane domain, a TCR β intracellular domain, and optionally one or more (e.g., two or three) costimulatory domains. [Figure 15]

[0197] Figure 15 shows the anti-CD19 chimeric antigen receptor (CAR) cassette used in Example 3. The CAR contains the EF1A promoter, CD8α signal peptide, FMC63 single-chain Fv that binds to CD19, a FLAG tag, a CD28 intracellular costimulatory domain, and a CD3ζ intracellular signaling domain. [Figure 16]

[0198] Figure 16 is a bar graph showing viable cell counts 6 days after activation of T cell or CAR T cell cultures from one of three donors (donor 010, donor 541, donor 871). One of three activation conditions was used: condition 1: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS); condition 2: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS) and IL2 (300 U / mL rIL-2-containing medium (catalog no. Pr21269, ProMab); condition 3: activation with equal amounts of anti-CD3ε and anti-CD28 antibodies (50 nM each in PBS). Viable cell counts were determined by FACS analysis. [Figure 17]

[0199] Figure 17 is a bar graph showing viable cell counts 9 days after activation of T cell or CAR T cell cultures from one of three donors (donor 010, donor 541, donor 871). One of three activation conditions was used: condition 1: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS); condition 2: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS) and IL2 (300 U / mL rIL-2-containing medium (catalog no. Pr21269, ProMab); condition 3: activation with equal amounts of anti-CD3ε and anti-CD28 antibodies (50 nM each in PBS). Viable cell counts were determined by FACS analysis. [Figure 18]

[0200] Figure 18 is a bar graph showing CD3+ cell counts 9 days after activation of T cell or CAR T cell cultures from one of three donors (donor 010, donor 541, donor 871). One of three activation conditions was used: condition 1: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS); condition 2: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS) and IL2 (300 U / mL rIL-2-containing medium (catalog no. Pr21269, ProMab); condition 3: activation with equal amounts of anti-CD3ε and anti-CD28 antibodies (50 nM each in PBS). CD3+ cell counts were determined by FACS analysis. [Figure 19]

[0201] Figure 19 is a bar graph showing the ratio of CD4+ to CD8+ T cells 9 days after activation of T cell or CAR T cell cultures from one of three donors (donor 010, donor 541, donor 871). One of three activation conditions was used: condition 1: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS); condition 2: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS) and IL2 (300 U / mL rIL-2-containing medium (catalog no. Pr21269, ProMab); condition 3: activation with equal amounts of anti-CD3ε and anti-CD28 antibodies (50 nM each in PBS). The ratio of CD4+ to CD8+ T cells was determined by FACS analysis. [Figure 20]

[0202] Figure 20 is a bar graph showing the percentage of TCRβV+ cells 9 days after activation of T cell or CAR T cell cultures from one of three donors (donor 010, donor 541, donor 871). One of three activation conditions was used: condition 1: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS); condition 2: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS) and IL2 (300 U / mL rIL-2-containing medium (catalog no. Pr21269, ProMab); condition 3: activation with equal amounts of anti-CD3ε and anti-CD28 antibodies (50 nM each in PBS). The ratio of CD4+ to CD8+ T cells was determined by FACS analysis using 16G8-PE-labeled antibody. [Figure 21]

[0203] Figure 21 is a bar graph showing the percentage of CAR+ T cells 9 days after activation of T cells from one of three donors (donor 010, donor 541, donor 871). One of three activation conditions was used: condition 1: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS); condition 2: activation with equal amounts of TCRβV clonotype-specific antibodies H131 and 16G8 (50 nM each in PBS) and IL2 (300 U / mL rIL-2-containing medium (catalog no. Pr21269, ProMab); condition 3: activation with equal amounts of anti-CD3ε and anti-CD28 antibodies (50 nM each in PBS). The ratio of CD4+ to CD8+ T cells was determined by FACS analysis using FLAG staining, where the CAR constructs shown in Figure 15 contain a FLAG tag. [Figure 22]

[0204] Figure 22 is a depiction of the T cell (e.g., CART cell) expansion protocol described herein. T cells expanded using clonal anti-TCRβV antibodies target and expand only a specific subset of T cells, in contrast to the use of anti-CD3ε antibodies, which activate all T cells. Activation and expansion of T cells using anti-TCRβV antibodies prevents the systemic release of cytokines, which can result in toxicity (e.g., CRS) when administered to a subject. [Figure 23]

[0205] FIG. 23 is a FACS plot showing the expansion of TCRvb6-5+ T cells over 8 days using anti-TCRvb6-5v1. [Figure 24]

[0206] FIG. 24 is a bar graph showing the expansion of TCRvb6-5+ CD4+ and TCRvb6-5+ CD8+ T cells over an 8-day period using the anti-CD3ε antibody OKT3 (100 nM). [Figure 25]

[0207] FIG. 25 is a bar graph showing the expansion of TCRvb6-5+ CD4+ and TCRvb6-5+ CD8+ T cells over an 8 day period using anti-TCRvb6-5v1 antibody (100 nM). [Figure 26]

[0208] FIG. 26 is a FACS plot showing the expansion of TCRvb6-5+ T cells over an 8 day period using anti-TCRvb6-5v1 or anti-CD3ε antibody OKT3. [Figure 27A]

[0209] Figure 27A is a bar graph showing the percentage of TCRβV6-5+ T cells in PBMC cultures after 8 days of culture with the indicated antibodies. Data for 5 replicates are shown. [Figure 27B] Figure 27B is a bar graph showing the percentage of TCRβV6-5+ T cells in purified T cell cultures after 8 days of culture with the indicated antibodies. Data for 5 replicates are shown. [Figure 28A]

[0210] FIG. 28A is a bar graph showing the relative counts of TCRβV6-5+ T cells in PBMC cultures after 8 days of culture with the indicated antibodies. [Figure 28B] FIG. 28B is a bar graph showing the relative counts of TCRβV6-5+ T cells in PBMC cultures after 8 days of culture with the indicated antibodies. [Figure 29A]

[0211] FIG. 29A is a bar graph showing the relative counts of TCRβV6-5+ T cells in purified T cell cultures after 8 days of culture with the indicated antibodies. [Figure 29B] FIG. 29B is a bar graph showing the relative counts of TCRβV6-5+ T cells in purified T cell cultures after 8 days of culture with the indicated antibodies. [Figure 30]

[0212] FIG. 30 is a line graph showing total CD3+ T cell counts (fold increase) after 8 days of T cell culture with either anti-CD3ε antibody OKT3 or anti-TCRvb6-5v1 antibody. [Figure 31]

[0213] Figure 31 is a series of line graphs showing target cell kinetics by TCRβV6-5v1-activated T cells or anti-CD3ε (OKT3)-activated T cells. T cells from three different donors (donor 6769, donor 9880, donor 5411) were utilized. [Figure 32A]

[0214] Figure 32A is a scatter plot showing the percent of target cell lysis by T cells with TCRβV6-5v1-activated T cells or anti-CD3ε (OKT3)-activated T cells without prior T cell activation. Data are shown at day 6 of co-culture of target cells with effector T cells. [Figure 32B] Figure 32B is a scatter plot showing the percent of target cell lysis by T cells with TCRβV6-5v1-activated T cells or anti-CD3ε (OKT3)-activated T cells with 4 days of T cell preactivation. Data are presented on day 2 of coculture of target cells with effector T cells (after 4 days of T cell preactivation). [Figure 33]

[0215] Figure 33 is a scatter plot showing the percent of target cell lysis by T cells with TCRβV6-5v1-activated T cells or anti-CD3ε (OKT3)-activated T cells with 4 days of T cell preactivation. Data are presented on day 2 of co-culture of target cells with effector T cells (after 4 days of T cell preactivation). [Figure 34]

[0216] Figure 34 is a bar graph showing target cell lysis by T cells with TCRβV6-5v1-activated T cells or anti-CD3ε (OKT3)-activated T cells (100 nM antibody each). Data include seven replicates for each experimental condition. [Figure 35]

[0217] Figure 35 is a series of FACS plots showing cell surface expression of CD3ε on CD4+ TCRβV6-5− or CD4+ TCRβV6-5+ T cells activated with either SP34-2 (anti-CD3ε antibody) or anti-TCRβV6-5v1 (anti-TCRβV6-5 antibody) on days 0, 1, 2, 4, 6, or 8 after antibody activation. [Figure 36]

[0218] Figure 36 is a series of FACS plots showing cell surface expression of CD3ε on CD8+ TCRβV6-5− or CD8+ TCRβV6-5+ T cells activated with either SP34-2 (anti-CD3ε antibody) or anti-TCRβV6-5v1 (anti-TCRβV6-5 antibody) on days 0, 1, 2, 4, 6, or 8 after antibody activation. [Figure 37]

[0219] Figure 37 is a series of FACS plots showing cell surface expression of TCRβV on CD4+ TCRβV6-5- or CD4+ TCRβV6-5+ T cells activated with either SP34-2 (anti-CD3ε antibody) or anti-TCRβV6-5v1 (anti-TCRβV6-5 antibody) on days 0, 1, 2, 4, 6, or 8 after antibody activation. [Figure 38]

[0220] Figure 38 is a series of FACS plots showing cell surface expression of TCRβV on CD8+ TCRβV6-5- or CD8+ TCRβV6-5+ T cells activated with either SP34-2 (anti-CD3ε antibody) or anti-TCRβV6-5v1 (anti-TCRβV6-5 antibody) on days 0, 1, 2, 4, 6, or 8 after antibody activation. [Figure 39A]

[0221] Figure 39A shows FACS plots of TCRβV6-5+ cynomolgus T cell expansion 7 days after activation of cynomolgus PBMCs, either unstimulated (left) or stimulated with anti-TCRβV6-5v1 (right). PBMCs from donor DW8N (fresh PBMC sample, male, 8 years old, weighing 7.9 kg) were used. [Figure 39B] Figure 39B shows FACS plots of TCRβV6-5+ cynomolgus T cell expansion 7 days after activation of cynomolgus PBMCs, either unstimulated (left) or stimulated with anti-TCRβV6-5v1 (right). PBMCs from donor G709 (cryopreserved sample, male, 6 years old, weighing 4.7 kg) were used. [Figure 40]

[0222] Figure 40 shows FACS plots and corresponding microscopic images of TCRβV6-5+ cynomolgus T cell expansion following activation of cryopreserved donor DW8N cynomolgus PBMCs, either unstimulated (left), stimulated with SP34-2 (anti-CD3ε antibody) (center), or stimulated with anti-TCRβV6-5v1 (right). The microscopic images show the formation of cell clusters (indicated by circles). [Figure 41]

[0223] FIG. 41 shows a schematic of a FACS plot showing FACS gating / staining of PBMCs prior to γδ T cell purification. [Figure 42]

[0224] FIG. 42 shows a schematic representation of a FACS plot showing FACS gating / staining of purified γδ T cell populations. [Figure 43]

[0225] FIG. 43 shows activation of purified γδ T cell populations with anti-CD3ε antibody (SP34-2) (left) or anti-TCRβV antibody (anti-TCRβV6-5v1) (right). [Figure 44A]

[0226] FIG. 44A shows the release of IFNγ from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), anti-TCRβV antibody (anti-TCRβV6-5v1), or unstimulated. [Figure 44B] FIG. 44B shows the release of TNFα from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), activated with anti-TCRβV antibody (anti-TCRβV6-5v1), or unstimulated. [Figure 44C] FIG. 44C shows IL-2 release from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), activated with anti-TCRβV antibody (anti-TCRβV6-5v1), or unstimulated. [Figure 44D] FIG. 44D shows the release of IL-17A from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), activated with anti-TCRβV antibody (anti-TCRβV6-5v1), or unstimulated. [Figure 44E] FIG. 44E shows the release of IL-1α from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), activated with anti-TCRβV antibody (anti-TCRβV6-5v1), or unstimulated. [Figure 44F] FIG. 44F shows the release of IL-1β from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), activated with anti-TCRβV antibody (anti-TCRβV6-5v1), or unstimulated. [Figure 44G] FIG. 44G shows IL-6 release from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), activated with anti-TCRβV antibody (anti-TCRβV6-5v1), or unstimulated. [Figure 44H] FIG. 44H shows IL-10 release from purified γδ T cell populations activated with anti-CD3ε antibody (SP34-2), activated with anti-TCRβV antibody (anti-TCRβV6-5v1), or unstimulated. [Figure 45]

[0227] Figure 45 shows the relative representation of all TCR alpha V-segments (TRAV gene cluster) and their variants (top), all TCR beta V-segment 6-5 variants (TRBV6-5 gene) (bottom left), and all TCR beta V-segments and variants except 6-5 (bottom right). [Figure 46A]

[0228] Figure 46A is a FACS plot showing phenotypic markers of CD4+ T cells expanded with an anti-TCRβV antibody (anti-TCRβV6-5v1). Defined phenotypes include TEMRA (top left), naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). [Figure 46B] Figure 46B is a FACS plot showing phenotypic markers of CD4+ T cells expanded with anti-CD3ε antibody (OKT3). Defined phenotypes include TEMRA (top left), naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). [Figure 47A]

[0229] Figure 47A is a FACS plot showing phenotypic markers of CD8+ T cells expanded with an anti-TCRβV antibody (anti-TCRβV6-5v1). Defined phenotypes include TEMRA (top left), naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). [Figure 47B] Figure 47B is a FACS plot showing phenotypic markers of CD8+ T cells expanded with anti-CD3ε antibody (OKT3). Defined phenotypes include TEMRA (top left), naive / TSCM (top right), TEM (bottom left), and TCM (bottom right). [Figure 48A]

[0230] Figure 48A is a bar graph showing the percentage of PD1-expressing CD4+ T cells from T cell cultures activated with an anti-TCRβV antibody (anti-TCRβV6-5v1), activated with an anti-CD3ε antibody (OKT3), or unstimulated. [Figure 48B] Figure 48B is a bar graph showing the percentage of PD1-expressing CD8+ T cells from T cell cultures activated with anti-TCRβV antibody (anti-TCRβV6-5v1), activated with anti-CD3ε antibody (OKT3), or unstimulated. [Figure 49A]

[0231] Figure 49A is a bar graph showing Ki-67 expression by CD4+ T cells from T cell cultures activated with anti-TCRβV antibody (anti-TCRβV6-5v1), activated with anti-CD3ε antibody (OKT3), or unstimulated. [Figure 49B] Figure 49B is a bar graph showing Ki-67 expression by CD8+ T cells from T cell cultures activated with anti-TCRβV antibody (anti-TCRβV6-5v1), activated with anti-CD3ε antibody (OKT3), or unstimulated. [Figure 50A]

[0232] FIG. 50A is a FACS plot showing the percentage of TEMRA-like CD8+ T cells activated using an anti-TCRβV antibody (anti-TCRβV6-5v1) that express CD57 (18.7%). [Figure 50B] Figure 50B is a FACS plot showing the percentage of TEM-like CD8+ T cells activated using anti-CD3ε antibody (OKT3) that express CD57 (46.8%) and the percentage of TCM-like CD8+ T cells activated using anti-CD3ε antibody (OKT3) that express CD57 (18.9%). [Figure 51]

[0233] Figure 51 is a FACS plot showing CD27 expression by CD4+ T cells (top) or CD8+ T cells (bottom) from T cell cultures activated with an anti-TCRβV antibody (anti-TCRβV6-5v1), activated with an anti-CD3ε antibody (OKT3), or unstimulated. [Figure 52]

[0234] Figure 52 is a FACS plot showing the expression of OX40, 41BB, and ICOS by CD4+ T cells (top) or CD8+ T cells (bottom) from T cell cultures activated with an anti-TCRβV antibody (anti-TCRβV6-5v1), activated with an anti-CD3ε antibody (OKT3), or unstimulated. [Figure 53]

[0235] Figure 53 shows a series of FACS plots showing the expression levels of TCRβV6-5 by Jurkat cells passaged through passage 11 (P11), passage 15 (P15), and passage 21 (P21). [Figure 54]

[0236] Figure 54 shows a series of FACS plots showing the percentage of CD3+ (CD4 gated) TCRβV6-5+ T cells after 1, 2, 3, 4, 5, 6, and 8 days of activation with BCMA and the anti-TCRVβ antibody anti-TCRVβ6-5v1. [Figure 55A]

[0237] Figure 55A shows a series of FACS plots showing the percentage of CD4+ T cells expanded with isotype control (IgG1 N297A), anti-TCRβV (anti-TCRVβ6-5v1), or anti-CD3ε (OKT3) antibodies on day 0 after activation. [Figure 55B] Figure 55B shows a series of FACS plots showing the percentage of CD4+ T cells expanded with isotype control (IgG1 N297A), anti-TCRβV (anti-TCRVβ6-5v1), or anti-CD3ε (OKT3) antibodies 1 day after activation. [Figure 55C] Figure 55C shows a series of FACS plots showing the percentage of CD4+ T cells expanded with isotype control (IgG1 N297A), anti-TCRβV (anti-TCRVβ6-5v1), or anti-CD3ε (OKT3) antibodies 2 days after activation. [Figure 55D] Figure 55D shows a series of FACS plots showing the percentage of CD4+ T cells expanded with isotype control (IgG1 N297A), anti-TCRβV (anti-TCRVβ6-5v1), or anti-CD3ε (OKT3) antibodies 3 days after activation. [Figure 55E] Figure 55E shows a series of FACS plots showing the percentage of CD4+ T cells expanded with isotype control (IgG1 N297A), anti-TCRβV (anti-TCRVβ6-5v1), or anti-CD3ε (OKT3) antibodies on day 4 post-activation. [Figure 55F]Figure 55F shows a series of FACS plots showing the percentage of CD4+ T cells expanded with isotype control (IgG1 N297A), anti-TCRβV (anti-TCRVβ6-5v1), or anti-CD3ε (OKT3) antibodies 5 days after activation. [Figure 55G] Figure 55G shows a series of FACS plots showing the percentage of CD4+ T cells expanded with isotype control (IgG1 N297A), anti-TCRβV (anti-TCRVβ6-5v1), or anti-CD3ε (OKT3) antibodies 6 days after activation. [Figure 55H] Figure 55H shows a series of FACS plots showing the percentage of CD4+ T cells expanded with isotype control (IgG1 N297A), anti-TCRβV (anti-TCRVβ6-5v1), or anti-CD3ε (OKT3) antibodies 8 days after activation. [Figure 56A]

[0238] Figure 56A is a map showing differential gene expression between cells activated with anti-TCRvb6-5v1 antibody and unstimulated cells. [Figure 56B] Figure 56B is a map showing differential gene expression between OKT3-activated and unstimulated cells. [Figure 56C] Figure 56C is a map showing differential gene expression between SP34-2-activated and unstimulated cells. [Figure 56D] Figure 56D is a map showing differential gene expression between cells activated with anti-TCRvb6-5v1 antibody and cells activated with OKT3. [Figure 56E] Figure 56E is a map showing that no differential gene expression was detected between cells activated with OKT3 and cells activated with SP34-2. [Figure 57A]

[0239] Figure 57A shows the distribution of differentially upregulated genes following T cell stimulation with the indicated antibodies. [Figure 57B] Figure 57B shows the distribution of differentially downregulated genes following T cell stimulation with the indicated antibodies. [Figure 57C]Figure 57C shows the distribution of differentially up- or down-regulated genes following T cell stimulation with the indicated antibodies. [Figure 57D] Figure 57D shows the distribution of differentially up- or down-regulated genes following T cell stimulation with the indicated antibodies. [Figure 58]

[0240] Figure 58 shows a heatmap of pathway scores of differentially regulated genes associated with various cellular pathways. Purified T cell samples include unstimulated (n=3), OKT3-stimulated (n=3), SP34-2-stimulated (n=3), and anti-TCRβV6-5v1-stimulated (n=3). [Figure 59A]

[0241] FIG. 59A shows plots of cytokine and chemokine pathways that were up-regulated, down-regulated, or unstimulated by activation with the indicated antibodies. [Figure 59B] FIG. 59B shows plots of TNF superfamily and interleukin pathways that were up-regulated, down-regulated, or unstimulated by activation with the indicated antibodies. [Figure 59C] Figure 59C shows plots of T cell function and senescence pathways upregulated or downregulated by activation with the indicated antibodies or unstimulated. [Figure 59D] Figure 59D shows plots of cell cycle and cytotoxic pathways that were up-regulated, down-regulated, or unstimulated by activation with the indicated antibodies. [Figure 60A]

[0242] Figure 60A shows plots of T cell functional pathways that were upregulated, downregulated, or unstimulated by activation with the indicated antibodies. [Figure 60B] Figure 60B shows plots of senescence pathways that were upregulated, downregulated, or unstimulated by activation with the indicated antibodies. [Figure 61A]

[0243] Figure 61A shows differential regulation of granzyme B in cells activated with the indicated antibodies or unstimulated cells. *P<0.01****, p<0.05***, p<0.5*, p<0.5ns. [Figure 61B] Figure 61B shows differential regulation of perforin in cells activated with the indicated antibodies or unstimulated cells. P<0.01****, p<0.05***, p<0.5*, p<0.5ns. [Figure 61C] Figure 61C shows differential regulation of IL-2 in cells activated with the indicated antibodies or unstimulated cells. P<0.01****, p<0.05***, p<0.5*, p<0.5ns. [Figure 61D] Figure 61D shows differential regulation of LIF in cells activated with the indicated antibodies or unstimulated cells. P<0.01****, p<0.05***, p<0.5*, p<0.5ns. [Figure 61E] Figure 61E shows differential regulation of IFNγ in cells activated with the indicated antibodies or unstimulated cells. P≦0.01****, p≦0.05***, p≦0.5*, p≦0.5ns. [Figure 61F] Figure 61F shows differential regulation of IL-22 in cells activated with the indicated antibodies or unstimulated cells. *P<0.01****, p<0.05***, p<0.5*, p<0.5ns. [Figure 61G] Figure 61G shows differential regulation of CD40LG in cells activated with the indicated antibodies or unstimulated cells. P<0.01****, p<0.05***, p<0.5*, p<0.5ns. [Figure 61H] Figure 61H shows differential regulation of ICOS in cells activated with the indicated antibodies or unstimulated cells. P<0.01****, p<0.05***, p<0.5*, p<0.5ns. [Figure 61I]Figure 61I shows differential regulation of CXCL9 in cells activated with the indicated antibodies or unstimulated cells. P≦0.01****, p≦0.05***, p≦0.5*, p≦0.5ns. [Figure 61J] Figure 61J shows differential regulation of CXCL10 in cells activated with the indicated antibodies or unstimulated cells. *P<0.01****, p<0.05***, p<0.5*, p<0.5ns. [Figure 62]

[0244] Figure 62 shows a graph from a principal component analysis (PCA) of genes associated with T cell activation and exhaustion that are differentially expressed after activation of T cells with the indicated antibodies. [Figure 63]

[0245] Figure 63 shows a graph from a principal component analysis (PCA) of genes associated with costimulation expressed following activation of T cells with the indicated antibodies. [Figure 64]

[0246] Figure 64 shows a graph from a principal component analysis (PCA) of genes associated with regulatory functions expressed following activation of T cells with the indicated antibodies. [Figure 65A]

[0247] Figure 65A is a bar graph showing ATP production from glycolysis in T cell cultures activated with the indicated antibodies. [Figure 65B] Figure 65B is a bar graph showing ATP production from oxidative phosphorylation of T cell cultures activated with the indicated antibodies. [Figure 66]

[0248] Figure 66 is a line graph showing the oxygen consumption rate (OCR) of T cells activated with the indicated antibodies from about 0 to 75 minutes. [Figure 67A]

[0249] Figure 67A shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibodies during basal respiration. [Figure 67B] Figure 67B shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibodies during maximal respiration. [Figure 67C] Figure 67C shows the oxygen consumption rate (OCR) of T cells activated with the indicated antibodies during spare respiratory capacity. [Figure 67D] FIG. 67D is a line graph showing the areas of basal and maximal respiration shown in FIGS. 67A and 67B, respectively. [Figure 68A]

[0250] Figure 68A is a bar graph showing ATP production from glycolysis in T cell cultures activated with anti-TCRβV6-5v1 and restimulated with the indicated antibodies. [Figure 68B] Figure 68B is a bar graph showing ATP production from oxidative phosphorylation of T cell cultures activated with anti-TCRβV6-5v1 and restimulated with the indicated antibodies. [Figure 69A]

[0251] Figure 69A is a FACS plot showing the percentage of CMV(pp65)-specific anti-TCRβV6-5v1 activated TCR Vβ6-5+ CD8+ T cells from the indicated donors (donor 14497 or donor 14693). [Figure 69B] Figure 69B is a FACS plot showing the percentage of EBV(LMP2)-specific anti-TCRβV6-5v1 activated TCR Vβ6-5+ CD8+ T cells from the indicated donors (donor 14497 or donor 14693). [Figure 69C] Figure 69C is a FACS plot showing the percentage of EBV (mixed peptide)-specific anti-TCRβV6-5v1 activated TCR Vβ6-5+ CD8+ T cells from the indicated donors (donor 14497 or donor 14693). [Figure 69D] Figure 69D is a FACS plot showing the percentage of influenza-specific anti-TCRβV6-5v1 activated TCR Vβ6-5+ CD8+ T cells from the indicated donors (donor 14497 or donor 14693). [Figure 69E] Figure 69E is a FACS plot showing the percentage of influenza-specific anti-TCRβV6-5v1 activated TCR Vβ6-5+ CD8+ T cells from the indicated donor (donor 11011). [Figure 69F]Figure 69F is a bar graph showing the viral peptide-specific percent (CD8+ T cells) for the indicated viruses. [Figure 70]

[0252] Figure 70 is a FACS plot showing the percentage of NK cells expanded from T cell cultures activated with the indicated antibodies. [Figure 71]

[0253] Figure 71 is a bar graph showing the number of NK cells expanded from T cell cultures activated with the indicated antibodies. [Figure 72]

[0254] Figure 72 shows a series of FACS plots demonstrating NK cell proliferation induced by T cell cultures activated with the indicated antibodies. [Figure 73]

[0255] FIG. 73 is a schematic diagram showing the assay described in the Examples for determining NK cell-mediated lysis of target K562 cells. [Figure 74]

[0256] Figure 74 is a bar graph showing the percent of target cell lysis mediated by NK cells activated by PBMCs activated with the indicated antibodies. [Figure 75]

[0257] Figure 75 is a bar graph showing secreted IFNγ levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34) and cultured with the antibodies for the indicated number of days (1, 3, or 5). [Figure 76]

[0258] Figure 76 is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34) and cultured with the antibodies for the indicated number of days (1, 3, or 5). [Figure 77]

[0259] Figure 77 is a bar graph showing secreted IL-15 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34) and cultured with the antibodies for the indicated number of days (1, 3, or 5). [Figure 78]

[0260] Figure 78 is a bar graph showing secreted IL-1β levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34) and cultured with the antibodies for the indicated number of days (1, 3, or 5). [Figure 79]

[0261] Figure 79 is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34) and cultured with the antibodies for the indicated number of days (1, 3, or 5). [Figure 80]

[0262] Figure 80 is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34) and cultured with the antibodies for the indicated number of days (1, 3, or 5). [Figure 81]

[0263] Figure 81 is a bar graph showing the levels of the indicated cytokines secreted by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 or SP34). Data includes the use of 17 individual PBMC donors. [Figure 82A]

[0264] Figure 82A is a bar graph showing secreted IFNγ levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 or OKT3) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 82B] Figure 82B is a bar graph showing secreted IL-1β levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 or OKT3) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 82C] Figure 82C is a bar graph showing secreted IL-4 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 or OKT3) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 82D]Figure 82D is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 or OKT3) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 82E] Figure 82E is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 or OKT3) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 82F] Figure 82F is a bar graph showing secreted TNFα levels by T cells activated / expanded with the indicated antibody (anti-TCRβV6-5v1 or OKT3) and cultured with the antibody for the indicated number of days (1, 2, 3, 5, or 6). [Figure 82G] Figure 82G is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 or OKT3) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 83A]

[0265] Figure 83A is a bar graph showing secreted IFNγ levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 83B] Figure 83B is a bar graph showing secreted IL-1β levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 83C] Figure 83C is a bar graph showing secreted IL-4 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 83D] Figure 83D is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 83E] Figure 83E is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 83F] Figure 83F is a bar graph showing secreted TNFα levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 83G] Figure 83G is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, SP34-2, or isotype control) and cultured with the antibodies for the indicated number of days (1, 2, 3, 5, or 6). [Figure 84A]

[0266] Figure 84A is a bar graph showing secreted IFNγ levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 84B] Figure 84B is a bar graph showing secreted IL-1β levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 84C]Figure 84C is a bar graph showing secreted IL-4 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 84D] Figure 84D is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 84E] Figure 84E is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 84F] Figure 84F is a bar graph showing secreted TNFα levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 84G] Figure 84G is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 85A]

[0267] Figure 85A is a bar graph showing secreted IL-17A levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (2, 5, or 7). [Figure 85B]Figure 85B is a bar graph showing secreted IL-17A levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (2, 5, or 8). [Figure 85C] Figure 85C is a bar graph showing secreted IL-17A levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1, OKT3, or SP34-2) and cultured with the antibodies for the indicated number of days (2, 5, or 7). [Figure 85D] Figure 85D is a bar graph showing secreted IL-17A levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 or SP34-2) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 86A]

[0268] Figure 86A is a bar graph showing secreted IFNγ levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86B] Figure 86B is a bar graph showing secreted IL-1β levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86C] Figure 86C is a bar graph showing secreted IL-4 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86D]Figure 86D is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86E] Figure 86E is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86F] Figure 86F is a bar graph showing secreted TNFα levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86G] Figure 86G is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86H] Figure 86H is a bar graph showing secreted IL-12p70 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86I]Figure 86I is a bar graph showing secreted IL-13 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86J] Figure 86J is a bar graph showing secreted IL-8 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86K] Figure 86K is a bar graph showing secreted exotaxin levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86L] Figure 86L is a bar graph showing secreted exotoxin-3 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86M] Figure 86M is a bar graph showing secreted IL-8 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86N]Figure 86N is a bar graph showing secreted IP-10 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86O] Figure 86O is a bar graph showing secreted MCP-1 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86P] Figure 86P is a bar graph showing secreted MCP-4 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86Q] Figure 86Q is a bar graph showing secreted MDC levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86R] Figure 86R is a bar graph showing secreted MIP-1a levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86S]Figure 86S is a bar graph showing secreted MIP-1b levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86T] Figure 86T is a bar graph showing secreted TARC levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86U] Figure 86U is a bar graph showing secreted GMCSF levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86V] Figure 86V is a bar graph showing secreted IL-12-23p40 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86W] Figure 86W is a bar graph showing secreted IL-15 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86X]Figure 86X is a bar graph showing secreted IL-16 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86Y] Figure 86Y is a bar graph showing secreted IL-17a levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86Z] Figure 86Z is a bar graph showing secreted IL-1a levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86AA] Figure 86AA is a bar graph showing secreted IL-5 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86BB] Figure 86BB is a bar graph showing secreted IL-7 levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86CC]Figure 86CC is a bar graph showing secreted TNF-B levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 86DD] Figure 86DD is a bar graph showing secreted VEGF levels by T cells activated / expanded with the indicated antibodies (isotype control, anti-TCRβV6-5v1 with anti-BCMA antibody, anti-TCRβV6-5v1, anti-TCRβV123 / 4v1, or SP34-2) and cultured with the antibodies for the indicated number of days (1, 2, 3, 4, 5, 6, or 8). [Figure 87A]

[0269] Figure 87A is a bar graph showing secreted IFN-γ levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87B] Figure 87B is a bar graph showing secreted IFN-γ levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87C] Figure 87C is a bar graph showing secreted IL-1b levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87D]Figure 87D is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87E] Figure 87E is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87F] Figure 87F is a bar graph showing secreted IL-15 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87G] Figure 87G is a bar graph showing secreted IL-17A levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87H] Figure 87H is a bar graph showing secreted IL-1a levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87I]Figure 87I is a bar graph showing secreted IL-1b levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87J] Figure 87J is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87K] Figure 87K is a bar graph showing secreted IL-4 levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 87L] Figure 87L is a bar graph showing secreted TNF-α levels by T cells activated / expanded with the indicated antibodies (anti-TCRβV6-5v1 (plate coating), anti-CD3ε (plate coating), anti-TCRβV6-5v1 (in solution), or anti-CD3ε (in solution)) and cultured with the antibodies for the indicated number of days (1, 3, 5, or 7). [Figure 88]

[0270] Figure 88 shows a graphical representation of the sequence relationships between different TCRVB clonotype subfamilies. [Figure 89A]

[0271] Figure 89A is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for 8 days using the indicated antibodies (anti-TCRβV12-3 / 4v1 or SP34-2). [Figure 89B]Figure 89B is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for 8 days using the indicated antibodies (anti-TCRβV5 or SP34-2). [Figure 89C] Figure 89C is a bar graph showing the percentage of cytokine release from PBMCs activated / expanded for 8 days using the indicated antibodies (anti-TCRβV10 or SP34-2). [Figure 90]

[0272] Figure 90 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibodies (isotype control or OKT3). PBMCs from 3 donors (D1, D2, and D3) were analyzed. [Figure 91]

[0273] Figure 91 shows a series of FACS plots showing proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibodies (anti-TCRvβ12-3 / 4v1 or anti-TCRVβ12-3 / 4v2). PBMCs from 3 donors (D1, D2, and D3) were analyzed. [Figure 92]

[0274] Figure 92 shows a series of FACS plots showing the proliferation of NK cells from PBMC cultures activated / expanded with the indicated antibodies (anti-TCRvβ12-3 / 4v3 or SP34-2). PBMCs from 3 donors (D1, D2, and D3) were analyzed. [Figure 93A]

[0275] Figure 93A is a bar graph showing secreted IFNγ levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 93B] Figure 93B is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 93C] Figure 93C is a bar graph showing secreted IL-17A levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 93D]Figure 93D is a bar graph showing secreted IL-1α levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 93E] Figure 93E is a bar graph showing secreted IL-1β levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 93F] Figure 93F is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 93G] Figure 93G is a bar graph showing secreted TNFα levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 93H] Figure 93H is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 94]

[0276] Figure 94 is a bar graph summarizing data from FACS analysis of PBMCs activated / expanded over 6 days using the indicated anti-TCRVβ antibodies. [Figure 95A]

[0277] Figure 95A is a bar graph showing secreted IFNγ levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (1, 3, 5, or 7). [Figure 95B] Figure 95B is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (1, 3, 5, or 7). [Figure 95C] Figure 95C is a bar graph showing secreted IL-17A levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (1, 3, 5, or 7). [Figure 95D] Figure 95D is a bar graph showing secreted IL-1α levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (1, 3, 5, or 7). [Figure 95E]Figure 95E is a bar graph showing secreted IL-1β levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (1, 3, 5, or 7). [Figure 95F] Figure 95F is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (1, 3, 5, or 7). [Figure 95G] Figure 95G is a bar graph showing secreted IL-4 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (1, 3, 5, or 7). [Figure 95H] Figure 95H is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (1, 3, 5, or 7). [Figure 96]

[0278] Figure 96 is a bar graph summarizing data from FACS analysis of PBMCs activated / expanded over 7 days using the indicated anti-TCRVβ antibodies. [Figure 97A]

[0279] Figure 97A is a bar graph showing secreted IFNγ levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 97B] Figure 97B is a bar graph showing secreted IL-10 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 97C] Figure 97C is a bar graph showing secreted IL-17A levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 97D] Figure 97D is a bar graph showing secreted IL-1α levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 97E] Figure 97E is a bar graph showing secreted IL-1β levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 97F]Figure 97F is a bar graph showing secreted IL-6 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 97G] Figure 97G is a bar graph showing secreted IL-4 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 97H] Figure 97H is a bar graph showing secreted TNFα levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 97I] Figure 97I is a bar graph showing secreted IL-2 levels by T cells activated / expanded with the indicated antibodies over the indicated number of days (3 or 6). [Figure 98]

[0280] Figure 98 is a FACS plot showing the ability of MH3-2 to bind to PBMC from one of two donors when the PBMC were either pre-incubated with TM23 or not (MH3-2 only). [Figure 99]

[0281] Figure 99 is a FACS plot showing the ability of MH3-2 to bind to PBMC from one of two donors when the PBMC are either pre-incubated with TM23 or not (MH3-2 only). [Figure 100A]

[0282] Figure 100A is a bar graph showing the polyfunctional strength index (PSI) of PBMC CD4+ T cells, CD4+ T cells expanded with anti-CD3 antibody (CD3-expanded T cells), and CD4+ T cells expanded with anti-TCRVβ6-5 antibody (drug-expanded T cells). The effector mediators are granzyme B, IFNγ, MIP-1α, perforin, TNFα, and TNFβ. The stimulatory mediator is IL-5. The chemoattractant mediator is MIP-1b. [Figure 100B]Figure 100B is a bar graph showing the polyfunctional strength index (PSI) of PBMC CD8+ T cells, CD8+ T cells expanded with anti-CD3 antibody (CD3-expanded T cells), and CD8+ T cells expanded with anti-TCRVβ6-5 antibody (drug-expanded T cells). Effector mediators are granzyme B, IFNγ, MIP-1α, perforin, and TNFβ. Chemoattractant mediators are MIP-1b and RANTES. [Figure 101A]

[0283] Figure 101A is a line graph showing cell counts on days 0, 7, 9, and 11 of CAR T cells cultured with the indicated antibodies and media made from donor 177 PBMCs (or no virus control). [Figure 101B] Figure 101B is a line graph showing cell counts on days 0, 7, 9, and 11 of CAR T cells cultured with the indicated antibodies and media made from donor 178 PBMCs (or no virus control). [Figure 101C] Figure 101C is a line graph showing cell counts on days 0, 7, 9, and 11 of CAR T cells cultured with the indicated antibodies and media made from donor 890 PBMCs (or no virus control). [Figure 102]

[0284] Figure 102 is a schematic diagram of the flow cytometry protocol for staining CAR-T cells on day 11. [Figure 103]

[0285] Figure 103 is a bar graph showing CAR-T cell frequencies at day 11 of CAR T cells cultured with the indicated antibodies and media (or no virus control). [Figure 104A]

[0286] Figure 104A is a bar graph showing the percentage of CAR-T cells of Teff, Tem, Tcm, and Tn phenotypes based on CD45RO-APC and CD62L-FITC staining of CAR-T cells generated from PBMCs of donor 177 on day 11. [Figure 104B]Figure 104B is a bar graph showing the percentage of CAR-T cells of Teff, Tem, Tcm, and Tn phenotypes based on CD45RO-APC and CD62L-FITC staining of CAR-T cells generated from PBMCs of donor 178 on day 11. [Figure 104C] Figure 104C is a bar graph showing the percentage of CAR-T cells of Teff, Tem, Tcm, and Tn phenotypes based on CD45RO-APC and CD62L-FITC staining of CAR-T cells generated from PBMCs of donor 890 on day 11. [Figure 105A]

[0287] Figure 105A shows the cytotoxicity of CAR-T cells generated by activation with the indicated antibodies and medium from PBMCs of donor 177. [Figure 105B] Figure 105B shows the cytotoxicity of CAR-T cells generated by activation with the indicated antibodies and medium from PBMCs of donor 178. [Figure 105C] Figure 105C shows the cytotoxicity of CAR-T cells generated by activation with the indicated antibodies and medium from PBMCs of donor 890. [Figure 105D] Figure 105D is a bar graph summarizing the cytotoxicity of CAR-T cells generated by activation with the indicated antibodies and media 8 hours after addition of target cells. [Figure 105E] Figure 105E is a bar graph summarizing the cytotoxicity of CAR-T cells generated by activation with the indicated antibodies and media 24 hours after addition of target cells. [Figure 106]

[0288] Figure 106 is a bar graph showing IFNγ production by CAR-T cells activated with the indicated antibodies and used in a cytotoxicity assay. [Figure 107]

[0289] Figure 107 shows a sequence alignment of eight functional human TCR Vβ6 family sequences, with boxes indicating three unique amino acids in subfamily 6-5. [Figure 108A]

[0290] Figure 108A is a line graph showing H131 antibody binding to the WT TCR receptor. [Figure 108B] Figure 108B is a line graph showing H131 antibody binding to the Q78A TCR receptor. [Figure 108C] Figure 108C is a line graph showing H131 antibody binding to the L101A TCR receptor. [Figure 108D] Figure 108D is a line graph showing H131 antibody binding to the S102A TCR receptor. DETAILED DESCRIPTION OF THE INVENTION

[0155] Incorporation by Reference

[0291] All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0156] definition

[0292] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0157]

[0293] Ranges: Throughout this disclosure, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be construed as specifically disclosing all possible subranges and individual numerical values ​​within that range. For example, description of a range such as 1 to 6 should be construed as specifically disclosing the specifically disclosed subranges, e.g., 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99% identical includes those having 95%, 96%, 97%, 98%, or 99%, and includes 96-99%, 96-98%, etc. , 96-97%, 97-99%, 97-98%, and 98-99% identical. This applies regardless of the breadth of the range.

[0158]

[0294] The words "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the thing. By way of example, "an element" means one element or more than one element.

[0159]

[0295] As used herein, "T cell receptor beta variable chain", "TCRβV", "TCRβ V", "TCR βV", "TCRβv", "TCR βv", "TCRβ v", "T cell receptor variable beta chain", "TCRβV", "TCR Vβ", "TCRV" The terms "TCRβ," "TCRβV," "TCRvβ," or "TCRvβ" are used interchangeably herein and refer to the extracellular region of the T cell receptor beta chain that contains the antigen recognition domain of the T cell receptor. The term TCRβV includes isoforms, mammalian, e.g., human, TCRβV, human species homologs, and analogs that share at least one common epitope with TCRβV. Human TCRβV is a member of the TCRβV6 subfamily, TCRβ The gene families include gene families that contain subfamilies, including, but not limited to, the V10 subfamily, the TCRβ V12 subfamily, the TCRβ V5 subfamily, the TCRβ V7 subfamily, the TCRβ V11 subfamily, the TCRβ V14 subfamily, the TCRβ V16 subfamily, the TCRβ V18 subfamily, the TCRβ V9 subfamily, the TCRβ V13 subfamily, the TCRβ V4 subfamily, the TCRβ V3 subfamily, the TCRβ V2 subfamily, the TCRβ V15 subfamily, the TCRβ V30 subfamily, the TCRβ V19 subfamily, the TCRβ V27 subfamily, the TCRβ V28 subfamily, the TCRβ V24 subfamily, the TCRβ V20 subfamily, the TCRβ V25 subfamily, or the TCRβ V29 subfamily. In some embodiments, the TCRβ V6 subfamily includes TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the TCRβ V includes TCRβ V6-5*01. TCRβ V6-5*01 is also known as TRBV65, TCRβ V 6S5, TCRβ V 13S1, or TCRβ V 13.1. The amino acid sequence of TCRβ V6-5*01, e.g., human TCRβ V6-5*01, is known in the art and is provided, for example, by IMGT ID L36092.

[0160]

[0296] As used herein, the term "molecule" includes full-length, native molecules, as well as variants, e.g., functional variants (e.g., truncated, fragments, mutants (e.g., substantially similar sequences), or derivatized forms thereof), so long as at least one function and / or activity of the unmodified (e.g., full-length, native) molecule remains.

[0161]

[0297] The terms "antibody" and "antibody molecule" are used interchangeably herein and refer to a protein comprising at least one immunoglobulin variable domain sequence. The term "antibody" encompasses full-length antibodies, antibody fragments (e.g., functional fragments thereof), and variants (e.g., functional variants thereof). Antibodies may be polyclonal or monoclonal, multi-chain or single-chain, or intact immunoglobulins, and may be derived from natural or recombinant sources. An antibody may be a tetramer of immunoglobulin molecules. In one embodiment, an antibody molecule comprises an antigen-binding or functional fragment of a full-length antibody, or a full-length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that occurs naturally or is formed by the recombinant process of normal immunoglobulin gene fragments. In embodiments, an antibody molecule is an immunologically distinct portion of an immunoglobulin molecule. The term "antibody fragment" refers to an antigen-binding portion, e.g., an antibody fragment, that is active in binding to a target, such as an antigen. The term "antibody fragment" refers to at least a portion of an intact antibody, or a recombinant variant thereof, and refers to the antigen-binding domain, e.g., the antigen-determining variable region, of the intact antibody sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen. An antibody fragment, e.g., a functional fragment, is a portion of an antibody, such as Fab, Fab', F(ab')2, F(ab)2, a variable fragment (Fv), a domain antibody (dAb), or a single-chain variable fragment (scFv). A functional antibody fragment binds to the same antigen recognized by an intact (e.g., full-length) antibody. The term "antibody fragment" or "functional fragment" also includes isolated fragments consisting of variable regions, such as an "Fv" fragment consisting of the variable regions of the heavy and light chains, or a recombinant single-chain polypeptide molecule in which the light and heavy variable regions are linked by a peptide linker ("scFv protein"). In some embodiments, an antibody fragment does not include a portion of an antibody that does not have antigen-binding activity, e.g., an Fc fragment or a single amino acid residue. Exemplary antibody molecules include full-length antibodies and antibody fragments, such as dAbs (domain antibodies), single chain, Fab, Fab', and F(ab')2 fragments, and single chain variable fragments (scFv). Examples of antibody fragments include single domain antibodies (V), such as Fab, Fab', F(ab')2, and Fv fragments, scFv antibody fragments, linear antibodies, and sdAbs. L or V H Camelidae V HExamples of antigen-binding fragments include, but are not limited to, multispecific antibodies formed from antibody fragments, such as a bivalent fragment comprising an H domain and two Fab fragments linked by a disulfide bridge at the hinge region, and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments can also be incorporated into single-domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs. Antigen-binding fragments can also be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see, e.g., U.S. Patent No. 6,703,199, which describes fibronectin polypeptide minibodies and is incorporated herein by reference). The antigen-binding domain may comprise a nanobody. In some embodiments, the antigen-binding domain may be a non-antibody targeting domain. In some embodiments, the antigen-binding domain may be a nanobody.

[0162]

[0298] The term "scFv" refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short, flexible polypeptide linker and capable of being expressed as a single polypeptide chain, and wherein the scFv retains the specificity of the intact antibody from which it is derived. As used herein, unless specified, an scFv refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short, flexible polypeptide linker and capable of being expressed as a single polypeptide chain, and wherein the scFv retains the specificity of the intact antibody from which it is derived. L and V H The variable regions may be in any order, e.g., relative to the N-terminus and C-terminus of the polypeptide, and scFvs may have V L -Linker-V H or V H -Linker-V L may include:

[0163]

[0299] The terms "complementarity-determining region" or "CDR" are used interchangeably herein and refer to the sequence of amino acids within an antibody variable region that confers antigen specificity and binding affinity. For example, typically, there are three CDRs in each heavy chain variable region (e.g., HCDR1, HCDR2, and HCDR3), and three CDRs in each light chain variable region (LCDR1, LCDR2, and LCDR3). The exact amino acid sequence boundaries of a given CDR can be determined using any of several well-known schemes, such as Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. ("Kabat" numbering scheme), Al-Lazikani et al. (1997) JMB 273, 927-948 ("Chothia" numbering scheme), or a combination thereof. Under the Kabat numbering scheme, in some embodiments, the heavy chain variable domain (V H The CDR amino acid residues in 5 (HCDR2), and 95-102 (HCDR3), and the light chain variable domain (V L ) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). Under the Chothia numbering scheme, in some embodiments, V H The CDR amino acid residues in are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3), and V L The CDR amino acid residues in are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). In a combined Kabat and Chothia numbering scheme, in some embodiments, the CDRs correspond to amino acid residues that are part of a Kabat CDR, a Chothia CDR, or both. For example, in some embodiments, the CDRs are H , e.g., mammalian V H, e.g., human V H Amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in V L , e.g., mammalian V L , e.g., human V L These correspond to amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in

[0164]

[0300] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., antibody Fv, Fab, Fab', F(ab')2, or other antigen-binding chains) that contain minimal sequence derived from non-human immunoglobulin. In most cases, humanized antibodies and antibody fragments are human immunoglobulins (recipient antibody or antibody fragment) in which residues from a complementarity-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some embodiments, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies / antibody fragments can comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications can further refine and optimize antibody or antibody fragment performance. Generally, a humanized antibody or antibody fragment thereof will comprise substantially all of at least one, and typically two, variable domains, with all or substantially all of the CDR regions corresponding to those of a non-human immunoglobulin and all or a substantial portion of the FR regions being those of a human immunoglobulin sequence. The humanized antibody or antibody fragment may also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature, 321:522-525, 1986; Reichmann et al., Nature, 332:323-329, 1988; Presta, Curr. Op. Struct. Biol., 2:593-596, 1992.

[0165]

[0301] "Fully human" refers to an immunoglobulin, such as an antibody or antibody fragment, in which the entire molecule is of human origin or consists of an amino acid sequence identical to the human form of the antibody or immunoglobulin.

[0166]

[0302] The term "specifically binds" refers to an antibody or ligand that recognizes and binds to a cognate binding partner protein present in a sample (e.g., a stimulatory and / or costimulatory molecule present on a T cell) but does not substantially recognize or bind to other molecules in the sample.

[0167]

[0303] As used herein, "immune cell" refers to any of a variety of cells that function in the immune system, e.g., to protect against infectious agents and foreign substances. In embodiments, the term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Innate leukocytes attack larger pathogens through contact or ingest microorganisms and then destroy them. They identify and eliminate pathogens by killing them and are mediators in the activation of the adaptive immune response. The cells of the adaptive immune system are specialized types of white blood cells called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, while T cells are involved in the cell-mediated immune response. The term "immune cell" includes immune effector cells.

[0168]

[0304] As used herein, the term "immune effector cell" refers to a cell that is involved in an immune response, e.g., promoting an immune effector response. Examples of immune effector cells include, but are not limited to, T cells (e.g., α / β T cells, γ / δ T cells, CD4+ T cells, CD8+ T cells, etc.), B cells, natural killer (NK) cells, natural killer T (NK T) cells, monocytes, macrophages, neutrophils, basophils, dendritic cells, and mast cells.

[0169]

[0305] The term "effector function" or "effector response" refers to a specialized function of a cell. The effector function of a T cell can be, for example, cytolytic activity (e.g., CD8+ T cells) or helper activity, including the secretion of cytokines (e.g., CD4+ T cells).

[0170]

[0306] The term "antigen-presenting cell" or "APC" refers to a cell of the immune system, such as an accessory cell (e.g., a B cell, a dendritic cell, etc.), that presents foreign antigens complexed with major histocompatibility complexes (MHC) on its surface. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process and present antigens to T cells.

[0171]

[0307] The term "substantially purified cells" or "substantially purified cell population" refers to cells or a population of cells that are essentially free of other cell types. Substantially purified cells also refer to cells that have been separated from other cell types with which they are normally associated in nature. In some instances, a population of substantially purified cells refers to a homogenous population of cells. In other instances, the term simply refers to cells that have been separated from the cells with which they are naturally associated in nature. In some aspects, the cells are cultured in vitro. In other aspects, the cells are not cultured in vitro.

[0172]

[0308] The term "derived from," as used herein, indicates a relationship between a first molecule and a second molecule. It generally refers to the structural similarity between the first molecule and the second molecule and does not imply or imply any process or source limitation on the first molecule from which the second molecule is derived. For example, in the case of an intracellular signaling domain derived from a CD3 zeta molecule, the intracellular signaling domain retains sufficient CD3 zeta structure to have the required function, i.e., the ability to generate a signal under appropriate conditions. This does not imply or imply any limitation to a particular process for producing the intracellular signaling domain, e.g., it does not mean that one must start with the CD3 zeta sequence and delete or mutate unnecessary sequences to arrive at the intracellular signaling domain in order to provide the intracellular signaling domain.

[0173]

[0309] The term "encode" refers to the inherent property of a particular nucleotide sequence in a polynucleotide, e.g., a gene, cDNA, or mRNA, to serve as a template for the synthesis of other polymers and macromolecules in biological processes that have either a defined sequence of nucleotides (e.g., rRNA, tRNA, and mRNA) or a defined sequence of amino acids, and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of the mRNA corresponding to the gene produces that protein in a cell or other biological system. Both the coding strand, the sequence of which is identical to the mRNA sequence and is usually provided in a sequence listing, and the non-coding strand, which is used as a template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

[0174]

[0310] Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. A reference to a nucleotide sequence encoding a protein or RNA may include introns, to the extent that some versions of a nucleotide sequence that encodes a protein may contain introns.

[0175]

[0311] The term "isolated," as used herein, refers to material that has been removed from its original or native environment (e.g., the natural environment, if it occurs in nature). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide separated by human intervention from some or all of the coexisting materials in the natural system is isolated. Such a polynucleotide can be part of a vector, and / or such a polynucleotide or polypeptide can be part of a composition and still be isolated in that such a vector or composition is not part of the environment in which it is found in nature. An isolated nucleic acid or protein can exist in a substantially purified form, or can exist in a non-native environment, such as, for example, a host cell.

[0176]

[0312] Some compositions and methods described herein encompass polypeptides and nucleic acids having a designated sequence or a sequence substantially identical or similar thereto, for example, a sequence at least 80%, 85%, 90%, 95% or more identical to the designated sequence. In the context of amino acid sequences, the term "substantially identical" is used herein to refer to a first amino acid sequence containing a sufficient or minimum number of amino acid residues in a second amino acid sequence that are i) identical or ii) conservative substitutions of aligned amino acid residues, such that the first and second amino acid sequences can have a common structural domain and / or a common functional activity. For example, an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a reference sequence, such as a sequence provided herein. In the context of nucleotide sequences, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode polypeptides having a common functional activity or encode a common structural domain or common functional polypeptide activity. For example, a nucleotide sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a reference sequence, e.g., a sequence provided herein.

[0177]

[0313] The terms "homology" and "sequence identity" are used interchangeably herein and refer to the subunit sequence identity between two polymer molecules, e.g., between two nucleic acid molecules, such as between two DNA molecules or two RNA molecules, or between two polypeptide molecules. If a position in both subunits of two molecules is occupied by the same monomer subunit, e.g., if each position in two DNA molecules is occupied by adenine, then they are homologous or identical at that position. The homology between two sequences is a direct function of the number of positions that are matched or homologous; for example, if half of the positions in two sequences (e.g., 5 positions in a polymer 10 subunits long) are homologous, then the two sequences are 50% homologous; if 90% of the positions (e.g., 9 out of 10) are matched or homologous, then the two sequences are 90% homologous. Calculation of homology between sequences is as follows: This is done as follows: To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps may be introduced into one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences may be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, or 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid or nucleotide positions are then compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap. Comparison of sequences and determination of percent identity between two sequences can be achieved using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm incorporated into the GAP program in the GCG software package, using either a Blossum62 matrix or a PAM250 matrix, a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com) using the NWSgapdna.CMP matrix, a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6.A particularly preferred set of parameters (and should be used unless otherwise specified) is the Blossum 62 scoring matrix, with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. Percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) as 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. The nucleic acid and protein sequences described herein can be used as "query sequences" to perform searches against public databases to identify, for example, other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches may be performed with the NBLAST program, score = 100, word length = 12, to obtain nucleotide sequences homologous to nucleic acid molecules. BLAST protein searches may be performed with the XBLAST program, score = 50, word length = 3, to obtain amino acid sequences homologous to protein molecules. To obtain gapped alignments for comparison purposes, Gapped BLAST may be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) may be utilized. It is understood that a molecule may have additional conservative or non-essential amino acid substitutions that do not substantially affect its function.

[0178]

[0314] The term "amino acid" is intended to encompass all molecules, natural or synthetic, that contain both an amino functional group and an acid functional group and that can be included in a polymer of natural amino acids. Exemplary amino acids include the natural amino acids; their analogs and derivatives. and congeners; amino acid analogs with variant side chains; and all stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes both D- or L-optical isomers and peptidomimetics.

[0179]

[0315] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids with nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids with beta-branched side chains (e.g., threonine, valine, isoleucine), and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into antibodies or antibody fragments by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative substitutions are those in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues in a CAR may be replaced with other amino acid residues from the same side chain family, and the modified CAR may be tested using the functional assays described herein.

[0180]

[0316] The terms "polypeptide," "peptide," and "protein" (when single-chain) are used interchangeably herein to refer to polymers of amino acids of any length. Polymers may be linear or branched, may contain modified amino acids, or may be interrupted by non-amino acids. These terms also include amino acid polymers that have been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. Polypeptides may be isolated from natural sources, produced by recombinant technology from eukaryotic or prokaryotic hosts, or obtained by synthetic means.

[0181]

[0317] The terms "nucleic acid," "nucleic acid sequence," "nucleotide sequence," "polynucleotide sequence," and "polynucleotide" are used interchangeably herein. These terms refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or their analogs. A polynucleotide may be single-stranded or double-stranded, and if single-stranded, may be the coding strand or non-coding (antisense) strand. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. A nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin that is not naturally occurring or linked to another polynucleotide in a non-natural configuration. In general, The following abbreviations for the nucleobases present are used: "A" for adenosine, "C" for cytosine, "G" for guanosine, "T" for thymidine, and "U" for uridine.

[0182]

[0318] The term "endogenous" refers to any substance that originates from or within an organism, cell, tissue, or system.

[0319] The term "exogenous" refers to any substance introduced from or originating outside an organism, cell, tissue or system.

[0183]

[0320] The term "expression" refers to the transcription and / or translation of a particular nucleotide sequence driven by a promoter.

[0321] The term "transfer vector" refers to a material composition that contains an isolated nucleic acid and can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art, including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term "transfer vector" includes autonomously replicating plasmids or viruses. This term should also be interpreted to include non-plasmid and non-viral compounds that facilitate the transfer of nucleic acids into cells, such as polylysine compounds, liposomes, etc. Viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated viral vectors, retroviral vectors, lentiviral vectors, etc.

[0184]

[0322] The term "expression vector" refers to a vector containing a recombinant polynucleotide comprising expression control sequences operably linked to a nucleotide sequence to be expressed. An expression vector contains sufficient cis-acting elements for expression; other elements for expression may be supplied by the host cell or by an in vitro expression system. Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes), and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) incorporating the recombinant polynucleotide.

[0185]

[0323] As used herein, the term "vector" refers to any vehicle that can be used to deliver and / or express a nucleic acid molecule. The vector may be a transfer vector or an expression vector as described herein.

[0186]

[0324] The term "lentivirus" refers to a genus of the Retroviridae family. Lentiviruses are unique among retroviruses in that they can infect non-dividing cells and deliver significant amounts of genetic information into the DNA of host cells. Therefore, lentiviruses are one of the most efficient gene delivery vectors.

[0187]

[0325] The term "lentiviral vector" refers to a vector derived from at least a portion of a lentiviral genome, such as the self-inactivating lentiviral vector provided in Milone et al., Mol. Ther. 17(8):1453-1464 (2009). Other examples of lentiviral vectors that may be used clinically include, but are not limited to, the LENTIVECTOR® gene delivery technology from Oxford BioMedica, the LENTIMAX™ vector system from Lentigen, and the like. Non-clinical lentiviral vectors are also available and known to those skilled in the art.

[0188]

[0326] The term "operably linked" or "transcriptional control" refers to a functional linkage between a regulatory sequence and a heterologous nucleic acid sequence that results in expression of the heterologous nucleic acid sequence. For example, A first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed into a functional relationship with the second nucleic acid sequence. For example, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences can be contiguous with each other, and, for example, in the same reading frame as necessary to link two protein-coding regions.

[0189]

[0327] The term "parenteral" administration of an immunogenic composition includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection, intratumoral or infusion techniques.

[0190]

[0328] The term "promoter" refers to a DNA sequence recognized by the synthetic machinery of a cell or introduced synthetic machinery necessary to initiate the specific transcription of a polynucleotide sequence.

[0191]

[0329] The term "promoter / regulatory sequence" refers to a nucleic acid sequence required for expression of a gene product operably linked to the promoter / regulatory sequence. In some instances, this sequence may be the core promoter sequence, and in other instances, this sequence may include an enhancer sequence and other regulatory elements required for expression of the gene product. The promoter / regulatory sequence may, for example, be one that expresses the gene product in a tissue-specific manner.

[0192]

[0330] The term "constitutive promoter" refers to a nucleotide sequence that, when operably linked to a polynucleotide encoding or specifying a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell.

[0193]

[0331] The term "inducible promoter" refers to a nucleotide sequence that, when operably linked to a polynucleotide encoding or specifying a gene product, causes the gene product to be produced in a cell only when a derivative corresponding to the promoter is present in the cell.

[0194]

[0332] The term "tissue-specific promoter" refers to a nucleotide sequence that, when operably linked to a polynucleotide encoded or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.

[0195]

[0333] As used herein, "transient" refers to a period of expression of a non-integrated transgene lasting hours, days, or weeks, which is shorter than the period of expression when the gene is integrated into the genome of the host cell or contained within a stable plasmid replicon.

[0196]

[0334] "Transfected" or "transformed" or "transduced" refers to the process by which exogenous nucleic acid is transferred or introduced into a host cell. A "transfected" or "transformed" or "transduced" cell is one that has been transfected, transformed, or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny.

[0197]

[0335] The terms "chimeric antigen receptor" or alternatively "CAR" are used interchangeably herein and refer to a recombinant polypeptide construct comprising at least an extracellular antigen-binding domain, a transmembrane domain, and a cytoplasmic signaling domain (also referred to herein as an "intracellular signaling domain") that comprises a functional signaling domain derived from a stimulatory molecule, as defined below. In some embodiments, the domains in a CAR polypeptide construct are , are within the same polypeptide chain, e.g., comprise a chimeric fusion protein. In some embodiments, the domains in the CAR polypeptide construct are not contiguous with each other, e.g., are within different polypeptide chains. In one aspect, the stimulatory molecule of the CAR is the zeta chain associated with the T cell receptor complex. In one aspect, the cytoplasmic signaling domain comprises a primary signaling domain (e.g., a primary signaling domain of CD3-zeta). In one aspect, the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one costimulatory molecule as defined below. In one aspect, the costimulatory molecule is selected from 4-1BB (i.e., CD137), CD27, ICOS, and / or CD28. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain, and an intracellular signaling domain comprising a functional signaling domain derived from the stimulatory molecule. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain, and an intracellular signaling domain comprising a functional signaling domain derived from the costimulatory molecule and a functional signaling domain derived from the stimulatory molecule. In one embodiment, the CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain, and an intracellular signaling domain comprising two functional signaling domains derived from one or more costimulatory molecules and a functional signaling domain derived from a stimulatory molecule. In one embodiment, the CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain, and an intracellular signaling domain comprising at least two functional signaling domains derived from one or more costimulatory molecules and a functional signaling domain derived from a stimulatory molecule. In one embodiment, the CAR comprises an optional leader sequence at the amino-terminus (N-terminus) of the CAR fusion protein. In one embodiment, the CAR further comprises a leader sequence at the N-terminus of the extracellular antigen recognition domain, where the leader sequence is optionally cleaved from the antigen recognition domain (e.g., scFv) during cellular processing of the CAR and localization to the cell membrane.

[0198]

[0336] As used herein, the term "signaling domain" refers to a functional portion of a protein that acts by transmitting information intracellularly to regulate cellular activity through a defined signaling pathway, either by generating second messengers or by functioning as an effector by responding to such messengers.

[0199]

[0337] As used herein, the term "intracellular signaling domain" refers to the intracellular portion of a molecule. The intracellular signaling domain can generate a signal that promotes immune effector function of a CAR cell, e.g., a CART cell or a CAR-expressing NK cell. Examples of immune effector function, e.g., in a CART cell or a CAR-expressing NK cell, include cytolytic activity and helper activity, including cytokine secretion. In embodiments, the intracellular signaling domain transmits an effector function signal, causing the cell to perform a specialized function. While the entire intracellular signaling domain can be employed, it is often not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such a truncated portion can be used in place of the intact chain, so long as it transmits the effector function signal. Thus, the term intracellular signaling domain is meant to include any truncated portion of the intracellular signaling domain sufficient to transmit the effector function signal. In some embodiments, the intracellular signaling domain comprises a primary intracellular signaling domain. Exemplary primary intracellular signaling domains include those derived from molecules responsible for primary or antigen-dependent stimulation. In one embodiment, the intracellular signaling domain can comprise a costimulatory intracellular domain. Exemplary costimulatory intracellular signaling domains include those derived from molecules responsible for costimulatory signals or antigen-independent stimulation. For example, in the case of CAR-expressing immune effector cells, e.g., CART cells or CAR-expressing NK cells, the primary intracellular signaling domain may comprise the cytoplasmic sequence of a T cell receptor, and may be involved in the costimulatory intracellular signaling. The delivery domain may comprise a cytoplasmic sequence from a co-receptor or co-stimulatory molecule. The primary intracellular signaling domain may comprise a signaling motif known as an immunoreceptor tyrosine-based activation motif, or ITAM. Examples of ITAMs containing primary cytoplasmic signaling sequences include, but are not limited to, those derived from CD3 zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CDS, CD22, CD79a, CD79b, CD278 ("ICOS"), FcεRI, CD66d, DAP10, and DAP12.

[0200]

[0338] "Zeta" or alternatively "zeta chain," "CD3-zeta," or "TCR-zeta" is defined as the protein provided by GenBank Accession No. BAG36664.1, or equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape, etc. A "zeta stimulatory domain" or alternatively "CD3-zeta stimulatory domain" or "TCR-zeta stimulatory domain" is defined as the amino acid residues from the cytoplasmic domain of the zeta chain sufficient to functionally transmit the initial signal required for T cell activation. In one embodiment, the cytoplasmic domain of zeta comprises residues 52-164 of GenBank Accession No. BAG36664.1, or equivalent residues from a functionally orthologous non-human species, e.g., mouse, rodent, monkey, ape, etc.

[0201]

[0339] The term "costimulatory molecule" refers to the cognate binding partner of a T cell that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. A costimulatory molecule is a cell surface molecule other than an antigen receptor or its ligand that is required for an efficient immune response. Costimulatory molecules include MHC class I molecules, TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocyte activation molecules (SLAM proteins), activating NK cell receptors, BTLA, and Toll ligand receptors, as well as OX40, CD2, CD7, CD27, CD28, CD30, CD40, CD5+, ICAM-1, LFA-1 (CD11a / CD18), 4-1BB (CD137), B7-H3, CD5+, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, and V L A1, CD49a, ITGA4, IA4, CD49D, ITGA6, V L A-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (tactile), CEACAM1, CR These include, but are not limited to, antibodies that specifically bind to TAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, and CD83.

[0202]

[0340] A "costimulatory intracellular signaling domain" refers to the intracellular portion of a costimulatory molecule. The intracellular signaling domain can include the entire intracellular portion of the molecule from which it is derived, or the entire native intracellular signaling domain, or a functional fragment thereof.

[0203]

[0341] The term "signaling pathway," as used herein, refers to the biochemical relationships between various signaling molecules that play a role in transmitting a signal from one part of a cell to another part of the cell.

[0204]

[0342] As used herein, the term "cell surface receptor" includes molecules and complexes of molecules that are capable of receiving and transmitting a signal across a cell membrane.

[0205]

[0343] The terms "anti-tumor effect" or "anti-cancer effect," as used interchangeably herein, refer to a biological effect that can be demonstrated by various means, including, but not limited to, a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in the number of metastases, an extension of lifespan, a reduction in tumor cell proliferation, a reduction in tumor cell survival, or an improvement in various physiological symptoms associated with the cancerous condition. An "anti-tumor effect" can also be demonstrated by the ability of peptides, polynucleotides, cells, and antibodies to prevent the development of tumors in the first place.

[0206]

[0344] As used interchangeably herein, the terms "cancer" or "tumor" encompass all types of oncogenic processes and / or cancerous growths. In embodiments, cancer includes primary tumors as well as metastatic tissues or malignantly transformed cells, tissues, or organs. In embodiments, cancer encompasses all histopathologies and stages of cancer, e.g., stages of invasiveness / severity. In embodiments, cancer includes recurrent and / or resistant cancers. For example, both terms encompass solid tumors and liquid tumors. As used herein, the term cancer includes pre-malignant and malignant cancers and tumors.

[0207]

[0345] The term "autologous" refers to any material derived from the same individual into which it is later reintroduced.

[0346] The term "allogeneic" refers to any material derived from a different animal of the same species as the individual into which the material is introduced. Two or more individuals are said to be allogeneic to one another if the genes at one or more loci are not identical. In some embodiments, allogeneic material derived from individuals of the same species may be sufficiently genetically distinct to interact antigenically.

[0208]

[0347] The term "xenogeneic" refers to a graft derived from an animal of a different species.

[0348] As used herein, the term "apheresis" refers to the art-recognized extracorporeal process in which a donor's or patient's blood is removed from the donor or patient, separated out, and passed through a device that returns the remainder to the donor's or patient's circulation, e.g., by reinfusion. Thus, in that context, an "apheresis sample" refers to a sample obtained using apheresis.

[0209]

[0349] The term "combination" refers to either a fixed combination in a single dosage unit form or combined administration, where the compound and combination partner (e.g., another drug described below, also known as a "therapeutic agent" or "combined drug") may be administered simultaneously and independently, or separately within a time interval, particularly within a time interval that allows a cooperative effect, e.g., a synergistic effect, with the combination partner to be demonstrated. Single components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose before administration. As used herein, terms such as "co-administration" or "administration in combination" are intended to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or at the same time. Thus, co-administration includes simultaneous or sequential administration of at least two agents of a treatment regimen. As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to a combination in which the active ingredients, e.g., a compound and a combination partner, are administered in a single dosage form at a specific time. The term "compounds" refers to the administration of two compounds to a patient as separate entities simultaneously, concurrently, or sequentially, without time restriction, such administration providing therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0210]

[0350] The terms "effective amount" or "therapeutically effective amount" are used interchangeably herein and refer to an amount of a compound, formulation, substance, or composition described herein that is effective to achieve a particular biological result.

[0211]

[0351] As used herein, the terms "treat," "treatment," and "treating" refer to a reduction or alleviation of the progression, severity, and / or duration of a proliferative disorder or the alleviation of one or more symptoms (preferably one or more discernible symptoms) of a proliferative disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents, such as a CAR). In specific embodiments, the terms "treat," "treatment," and "treating" refer to an improvement in at least one measurable physical parameter of a proliferative disorder, such as tumor growth, that is not necessarily discernible by the patient. In other embodiments, the terms "treat," "treatment," and "treating" refer to an inhibition of progression of a proliferative disorder, either physical, e.g., by stabilization of a discernible symptom, physiological, e.g., by stabilization of a physical parameter, or both. In other embodiments, the terms "treat," "treatment," and "treating" refer to a reduction or stabilization of tumor size or cancer cell count.

[0212]

[0352] As used herein, the term "therapeutic" means treatment. The therapeutic effect is achieved by the reduction, suppression, amelioration, or eradication of the disease state.

[0353] As used herein, the term "prophylaxis" means the prevention or protective treatment of a disease or disease state.

[0213]

[0354] The term "subject" is intended to include living organisms (eg, mammals, humans) in which an immune response can be elicited. Adoptive T cell therapy

[0355] In some aspects described herein, methods of treating a subject are provided, particularly methods comprising treating the subject using adoptive T cells. In some embodiments, the subject is administered a therapy comprising a plurality of T cells expressing an αβ TCR, e.g., comprising a T cell receptor (TCR) beta variable chain region. In some embodiments, the adoptive T cell therapy comprises CAR-T cell therapy, e.g., as described herein. In some embodiments, the adoptive T cell therapy comprises genetically modified cells. In some embodiments, the adoptive T cell therapy expresses one or more exogenous proteins, e.g., exogenous TCRs. In some embodiments, the cells comprise a genomic disruption in at least one gene that silences or completely inhibits expression of a functional protein encoded by the gene. In some embodiments, the gene is an immune checkpoint gene, e.g., as described herein. T cell source and isolation

[0356] In some aspects described herein, T cells are obtained from a subject (e.g., a human subject) prior to activation and expansion. Subjects include humans, dogs, cats, mice, rats, and transgenic species thereof. T cells can be obtained from several sources, including, but not limited to, blood, peripheral blood mononuclear cells (PBMCs), bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments, T cells are obtained from a unit of blood drawn from a subject using any of several techniques known to those of skill in the art, such as Ficoll separation.

[0214]

[0357] In some embodiments, cells from the circulating blood of an individual are obtained by apheresis or leukemia. Cells are obtained by cell apheresis. The apheresis product may include lymphocytes, such as T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. In one embodiment, cells collected by apheresis may be washed to remove the plasma fraction and placed in an appropriate buffer or medium for the next processing step. In some embodiments, cells are washed with phosphate-buffered saline (PBS). In some embodiments, the wash solution lacks calcium, magnesium, both calcium and magnesium, or all divalent cations. As one skilled in the art would readily understand, the washing step can be accomplished by methods known to those skilled in the art, such as by using a semi-automated "flow-through" centrifuge (e.g., a Cobe 2991 cell processor, a Baxter CytoMate, or a Haemonetics Cell Saver 5) according to the manufacturer's instructions. In some embodiments, after washing, the cells are resuspended in various biocompatible buffers, such as Ca-free, Mg-free PBS, PlasmaLyte A, or other saline solutions with or without buffers. Alternatively, in some embodiments, undesirable components of the apheresis sample may be removed and the cells suspended directly in culture medium.

[0215]

[0358] The collected apheresis product can be processed in a variety of ways depending on the downstream procedure. Haemonetics Cell Saver 5+, COBE2991, and Devices such as the Fresenius Kabi LOVO have the ability to remove total red blood cell and platelet contaminants. The Terumo Elutra and Biosafe Sepax systems offer size-based cell differentiation for monocyte depletion and lymphocyte isolation. Instruments such as the CliniMACS Plus and Prodigy systems use Miltenyi beads after cell washing to separate CD4 + , CD8 + , CD25 + , or CD62L + It allows for the enrichment of specific subsets of T cells, such as T cells.

[0216]

[0359] Enrichment of a T cell population by negative selection can be achieved using a combination of antibodies directed against surface markers unique to the negatively selected cells. For example, one method is cell sorting and / or selection via negative magnetic immunoadhesion, or flow cytometry using a cocktail of monoclonal antibodies directed against cell surface markers present on the negatively selected cells. For example, to enrich CD4+ cells by negative selection, the monoclonal antibody cocktail typically includes antibodies against CD14, CD20, CD11b, CD16, HLA-DR, and CD8. In certain embodiments, it may be desirable to enrich or positively select regulatory T cells, which typically express CD4+, CD25+, CD62Lhi, GITR+, and FoxP3+. Alternatively, in certain embodiments, regulatory T cells are depleted using anti-C25 conjugated beads or other similar selection methods.

[0217]

[0360] The cell concentration and surface (e.g., particles such as beads) may be varied to isolate a desired population of cells by positive or negative selection. In certain embodiments, it may be desirable to significantly reduce the volume in which the beads and cells are mixed together (i.e., increase the cell concentration) to ensure maximum cell-to-bead contact. For example, in one embodiment, a concentration of 2 billion cells / ml is used. For example, in one embodiment, a concentration of 1 billion cells / ml is used. In a further embodiment, a concentration of greater than 100 million cells / ml is used. In a further embodiment, a cell concentration of 10, 15, 20, 25, 30, 35, 40, 45, or 50 million cells / ml is used. In yet another embodiment, a cell concentration of 75, 80, 85, 90, 95, or 100 million cells / ml is used. In further embodiments, concentrations of 125 million or 150 million cells / ml may be used. The use of higher concentrations may lead to increased cell yield, cell activation, and cell expansion. Additionally, the use of higher cell concentrations may result in increased cell proliferation of target antibodies of interest, such as CD28-negative T cells. This allows for more efficient capture of cells that may weakly express CD28 or capture cells from samples containing many tumor cells (i.e., leukemic blood, tumor tissue, etc.). Such cell populations may have therapeutic value and be desirable to obtain. For example, using a high concentration of cells allows for more efficient selection of CD8+ T cells, which normally have weak CD28 expression.

[0218]

[0361] In some embodiments, monocyte populations (i.e., CD14+ cells) are depleted from blood preparations prior to ex vivo expansion by various methodologies, including anti-CD14-coated beads or columns, or by utilizing phagocytosis of these cells to facilitate removal, or by using counterflow centrifugal elutriation. In certain embodiments, paramagnetic particles of a size sufficient for uptake by phagocytic monocytes are used. In certain embodiments, the paramagnetic particles are commercially available beads, such as those manufactured by Dynal AS under the trade name Dynabeads™. Exemplary Dynabeads™ in this regard are M-280, M-450, and M-500. In some embodiments, other nonspecific cells are removed by coating the paramagnetic particles with "irrelevant" proteins (e.g., serum proteins or antibodies). Irrelevant proteins and antibodies include proteins and antibodies or fragments thereof that do not specifically target the T cells being expanded. In certain embodiments, irrelevant beads include beads coated with sheep anti-mouse antibody, goat anti-mouse antibody, and human serum albumin.

[0219]

[0362] In some embodiments, T cells are obtained from a patient immediately after a therapeutic agent (e.g., a drug administered to a subject to treat cancer). In this regard, it has been observed that after certain cancer treatments, particularly treatments with drugs that damage the immune system, the quality of T cells obtained immediately after treatment, during the period when patients typically recover from treatment, may be optimal or improved for their ability to be expanded ex vivo. Similarly, after ex vivo manipulation using the methods described herein, these cells may be in a favorable state for enhanced engraftment and in vivo expansion. Thus, it is contemplated within this context to collect blood cells, including T cells, dendritic cells, or other cells of the hematopoietic system, during this recovery period. Furthermore, in certain embodiments, mobilization (e.g., mobilization with GM-CSF) and conditioning regimens may be used in a subject to create a state favorable for the repopulation, recirculation, regeneration, and / or expansion of specific cell types, particularly during a defined period after treatment. Exemplary cell types include T cells, B cells, dendritic cells, and other cells of the immune system.

[0220]

[0363] In some embodiments, T cells are cultured ex vivo on a substantially non-toxic biocompatible surface. In some embodiments, the surface comprises an agent and / or ligand that binds to the surface. The biocompatible surface may be biodegradable or non-biodegradable. The surface may be natural or synthetic (e.g., polymeric).

[0221]

[0364] In some embodiments, the agent is bound or coupled to or incorporated into the surface by various methods known and available in the art. In some embodiments, the agent is a natural ligand, a protein ligand, or a synthetic ligand. Binding can be covalent or non-covalent, electrostatic, or hydrophobic, and can be achieved by various binding means, including, for example, chemical, mechanical, enzymatic, electrostatic, or other means by which the ligand can stimulate the cell. For example, an antibody against the ligand can be first bound to the surface, or avidin or streptavidin can be bound to the surface to bind to the biotinylated ligand. An antibody against the ligand can be bound to the surface via an anti-idiotypic antibody. Another example is to bind protein A or protein G or other nonspecific antibody-binding molecules to the surface to bind to the antibody. Alternatively, the ligand can be bound to the surface by chemical means, such as cross-linking to the surface using commercially available cross-linking reagents (Pierce, Rockford, Ill.) or other means. In certain embodiments, the ligand is covalently attached to the surface.

[0222]

[0365] In some embodiments, the agent, such as a specific ligand, is a single-origin or multi-origin agent. In some embodiments, the agent is an antibody or a functional fragment thereof. Furthermore, those skilled in the art will recognize that any ligand useful for activating and inducing proliferation of a T cell subset may also be immobilized on the surface of a biocompatible material. Additionally, while covalent binding of the ligand to the surface is one preferred methodology, adsorption or capture by a secondary monoclonal antibody may also be used. When the surface is that of a bead, the amount of specific ligand bound to the surface can be readily determined by flow cytometry analysis, and when the surface is, for example, a tissue culture dish, mesh, fiber, or bag, it can be determined by enzyme-linked immunosorbent assay (ELISA).

[0223]

[0366] In some embodiments, a blood sample or cytapheresis product is collected from a subject at a time before the expanded cells described herein are needed. Thus, a source of expanded cells can be collected at any time needed, and desired cells, such as T cells, can be isolated and frozen for later use in T cell therapy for any number of diseases or conditions that would benefit from T cell therapy, such as those described herein. In one embodiment, a blood sample or cytapheresis product is collected from a generally healthy subject. In certain embodiments, a blood sample or cytapheresis product is collected from a generally healthy subject who is at risk for developing a disease but has not yet developed the disease, and the desired cells are isolated and frozen for later use. In certain embodiments, T cells can be expanded, frozen, and used at a later time. In some embodiments, a sample is collected from a patient shortly after diagnosis of a particular disease described herein but before any treatment. In further embodiments, cells are isolated from a blood sample or cytapheresis product from a subject prior to any number of associated treatment modalities. Relevant treatment modalities include, but are not limited to, treatment with antivirals, chemotherapy, radiation, immunosuppressants such as cyclosporine, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies, cytoxins, fludarivine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, and irradiation. These drugs inhibit the calcium-dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit p70S6 kinase, which is important for growth factor-induced signaling (rapamycin). (Liu et al., Cell 66:807-815, 1991; Henderson et al., Immun. 73:316-321, 1991; Bierer et al., Curr. Opin. Immun. 5:763-773, 1993; Isoniemi, supra).In a further embodiment, the cells are isolated for a patient and frozen for later use in combination with (e.g., before, concurrently with, or after) T cell ablative therapy using either a bone marrow transplant, a chemotherapeutic agent such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or an antibody such as OKT3 or CAMPATH. In another embodiment, the cells can be isolated prior to treatment after B cell ablative therapy, such as an agent reactive with CD20, e.g., Rituxan, and frozen for later use for that treatment.

[0224]

[0367] In some embodiments, after isolation, T cells are incubated in cell culture medium in a culture device for a period of time or until the cells reach confluence before transferring the cells to another culture device. The culture device can be any culture device typically used for culturing cells in vitro. The period can be any period suitable for culturing cells in vitro. The T cell culture medium can be replaced at any time during the culture of the T cells. In some embodiments, the T cell culture medium is replaced approximately every 2-3 days. In some embodiments, the T cells are then harvested from the culture device and used immediately or cryopreserved and stored for use at a later time point. In some embodiments, the T cells are trypsinized, EDTA-treated, or cultured. Harvested by any other procedure used to harvest cells from the device. T cell activation and expansion

[0368] In some embodiments, T cells administered to a subject with an anti-TCR Vβ antibody are activated and expanded ex vivo using the anti-TCR Vβ antibody. In some embodiments, the method includes expanding T cells ex vivo using an anti-TCR βV agent, e.g., an anti-TCR βV antibody, or a functional fragment or variant thereof. Thus, in some embodiments, the methods described herein allow any T cell population to be activated and expanded ex vivo, substantially increasing the number of T cells for subsequent use after expansion. Thus, in some aspects, provided herein are methods for doubling, expanding, or otherwise culturing T cells isolated from a subject ex vivo using the methods disclosed herein.

[0225]

[0369] In some embodiments, the anti-TCRβV agent, eg, an anti-TCRβV antibody, is bound to a solid surface, eg, a bead, a cell culture plate, or the like.

[0370] In some embodiments, at least a plurality of T cells to be expanded comprise an exogenous nucleic acid or polypeptide. In some embodiments, the exogenous nucleic acid encodes a chimeric polypeptide. In some embodiments, the exogenous nucleic acid encodes an exogenous polypeptide. In some embodiments, the chimeric polypeptide encodes a chimeric antigen receptor or a chimeric T cell receptor. In some embodiments, the exogenous nucleic acid encodes an exogenous cell receptor. In some embodiments, the exogenous cell receptor is an exogenous T cell receptor. In some embodiments, the polypeptide comprises a chimeric antigen receptor or a chimeric T cell receptor. In some embodiments, the polypeptide comprises an exogenous cell receptor. In some embodiments, the exogenous cell receptor is an exogenous T cell receptor.

[0226]

[0371] In some embodiments, the methods described herein comprise introducing an exogenous nucleic acid into a plurality of T cells before contacting the plurality of T cells with an anti-TCRβV agent, e.g., an anti-TCRβV antibody. In some embodiments, the methods described herein comprise introducing an exogenous nucleic acid into a plurality of T cells after contacting the plurality of T cells with an anti-TCRβV agent, e.g., an anti-TCRβV antibody. In some embodiments, the methods described herein comprise contacting a plurality of T cells with an anti-TCRβV agent, e.g., an anti-TCRβV antibody, and then introducing an exogenous nucleic acid into the plurality of T cells while continuing to contact the plurality of T cells with the anti-TCRβV agent, e.g., an anti-TCRβV antibody. In some embodiments, the exogenous nucleic acid encodes a chimeric antigen receptor (CAR). In some embodiments, the exogenous nucleic acid encodes a T cell receptor.

[0227]

[0372] In some embodiments, a method of ex vivo T cell expansion includes contacting a plurality of T cells with a first agent comprising a domain that specifically binds to the TCRβV region, thereby generating a first T cell population. In some embodiments, the first T cell population exhibits one or more of decreased IL-1β expression, lower levels of IL-6, decreased TNFα expression, increased IL-2 expression, and decreased IFNγ expression compared to the plurality of T cells contacted with an agent comprising a domain that specifically binds CD3ε.

[0228]

[0373] In some embodiments, the contacting comprises incubating or culturing the plurality of T cells with an anti-TCRβ antibody (e.g., an anti-TCRβ antibody described herein) for at least about 10 minutes, 20 minutes, 30 minutes, 1 hour, 6 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 5 days, 7 days, 10 days, 14 days, 15 days, or 30 days. In some embodiments, the contacting comprises incubating or culturing the plurality of T cells with an anti-TCRβ antibody (e.g., an anti-TCRβ antibody described herein) for up to about 10 minutes, 20 minutes, 30 minutes, 1 hour, 6 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 21 days, 30 days, 45 days, or In some embodiments, the contacting comprises incubating or culturing the plurality of T cells with an anti-TCRβ antibody (e.g., an anti-TCRβ antibody described herein) for about 10-60 minutes, 10-30 minutes, 1-30 days, 1-21 days, 1-14 days, 1-10 days, 1-9 days, 1-8 days, 1-7 days, 1-6 days, 1-5 days, 1-3 days, 1-2 days, 21-30 days, 14-30 days, 7-30 days, 5-30 days, or 3-30 days.

[0229]

[0374] In some embodiments, a method of activating or expanding T cells comprises contacting a plurality of T cells with a plurality of anti-TCRβV antibodies (e.g., anti-TCRβV antibodies described herein), wherein the plurality of agents comprises at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 agents, and each of the plurality of anti-TCRβV antibodies comprises a domain that specifically binds to a different TCRβV region, thereby generating a first T cell population. In some embodiments, each of the plurality of anti-TCRβV antibodies specifically binds to a different TCRβV, and each TCRβV belongs to a different TCRβV subfamily or is a different member of the same TCRβV subfamily. In some embodiments, each of the plurality of anti-TCRβV antibodies is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ and a domain that specifically binds to a TCRβV region of a TCRβV belonging to the V3 subfamily, the TCRβV2 subfamily, the TCRβV15 subfamily, the TCRβV30 subfamily, the TCRβV19 subfamily, the TCRβV27 subfamily, the TCRβV28 subfamily, the TCRβV24 subfamily, the TCRβV20 subfamily, the TCRβV25 subfamily, or the TCRβV29 subfamily. In some embodiments, each of the multiple agents specifically binds to a different TCRβV, and each TCRβV belongs to a different TCRβV subfamily.

[0230]

[0375] In some embodiments, the first anti-TCRβV antibody further comprises a second domain that binds to a protein expressed on the surface of multiple T cell populations. In some embodiments, the first anti-TCRβV antibody is a bispecific antibody molecule. In some embodiments, the second domain specifically binds to a TCRβV region. In some embodiments, the second domain and the first domain specifically bind to different TCRβV regions. In some embodiments, the second domain and the first domain specifically bind to TCRβVs belonging to different subfamilies or different members of the same TCRβV subfamily. In some embodiments, the first domain is selected from the group consisting of a TCRβ V6 subfamily, a TCRβ V10 subfamily, a TCRβ V12 subfamily, a TCRβ V5 subfamily, a TCRβ V7 subfamily, a TCRβ V11 subfamily, a TCRβ V14 subfamily, a TCRβ V16 subfamily, a TCRβ V18 subfamily, a TCRβ V9 subfamily, a TCRβ V13 subfamily, a TCRβ V4 subfamily, a TCRβ V3 subfamily, a TCRβ V2 subfamily, a TCRβ V15 subfamily, a TCRβ V30 subfamily, a TCRβ V19 subfamily, a TCRβ V27 subfamily, a TCRβ V28 subfamily, a TCRβ V24 subfamily, a TCRβ V20 subfamily, a TCRβ V25 subfamily, or a TCRβ The second domain specifically binds to the TCRβV region of TCRβV belonging to the V29 subfamily, and is also involved in the TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, and TCRβ V3 subfamily. The second domain specifically binds to a TCRβV region of a TCRβV belonging to the TCRβV subfamily, TCRβV2 subfamily, TCRβV15 subfamily, TCRβV30 subfamily, TCRβV19 subfamily, TCRβV27 subfamily, TCRβV28 subfamily, TCRβV24 subfamily, TCRβV20 subfamily, TCRβV25 subfamily, or TCRβV29 subfamily. In some embodiments, the second domain and the first domain specifically bind to TCRβVs belonging to different subfamilies. In some embodiments, the second domain and the first domain specifically bind to different members of the same TCRβV subfamily. In some embodiments, the second domain specifically binds to CD19 or 4-1BB. Human T cell receptor (TCR) complex

[0376] T cell receptors (TCRs) are expressed on the surface of T cells. TCRs recognize antigens, e.g., peptides, that are presented on the surface of cells, e.g., antigen-presenting cells, bound to, e.g., major histocompatibility complex (MHC) molecules. TCRs are heterodimeric molecules and can include an alpha chain, a beta chain, a gamma chain, or a delta chain. TCRs that include an alpha chain and a beta chain are also referred to as TCRαβ. The TCR beta chain consists of the following regions (also known as segments): variable (V), diversity (D), joining (J), and constant (C) (Mayer G. and Nyland J. (2010) Chapter 10: Roles in the Immune Response - Major Histocompatibility Complex and T-cell Receptors - Roles in the Immune Response) in Immune Responses).:Microbiology and Immunology online, University of South Carolina School of Medicine). The TCR alpha chain consists of the V region, J region, and C region. Rearrangement of the T cell receptor (TCR) by somatic recombination of the V (variable), D (diversity), J (joining), and C (constant) regions is a critical event in T cell development and maturation. TCR gene rearrangement occurs in the thymus.

[0231]

[0377] A TCR may comprise a receptor complex known as a TCR complex, which comprises a TCR heterodimer comprising an alpha chain and a beta chain, and a dimeric signaling molecule, such as a CD3 co-receptor, e.g., CD3δ / ε and / or CD3γ / ε. TCRβV

[0378] Diversity of the immune system allows protection against a vast array of pathogens. Because germline genomes are limited in size, diversity is achieved not only through the process of V(D)J recombination, but also through nucleotide junction (junction between VD and DJ segments) deletion and pseudorandom, non-templated nucleotide addition. TCR beta genes undergo genetic rearrangement to generate diversity.

[0232]

[0379] TCR V beta repertoires vary between individuals and populations due to, for example, seven frequent inactivating polymorphisms in functional gene segments and large insertion / deletion-associated polymorphisms encompassing two V beta gene segments.

[0233]

[0380] The present disclosure provides, inter alia, exemplary antibody molecules and functional fragments thereof that bind, e.g., specifically bind, to a human TCR beta V chain (TCRβV), e.g., a TCRβV gene family, e.g., a TCRβV subfamily, as described herein. TCR beta V families and subfamilies are known in the art and are described, e.g., in Yassai et al. (2009) Immunogenetics 61(7):493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3):201-206. The antibodies described herein can be recombinant antibodies, e.g., recombinant non-murine antibodies, e.g., recombinant human antibodies or humanized antibodies. These anti-TCR Vβ antibodies can, in some embodiments, be used in engineered cell therapy. In some embodiments, the subject has cancer, e.g., an engineered T cell therapy, e.g., a CAR-T cell therapy, or an exogenous TCR T cell therapy.

[0234]

[0381] In one aspect, the present disclosure provides an anti-TCRβ antibody molecule that binds to a human TCRβV, e.g., a TCRβV family, e.g., a gene family. In some embodiments, the TCRβV gene family includes one or more subfamilies, e.g., as described herein, e.g., in FIG. 1. In some embodiments, the TCRβV gene family includes one or more subfamilies, e.g., as described herein, e.g., in FIG. The subfamilies include the V6 subfamily, the TCRβ V10 subfamily, the TCRβ V12 subfamily, the TCRβ V5 subfamily, the TCRβ V7 subfamily, the TCRβ V11 subfamily, the TCRβ V14 subfamily, the TCRβ V16 subfamily, the TCRβ V18 subfamily, the TCRβ V9 subfamily, the TCRβ V13 subfamily, the TCRβ V4 subfamily, the TCRβ V3 subfamily, the TCRβ V2 subfamily, the TCRβ V15 subfamily, the TCRβ V30 subfamily, the TCRβ V19 subfamily, the TCRβ V27 subfamily, the TCRβ V28 subfamily, the TCRβ V24 subfamily, the TCRβ V20 subfamily, the TCRβ V25 subfamily, or the TCRβ V29 subfamily.

[0235]

[0382] The TCRβ V6 subfamily is also known as TCRβ V13.1. In some embodiments, the TCRβ V6 subfamily includes TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the TCRβ V6 includes TCRβ V6-5*01. In some embodiments, the TCRβ V6, e.g., TCRβ V6-5*01, is recognized by, e.g., is bound by, SEQ ID NO: 11 and / or SEQ ID NO: 10.

[0236]

[0383] The TCRβ V10 subfamily is also known as TCRβ V12. In some embodiments, the TCRβ V10 subfamily comprises TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, or TCRβ V10-2*01.

[0237]

[0384] The TCRβ V12 subfamily is also known as TCRβ V8.1. In some embodiments, the TCRβ V12 subfamily includes TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01. In some embodiments, TCRβ V12 is recognized, e.g., bound, by SEQ ID NO:58.

[0238]

[0385] In some embodiments, the TCRβ V5 subfamily is selected from TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, and TCRβ V5-1*01. In some embodiments, the TCRβ V7 subfamily comprises TCRβ V7-7*01, TCRβ V7-6*01, TCRβ V7-8*02, TCRβ V7-4*01, TCRβ V7-2*02, TCRβ V7-2*03, TCRβ V7-2*01, TCRβ V7-3*01, TCRβ V7-9*03, or TCRβ V7-9*01. In some embodiments, the TCRβ V11 subfamily comprises TCRβ V11-1*01, TCRβ V11-2*01, or TCRβ V11-3*01.

[0239]

[0386] In some embodiments, the TCRβ V14 subfamily includes TCRβ V14*01. In some embodiments, the TCRβ V16 subfamily includes TCRβ V1 In some embodiments, the TCRβ V18 subfamily comprises TCRβ V18*01. In some embodiments, the TCRβ V9 subfamily comprises TCRβ V9*01 or TCRβ V9*02. In some embodiments, the TCRβ V13 subfamily comprises TCRβ V13*01. In some embodiments, the TCRβ V4 subfamily comprises TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ V4-1*01. In some embodiments, the TCRβ V3 subfamily comprises TCRβ V3-1*01. In some embodiments, the TCRβ V2 subfamily comprises TCRβ V2*01. In some embodiments, the TCRβ V15 subfamily comprises TCRβ V15*01. In some embodiments, the TCRβ V30 subfamily comprises TCRβ V30*01 or TCRβ V30*02. In some embodiments, the TCRβ V19 subfamily comprises TCRβ V19*01 or TCRβ V19*02. In some embodiments, the TCRβ V27 subfamily comprises TCRβ V27*01. In some embodiments, the TCRβ V28 subfamily comprises TCRβ V28*01. In some embodiments, the TCRβ V24 subfamily comprises TCRβ V24-1*01. In some embodiments, the TCRβ V20 subfamily comprises TCRβ V20-1*01 or TCRβ V20-1*02. In some embodiments, the TCRβ V25 subfamily comprises TCRβ V25-1*01. In some embodiments, the TCRβ V29 subfamily comprises TCRβ V29-1*01.

[0240] [Table 1-1]

[0241] [Table 1-2]

[0242] First drug

[0387] In some embodiments, the methods described herein include administering to a patient in need thereof a first agent that includes a domain that specifically binds to the TCR beta variable chain (TCRβV) region of a T cell bearing an αβ TCR and activates the T cell. In some embodiments, the first agent that includes a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

[0243]

[0388] In some embodiments, the antibody comprises a full-length antibody, a Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-exchange engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD). Anti-TCRβV antibody

[0389] In some embodiments, the methods provided herein include administering an anti-TCRβV antibody molecule that binds to a human TCRβV to a human subject (e.g., a subject with cancer), e.g., who is being co-administered with T cell therapy. In some embodiments, the anti-TCRβV antibodies described herein bind to a human TCRβV protein of a family or subfamily disclosed in Table 1. In some embodiments, the anti-TCRβV antibody molecule binds to one or more TCRβV subfamilies selected from subfamilies including the TCRβ V6 subfamily, the TCRβ V10 subfamily, the TCRβ V12 subfamily, the TCRβ V5 subfamily, the TCRβ V7 subfamily, the TCRβ V11 subfamily, the TCRβ V14 subfamily, the TCRβ V16 subfamily, the TCRβ V18 subfamily, the TCRβ V9 subfamily, the TCRβ V13 subfamily, the TCRβ V4 subfamily, the TCRβ V3 subfamily, the TCRβ V2 subfamily, the TCRβ V15 subfamily, the TCRβ V30 subfamily, the TCRβ V19 subfamily, the TCRβ V27 subfamily, the TCRβ V28 subfamily, the TCRβ V24 subfamily, the TCRβ V20 subfamily, the TCRβ V25 subfamily, or the TCRβ V29 subfamily. In some embodiments, the anti-TCRβV antibody molecule binds to the TCRβ V6 subfamily, including TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the TCRβ V6 subfamily includes TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the anti-TCRβV antibody molecule binds to the TCRβ V10 subfamily, including TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, or TCRβ V10-2*01. In some embodiments, the anti-TCRβV antibody molecule binds to the TCRβ V12 subfamily, including TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01. In some embodiments, the anti-TCRβV antibody molecule binds to the TCRβ V12 subfamily, including TCRβ V5-5*01, It binds to the TCRβ V5 subfamily, which includes TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, and TCRβ V5-1*01.

[0244]

[0390] In some embodiments, the anti-TCRβV antibody binds to at least two TCRβV subfamilies of the subfamilies in Table 1. For example, in some embodiments, the anti-TCRβV antibody binds to at least two (e.g., at least three, four, five, or six) of TCRβ V6-4*01, TCRβ V6-4*02, TCRβ V6-9*01, TCRβ V6-8*01, TCRβ V6-5*01, TCRβ V6-6*02, TCRβ V6-6*01, TCRβ V6-2*01, TCRβ V6-3*01, or TCRβ V6-1*01. In some embodiments, the anti-TCRβ antibody binds to at least two (e.g., at least three, four, five, or six) of TCRβ V10-1*01, TCRβ V10-1*02, TCRβ V10-3*01, or TCRβ V10-2*01. In some embodiments, the anti-TCRβ antibody binds to at least two (e.g., at least three, four, five, or six) of TCRβ V12-4*01, TCRβ V12-3*01, or TCRβ V12-5*01. In some embodiments, the anti-TCRβ antibody binds to at least two (e.g., at least three, four, five, or six) of TCRβ V5-5*01, TCRβ V5-6*01, TCRβ V5-4*01, TCRβ V5-8*01, or TCRβ V5-1*01. In some embodiments, the anti-TCRβV antibody binds to at least two (e.g., at least three, four, five, or six) of TCRβ V7-7*01, TCRβ V7-6*01, TCRβ V7-8*02, TCRβ V7-4*01, TCRβ V7-2*02, TCRβ V7-2*03, TCRβ V7-2*01, TCRβ V7-3*01, TCRβ V7-9*03, or TCRβ V7-9*01. In some embodiments, the anti-TCRβV antibody binds to at least two (e.g., at least three, four, five, or six) of TCRβ V11-1*01, TCRβ V11-2*01, or TCRβ V11-3*01. In some embodiments, the anti-TCRβ antibody binds to at least two of TCRβ V9*01 or TCRβ V9*02. In some embodiments, the anti-TCRβ antibody binds to at least two of TCRβ V4-2*01, TCRβ V4-3*01, or TCRβ In some embodiments, the anti-TCRβV antibody binds to at least two (e.g., at least three) of TCRβ V4-1*01 or TCRβ V30*01. In some embodiments, the anti-TCRβV antibody binds to at least two of TCRβ V30*01 or TCRβ V30*02. In some embodiments, the anti-TCRβV antibody binds to at least two of TCRβ V19*01 or TCRβ V19*02. In some embodiments, the anti-TCRβV antibody binds to at least two of TCRβ V20-1*01 or TCRβ V20-1*02.

[0245]

[0391] In some embodiments, the anti-TCRβV antibody binds to at least two different subfamilies of TCRβV. For example, in ... The first TCRβV domain binds to the TCRβV region of a TCRβV belonging to the TCRβV27 subfamily, TCRβV28 subfamily, TCRβV24 subfamily, TCRβV20 subfamily, TCRβV25 subfamily, or TCRβV29 subfamily, and the second domain binds to the TCRβV region of a TCRβV belonging to the TCRβV6 subfamily, TCRβV10 subfamily, TCRβV12 subfamily, TCRβV5 subfamily, TCRβV7 subfamily, TCRβV11 subfamily, TCRβV14 subfamily, TCRβV16 subfamily, TCRβV18 subfamily, TCRβV9 subfamily, TCRβV10 subfamily, TCRβV12 subfamily, TCRβV14 subfamily, TCRβV16 subfamily, TCRβV18 ... specifically binds to the TCRβV region of TCRβVs belonging to the TCRβV13 subfamily, TCRβV4 subfamily, TCRβV3 subfamily, TCRβV2 subfamily, TCRβV15 subfamily, TCRβV30 subfamily, TCRβV19 subfamily, TCRβV27 subfamily, TCRβV28 subfamily, TCRβV24 subfamily, TCRβV20 subfamily, TCRβV25 subfamily, or TCRβV29 subfamily; and further binds to the TCRβV region of TCRβVs belonging to the TCRβV6 subfamily, TCRβV 10 subfamilies, TCRβV12 subfamily, TCRβV5 subfamily, TCRβV7 subfamily, TCRβV11 subfamily, TCRβV14 subfamily, TCRβV16 subfamily, TCRβV18 subfamily, TCRβV9 subfamily, TCRβV13 subfamily, TCRβV4 subfamily, TCRβV3 subfamily, TCRβV2 subfamily, TCRβV15 subfamily, TCRβV30 subfamily, TCRβV19 subfamily, TCRβV27 subfamily The second domain also binds to a second TCRβV region of a TCRβV belonging to the TCRβV28 subfamily, TCRβV24 subfamily, TCRβV20 subfamily, TCRβV25 subfamily, or TCRβV29 subfamily, and the second domain binds to a second TCRβV region of a TCRβV belonging to the TCRβV6 subfamily, TCRβV10 subfamily, TCRβV12 subfamily, TCRβV5 subfamily, TCRβV7 subfamily, TCRβV11 subfamily, TCRβV14 subfamily, TCRβV16 subfamily, TCRβV18 subfamily. specifically binds to the TCRβV region of a TCRβV belonging to the TCRβV subfamily, TCRβV9 subfamily, TCRβV13 subfamily, TCRβV4 subfamily, TCRβV3 subfamily, TCRβV2 subfamily, TCRβV15 subfamily, TCRβV30 subfamily, TCRβV19 subfamily, TCRβV27 subfamily, TCRβV28 subfamily, TCRβV24 subfamily, TCRβV20 subfamily, TCRβV25 subfamily, or TCRβV29 subfamily;The first TCRβV region and the second TCRβV region belong to different TCRβV subfamilies (e.g., the TCRβV5 subfamily and the TCRβV7 subfamily);

[0246]

[0392] In some embodiments, the anti-TCRβV antibody comprises antibody sequences, for example, the CDRs, VH, VL, humanized VH chain sequences and humanized VL chain sequences disclosed in U.S. Patent Application Publication No. 20180256716, the contents of which are incorporated by reference in their entirety.

[0247]

[0393] In some embodiments, the anti-TCRβV antibody is an idiotypic antibody. In some embodiments, the anti-TCRβV antibody is a human antibody. In some embodiments, the anti-TCRβV antibody is a mouse antibody. In some embodiments, the anti-TCRβV antibody is a humanized antibody. In some embodiments, the anti-TCRβV antibody is a single-chain Fv (scFv) or Fab. In some embodiments, the anti-TCRβV antibody is a complete antibody comprising two antibody heavy chains, each comprising a variable region and a constant region, and two antibody light chains, each comprising a variable region and a constant region.

[0248]

[0394] In some embodiments, the anti-TCRβ antibody molecule does not bind to TCRβ V12 or binds to TCRβ V12 with an affinity and / or binding specificity that is less (e.g., less than about 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, or less than about half-, five-, or ten-fold less) than the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155, which is incorporated herein by reference.

[0249]

[0395] In some embodiments, the anti-TCRβV antibody molecule is a TCRβV antibody molecule, and a TCRβ antibody with an affinity and / or binding specificity that is greater (e.g., about 10% greater, 20% greater, 30% greater, 40% greater, 50% greater, 60% greater, 70% greater, 80% greater, 90% greater, or about 2-fold greater, 5-fold greater, or 10-fold greater) than the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155, which is incorporated herein by reference. Binds to V12.

[0250]

[0396] In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ with an affinity and / or binding specificity that is greater (e.g., about 10% greater, 20% greater, 30% greater, 40% greater, 50% greater, 60% greater, 70% greater, 80% greater, 90% greater, or about 2-fold greater, 5-fold greater, or 10-fold greater) than the affinity and / or binding specificity of the 16G8 murine antibody or a humanized version thereof, as described in U.S. Pat. No. 5,861,155, which is incorporated herein by reference. Binds to a TCRβ V region other than V12 (e.g., a TCRβ V region described herein, e.g., TCRβ V6 subfamily (e.g., TCRβ V6-5*01)).

[0251]

[0397] In some embodiments, the anti-TCRβ antibody molecule does not bind to TCRβ V5-5*01 or TCRβ V5-1*01, or binds to TCRβ V5-5*01 or TCRβ V5-1*01 with an affinity and / or binding specificity that is less (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 2-fold, 5-fold, or 10-fold less) than the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155, which is incorporated herein by reference.

[0252]

[0398] In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ with an affinity and / or binding specificity that is greater (e.g., about 10% greater, 20% greater, 30% greater, 40% greater, 50% greater, 60% greater, 70% greater, 80% greater, 90% greater, or about 2-fold greater, 5-fold greater, or 10-fold greater) than the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155, which is incorporated herein by reference. Binds to TCRβ V5-5*01 or TCRβ V5-1*01.

[0253]

[0399] In some embodiments, the anti-TCRβ antibody molecule binds to TCRβ with an affinity and / or binding specificity that is greater (e.g., about 10% greater, 20% greater, 30% greater, 40% greater, 50% greater, 60% greater, 70% greater, 80% greater, 90% greater, or about 2-fold greater, 5-fold greater, or 10-fold greater) than the affinity and / or binding specificity of the TM23 murine antibody or a humanized version thereof described in U.S. Pat. No. 5,861,155, which is incorporated herein by reference. V5-5*01 or a TCRβ V region other than TCRβ V5-1*01 (e.g., a TCRβ V region described herein, e.g., a TCRβ V6 subfamily (e.g., TCRβ V6-5*01)).

[0254]

[0400] In one embodiment, the first anti-TCRβV antibody is an anti-TCRβV6 antibody. In some embodiments, the anti-TCRβV antibody molecule binds to a human TCRβV6, e.g., a TCRβV6 subfamily including TCRβV6-4*01, TCRβV6-4*02, TCRβV6-9*01, TCRβV6-8*01, TCRβV6-5*01, TCRβV6-6*02, TCRβV6-6*01, TCRβV6-2*01, TCRβV6-3*01, or TCRβV6-1*01. In some embodiments, the TCRβV6 subfamily includes TCRβV6-5*01. In some embodiments, the anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody comprises at least one, two, or three complementarity determining regions (CDRs) from the light chain variable region of an antibody described herein, e.g., an antibody described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 1 %, 99% or more identical). In some embodiments, an anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody comprises at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising the amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2.

[0255]

[0401] In some embodiments, an anti-TCR β V6 (e.g., TCR β V6-5*01) antibody molecule comprises a heavy chain (HC) having CDR1, CDR2 and CDR3, wherein CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, according to the combined CDR1, CDR2 and CDR3 definitions. In some embodiments, an anti-TCR β V6 (e.g., TCR β V6-5*01) antibody molecule comprises a heavy chain (HC) having CDR1, CDR2 and CDR3, wherein CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 4, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, according to the Kabat CDR1, CDR2 and CDR3 definitions. In some embodiments, an anti-TCRβ V6 (e.g., TCRβ V6-5*01) antibody molecule comprises a heavy chain (HC) having CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 have the sequences set forth in SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:3, respectively, according to the Chothia definitions of CDR1, CDR2, and CDR3.

[0256]

[0402] In some embodiments, an anti-TCR β V6 (e.g., TCR β V6-5*01) antibody molecule comprises a light chain (LC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, respectively, according to the combined CDR1, CDR2 and CDR3 definitions. In some embodiments, an anti-TCR β V6 (e.g., TCR β V6-5*01) antibody molecule comprises a light chain (LC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, respectively, according to the Kabat CDR1, CDR2 and CDR3 definitions. In some embodiments, an anti-TCR β V6 (e.g., TCR β V6-5*01) antibody comprises a light chain (LC) having CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 have the sequences set forth in SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively, according to the Chothia definitions of CDR1, CDR2, and CDR3. In some embodiments, an anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO:12, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO:12. In some embodiments, the anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 13, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 13. In some embodiments, the anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 14, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 14.In some embodiments, the anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 15, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 15. In some embodiments, the anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 15. 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 12. In some embodiments, the anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 17, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 17. In some embodiments, the anti-TCR β V6 (e.g., anti-TCR β V6-5*01) antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 16, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 16.

[0257]

[0403] In some embodiments, the anti-TCR β antibody comprises a sequence set forth in Table 3 or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to a sequence set forth in Table 3.

[0258]

[0404] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 49, SEQ ID NO: 50, and SEQ ID NO: 51, respectively, according to the combined CDR1, CDR2 and CDR3 definitions. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 52, SEQ ID NO: 50, and SEQ ID NO: 51, respectively, according to the Kabat CDR1, CDR2 and CDR3 definitions. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 53, SEQ ID NO: 54, and SEQ ID NO: 51, respectively, according to the Chothia CDR1, CDR2 and CDR3 definitions.

[0259]

[0405] In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57, respectively, according to the combined CDR1, CDR2 and CDR3 definitions. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57, respectively, according to the Kabat CDR1, CDR2 and CDR3 definitions. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57, respectively, according to the Chothia CDR1, CDR2 and CDR3 definitions. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 61, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 61. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 60, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 60. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 63, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 64. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VL) set forth in SEQ ID NO: 66, or a sequence substantially identical to SEQ ID NO: 66. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VL) set forth in SEQ ID NO: 64, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 64. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VL) set forth in SEQ ID NO: 63, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 63. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 62, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 62. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 65, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 65. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 67, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 67. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 68, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 68. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 69, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 69.

[0260]

[0406] In some embodiments, the anti-TCR β antibody comprises a sequence set forth in Table 4 or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to a sequence set forth in Table 4.

[0261]

[0407] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72, respectively, according to the combined CDR1, CDR2 and CDR3 definitions. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 73, SEQ ID NO: 74, and SEQ ID NO: 72, respectively, according to the Kabat CDR1, CDR2 and CDR3 definitions. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 75, SEQ ID NO: 71, and SEQ ID NO: 72, respectively, according to the Chothia CDR1, CDR2 and CDR3 definitions.

[0262]

[0408] In some embodiments, an anti-TCRβV antibody molecule comprises a light chain (LC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78, respectively, according to the combined CDR1, CDR2 and CDR3 definitions. In some embodiments, an anti-TCRβV antibody molecule comprises a light chain (LC) having CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 have the sequences set forth in SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78, respectively, according to the Kabat ... and a light chain (LC) having the sequence set forth in SEQ ID NO: 76, SEQ ID NO: 77, and SEQ ID NO: 78, respectively, according to the definitions of CDR1, CDR2, and CDR3 of Chothia. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 82, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 82. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 81, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 81. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 83, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 83. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 84, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 84. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VL) set forth in SEQ ID NO: 85, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 85. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 86, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 86.In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 87, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 87. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 88, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 88. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 89, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 89. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 90, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 90. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 91, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 91. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 92, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 92. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 93, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 93.In some embodiments, the anti-TCRβ antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 94, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 94. In some embodiments, the anti-TCRβ antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 95, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical to the sequence of the present invention.

[0263]

[0409] In some embodiments, the anti-TCR β antibody comprises a sequence set forth in Table 5 or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to a sequence set forth in Table 5.

[0264]

[0410] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 108, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 108. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 109, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 109. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 110, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 110. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 111, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 111. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 112, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 112. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 113, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 113. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 114, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 114.

[0265]

[0411] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 127, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 127. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 128, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 128. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 129, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 129. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 130, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 130. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 131, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 131.

[0266]

[0412] In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 132, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 132. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 133, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 133. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 134, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 134. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 135, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 135. In some embodiments, the anti-TCRβV antibody molecule comprises a light chain (LC) variable region (VL) set forth in SEQ ID NO: 136, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 136.

[0267]

[0413] In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 149, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 149. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 150, or a sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to SEQ ID NO: 150. In some embodiments, the anti-TCRβV antibody molecule comprises a heavy chain (HC) variable region (VH) set forth in SEQ ID NO: 151, or a sequence that is substantially identical (e.g., at l...

Claims

1. 1. A method of reducing or altering an immune response induced by adoptive T cell therapy in a subject, comprising: (a) administering to the subject an adoptive T cell therapy, the adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; (b) administering to the subject a first agent that includes a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell; A method comprising:

2. 2. The method of claim 1, wherein the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered in an amount sufficient to reduce or alter an immune response induced by the adoptive T cell therapy in the subject.

3. 3. The method of claim 1 or 2, wherein the decrease is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region, and the decrease is in comparison to the level of the cytokine or chemokine in a sample from the subject before administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region to the subject and after administration of the adoptive T cell therapy.

4. 1. A method of mitigating an excessive immune response induced by adoptive T cell therapy in a subject, comprising: (a) administering to the subject an adoptive T cell therapy, the adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; (b) administering to the subject a first agent that includes a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell; A method comprising:

5. 5. The method of claim 4, wherein the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered in an amount sufficient to mitigate an excessive immune response induced by the adoptive T cell therapy in the subject.

6. 6. The method of claim 4 or 5, wherein the alleviation is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the first agent that comprises the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region, the alleviation is in comparison to the level of the cytokine or chemokine in a control sample from the subject before administration of the first agent that comprises the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region to the subject and before administration of the adoptive T cell therapy, and the level of a cytokine or chemokine from a sample from the subject after administration of the first agent that comprises the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is within 1000 times, 500 times, 400 times, 300 times, 200 times, 100 times, 50 times, 25 times, 10 times, 5 times, or 2 times of the level in the control sample.

7. 1. A method of treating cancer in a subject, comprising: (a) administering to the subject an adoptive T cell therapy, wherein the adoptive T cell therapy is administered to a subject that expresses an αβ T cell receptor (TCR) that includes a T cell receptor beta variable chain (TCRβV) region. comprising a plurality of T cells expressing (b) administering to the subject a first agent that includes a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell; A method comprising:

8. 8. The method of claim 7, wherein the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered in an amount sufficient to reduce or alter the immune response induced by the adoptive T cell therapy in the subject.

9. 9. The method of claim 8, wherein the reduction is determined by measuring the level of a cytokine or chemokine in a sample from the subject following administration of the first agent, and the reduction is in comparison to the level of the cytokine or chemokine in a control sample from a subject administered the adoptive T cell therapy in the absence of the first agent.

10. 8. The method of claim 7, wherein the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to ameliorate a symptom induced by the adoptive T cell therapy.

11. 11. The method of claim 10, wherein the amelioration of symptoms is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the first agent, and wherein the reduction is in comparison to the level of the cytokine or chemokine in a sample from the subject before administration of the first agent to the subject and after administration of the adoptive T cell therapy.

12. 1. A method of treating cancer in a subject in need thereof, comprising: (a) administering to the subject a first pharmaceutical composition comprising an adoptive T cell therapy that induces an immune response against cancer cells in the subject, the adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; (b) administering to the subject a second pharmaceutical composition comprising a first agent that comprises a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell; A method comprising:

13. 13. The method of claim 12, wherein the second pharmaceutical composition comprising the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to reduce the immune response induced by the adoptive T cell therapy in the subject.

14. 14. The method of claim 13, wherein the reduction is determined by measuring the level of a cytokine or chemokine in a sample from the subject after administration of the second pharmaceutical composition, and the reduction is in comparison to the level of the cytokine or chemokine in a control sample from a subject administered the first pharmaceutical composition in the absence of the second pharmaceutical composition.

15. 13. The method of claim 12, wherein the second pharmaceutical composition comprising the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to ameliorate a symptom induced by the adoptive T cell therapy.

16. The decrease is in a cytokine or cytokine agonist in a sample from the subject after administration of the second pharmaceutical composition.

16. The method of claim 15, wherein the decrease is determined by measuring the level of a cytokine or chemokine in a sample from the subject before administration of the second pharmaceutical composition and after administration of the first pharmaceutical composition to the subject.

17. The first pharmaceutical composition is administered at a dose of 0.1 to 10.0 x 10 per kg of the subject's body weight. ６ cells per kg of the subject's body weight, ６ cells per kg of the subject's body weight, ６ cells per kg of the subject's body weight, ６ cells per kg of the subject's body weight, ６ cells per kg of the subject's body weight, ６ 0.1-4.0 x 10 cells per kg of the subject's body weight ６ 0.1-3.0 x 10 cells per kg of the subject's body weight ６ 0.1-2.0 x 10 cells per kg of the subject's body weight ６ cells, or 0.1-1.0 x 10 cells per kg of the subject's body weight ６ 17. The method of any one of claims 12 to 16, comprising cells.

18. The first pharmaceutical composition is administered at a dose of 0.2 to 5.0 x 10 per kg of the subject's body weight. ６ 20. The method of claim 17, comprising:

19. The first pharmaceutical composition is administered at a dose of 2.0×10 per kg of the subject's body weight. ６ 20. The method of claim 18, comprising:

20. The first pharmaceutical composition is 0.1 to 10×10 ８ Cells, 0.1-9 x 10 ８ Cells, 0.1-8 x 10 ８ Cells, 0.1-7 x 10 ８ Cells, 0.1-6 x 10 ８ Cells, 0.1-5 x 10 ８ Cells, 0.1-4 x 10 ８ Cells, 0.1-3 x 10 ８ Cells, 0.1-2 x 10 ８ cells, or 0.1-1 x 10 ８ 20. The method of claim 17, comprising:

21. The first pharmaceutical composition is 0.1 to 2.5 × 10 ８ 20. The method of claim 17, comprising:

22. The first pharmaceutical composition is 0.6 to 6.0 x 10 ８ 20. The method of claim 17, comprising:

23. The first pharmaceutical composition is administered at a dose of 2×10 per kg of body weight. ６ 20. The method of claim 17, comprising:

24. The first pharmaceutical composition is ８ 20. The method of claim 17, comprising:

25. 1. A method of reducing an immune response induced by adoptive T cell therapy in a subject, comprising: (a) administering an adoptive T cell therapy to the subject, the adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; (b) administering to the subject a first agent that comprises a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell when the level of the cytokine or chemokine in the sample from the subject is at least 1000-fold greater than a baseline level; A method comprising:

26. The first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is used to reduce an immune response induced by the adoptive T cell therapy.

26. The method of claim 25, wherein the therapeutic agent is administered in an amount sufficient to

27. 27. The method of claim 25 or 26, wherein the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject if the level of a cytokine or chemokine in a sample from the subject is at least 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 100,000 times higher than a baseline level.

28. 1. A method of reducing an immune response in a subject administered adoptive T cell therapy, comprising: (a) administering to the subject an adoptive T cell therapy, the adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβ V) region and activates the T cell in an amount sufficient to reduce an excessive immune response induced by the adoptive cell therapy, wherein the reduction is determined by measuring the presence or severity of at least one symptom associated with the excessive immune response in the subject after administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβ V) region, wherein the reduction is in comparison to the presence or severity of the at least one symptom in the subject before administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβ V) region to the subject and after administration of the adoptive cell therapy.

29. 29. The method of claim 28, wherein the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region is administered to the subject in an amount sufficient to reduce an excessive immune response induced by the adoptive T cell therapy in the subject.

30. 1. A method of mitigating an excessive immune response in a subject receiving an immunotherapeutic agent, comprising: (a) administering to the subject an adoptive T cell therapy, the adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; (b) administering to the subject a first agent that includes a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell, in an amount sufficient to reduce an excessive immune response induced by the adoptive cell therapy; the alleviation is determined by measuring the severity of at least one symptom associated with the excessive immune response in the subject following administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβ V) region, and the alleviation is in comparison to the severity of at least one symptom associated with the excessive immune response in the subject prior to administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβ V) region to the subject and prior to administration of the adoptive T cell therapy; The at least one symptom associated with the excessive immune response in the subject after administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβ V) region is less severe compared to the at least one symptom prior to administration of the first agent comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβ V) region to the subject and prior to administration of the adoptive T cell therapy.

31. The first agent, comprising the domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region, inhibits the excess T cell proliferation induced by adoptive T cell therapy in the subject.

31. The method of claim 30, administered to the subject in an amount sufficient to mitigate the immune response.

32. 32. The method of any one of claims 28 to 31, wherein the at least one symptom is associated with cytokine release syndrome, macrophage activation syndrome, neurotoxicity, or tumor lysis syndrome.

33. 33. The method of claim 32, wherein the at least one symptom is associated with cytokine release syndrome.

34. 34. The method of claim 33, wherein the at least one symptom comprises hemophagocytic lymphohistiocytosis (HLH), fever, nausea, vomiting, chills, hypotension, tachycardia, arrhythmia, cardiomyopathy, acute heart failure, asthenia, headache, rash, dyspnea, encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, hallucinations, cerebral edema, hepatomegaly, hypofibrinogenemia, liver failure, diarrhea, edema, stiffness, arthralgia, myalgia, acute renal failure, splenomegaly, respiratory failure, pulmonary edema, hypoxia, capillary leak syndrome, macrophage activation syndrome, or tachypnea.

35. 33. The method of claim 32, wherein the at least one symptom is associated with neurotoxicity.

36. 36. The method of claim 35, wherein the at least one symptom comprises encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, or cerebral edema.

37. 33. The method of claim 32, wherein the at least one symptom is associated with macrophage activation syndrome.

38. 38. The method of claim 37, wherein the at least one symptom comprises fever, headache, lymphadenopathy, hepatosplenomegaly, coagulopathy, rash, tachycardia, arrhythmia, cardiomyopathy, lethargy, pancytopenia, liver dysfunction, disseminated intravascular coagulation, hypofibrinogenemia, hyperferritinemia, or hypertriglyceridemia.

39. 33. The method of claim 32, wherein the at least one symptom is associated with tumor lysis syndrome.

40. 40. The method of claim 39, wherein the at least one symptom comprises nausea, vomiting, diarrhea, muscle cramps, muscle spasms, weakness, numbness, tingling, fatigue, lethargy, decreased urination, encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, cerebral edema, or hallucinations.

41. 1. A method of treating or alleviating an adoptive T cell therapy induced syndrome in a subject, comprising: (a) administering to the subject an adoptive T cell therapy, the adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; (b) administering to the subject a first agent comprising a domain that specifically binds to the T cell receptor beta variable chain (TCRβV) region and activates the T cell, in an amount sufficient to prevent, treat, or reduce the severity of at least one symptom associated with the adoptive T cell therapy induced syndrome; A method comprising:

42. 42. The method of claim 41, wherein the syndrome is cytokine release syndrome, macrophage activation syndrome, neurotoxicity, or tumor lysis syndrome.

43. 43. The method of claim 42, wherein the syndrome is cytokine release syndrome.

44. 44. The method of claim 43, wherein the at least one symptom comprises hemophagocytic lymphohistiocytosis, fever, nausea, vomiting, chills, hypotension, tachycardia, arrhythmia, cardiomyopathy, acute heart failure, asthenia, headache, rash, dyspnea, encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, cerebral edema, hepatomegaly, hypofibrinogenemia, liver failure, diarrhea, edema, stiffness, arthralgia, myalgia, acute renal failure, splenomegaly, respiratory failure, pulmonary edema, hypoxia, capillary leak syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis (HLH), or tachypnea.

45. 42. The method of claim 41, wherein the syndrome is neurotoxicity.

46. 46. ​​The method of claim 45, wherein the at least one symptom comprises encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, or cerebral edema.

47. 42. The method of claim 41, wherein the syndrome is macrophage activation syndrome.

48. 48. The method of claim 47, wherein the at least one symptom comprises fever, headache, lymphadenopathy, hepatosplenomegaly, coagulopathy, rash, tachycardia, arrhythmia, cardiomyopathy, lethargy, pancytopenia, liver dysfunction, disseminated intravascular coagulation, hypofibrinogenemia, hyperferritinemia, or hypertriglyceridemia.

49. 42. The method of claim 41, wherein the syndrome is tumor lysis syndrome.

50. 50. The method of claim 49, wherein the at least one symptom comprises nausea, vomiting, diarrhea, muscle cramps, muscle spasms, weakness, numbness, tingling, fatigue, lethargy, decreased urination, encephalopathy, aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, cerebral edema, or hallucinations.

51. 51. The method of any one of claims 1-50, wherein said administration of said first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region results in an increased proliferation rate of said plurality of T cells expressing an αβ T cell receptor (TCR) that comprises a T cell receptor beta variable chain (TCRβV) region.

52. 52. The method of claim 51, wherein the rate of proliferation is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold compared to the rate of proliferation of a comparable plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region administered in the absence of the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region.

53. 1. A method of in vivo expansion of a population of adoptively transferred T cells administered to a subject, comprising: (c) administering to the subject a population of T cells capable of inducing an immune response against cancer cells in the subject; (d) administering to the subject a first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, wherein administration of the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region increases the proliferation rate of the T cell population compared to a comparable T cell population administered in the absence of the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region; A method comprising:

54. 54. The method of claim 53, wherein the proliferation rate is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold compared to the proliferation rate of the equivalent T cell population administered in the absence of the first agent that comprises a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region.

55. 55. The method of any one of claims 1-54, wherein the subject is not administered a conditioning regimen comprising at least one lymphodepleting agent.

56. The at least one lymphodepleting agent may be cyclophosphamide, fludarabine, mechlorethamine, chlorambucil, melphalan, ifosfamide, thiotepa, hexamethylmelamine, busulfan, nitrosourea, platinum, methotrexate, azathioprine, mercaptopurine, procarbazine, dacarbazine, temozolomide, carmustine, lomustine, streptozocin, fluorouracil, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, mycophenolate mofetil, rapamycin, cyclosporine, deoxyspergualin, or cyclosporine.

56. The method of claim 55, wherein the antibody is a soluble complement receptor 1, cobra venom factor, compstatin, methylprednisolone, leflunomide, anti-thymocyte globulin antibody, anti-CD154 antibody, anti-CD40 antibody, anti-CD20 antibody, anti-IL-6R antibody, anti-IL-6 antibody, anti-IL-2R antibody, anti-CXCR3 antibody, anti-ICOS antibody, anti-OX40 antibody, or anti-CD122 antibody, anti-C5 antibody, abatacept, belatacept, sirolimus, everolimus, tacrolimus, daclizumab, basiliximab, infliximab, eculizumab, rituximab, alemtuzumab, tocilizumab, sarilumab, or olokizumab.

57. 57. The method of claim 56, wherein the at least one lymphodepleting agent is cyclophosphamide or fludarabine.

58. 58. The method of any one of claims 55 to 57, wherein the conditioning regimen comprises at least two lymphodepleting agents.

59. 59. The method of claim 58, wherein the at least two lymphodepleting agents are cyclophosphamide and fludarabine.

60. 60. The method of any one of claims 1-59, wherein the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is administered to the subject before, simultaneously with, or after the adoptive T cell therapy is administered to the subject.

61. the first agent comprises a domain that specifically binds to a T cell receptor beta variable chain (TCRβ V) region, the TCRβ V region being selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, and the second agent is a TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, or TCRβ V22 subfamily. subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ 61. The method of any one of claims 1 to 60, wherein the first agent and the second agent each comprise a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V28 subfamily, the TCRβ V24 subfamily, the TCRβ V20 subfamily, the TCRβ V25 subfamily, or the TCRβ V29 subfamily, and wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

62. The plurality of T cells express an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region, the TCRβV region being selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V30 subfamily, TCRβ V31 subfamily, TCRβ V32 subfamily, TCRβ V33 subfamily, TCRβ V34 subfamily, TCRβ V35 subfamily, TCRβ V36 subfamily, TCRβ V37 subfamily, TCRβ V38 subfamily, TCRβ V39 subfamily, TCRβ V38 subfamily, TCRβ V39 subfamily, TCRβ V36 subfamily, TCRβ V37 subfamily, TCRβ V38 subfamily, TCRβ V39 subfamily, TCRβ V39 subfamily, TCRβ V30 subfamily, TCRβ V30 subfamily, TCRβ V31 subfamily, TCRβ V32 subfamily, TCRβ V33 subfamily, TCRβ V34 subfamily, TCRβ V35 subfamily, TCRβ V36 subfamily, TCRβ V37 subfamily, TCRβ V38 subfamily, TCRβ V39 subfamily, TCRβ V39 subfamily, TCRβ V38 subfamily, TCRβ V39 subfamily, TCRβ V39 subfamily, TCRβ V39 subfamily, TCRβ V39 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily, and the second agent is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ 62. The method of any one of claims 1 to 61, wherein the first agent and the second agent each comprise a domain that specifically binds to a second TCRβV region of a TCRβV belonging to the V27 subfamily, the TCRβ V28 subfamily, the TCRβ V24 subfamily, the TCRβ V20 subfamily, the TCRβ V25 subfamily, or the TCRβ V29 subfamily, and wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

63. The method of any one of claims 1 to 62, wherein the subject has cancer.

64. 64. The method of claim 63, wherein the cancer is a hematological malignancy.

65. 64. The method of claim 63, wherein the cancer is a solid tumor.

66. 64. The method of claim 63, wherein the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, prostate cancer, sarcoma, stomach cancer, thyroid cancer, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, gastrointestinal carcinoid tumor, Hodgkin's lymphoma, kidney cancer, mesothelioma, mast cell tumor, melanoma, multiple myeloma, nasopharyngeal cancer, non-Hodgkin's lymphoma, pancreatic cancer, peritoneal cancer, renal cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, and thyroid cancer. Method of posting.

67. 64. The method of claim 63, wherein the cancer is bladder cancer, epithelial cancer, bone cancer, brain cancer, breast cancer, esophageal cancer, gastrointestinal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, stomach cancer, thyroid cancer, alveolar rhabdomyosarcoma, anal canal, rectal cancer, eye cancer, cervical cancer, gallbladder cancer, pleural cancer, oral cancer, vulvar cancer, colon cancer, cervical cancer, fibrosarcoma, renal cancer, mesothelioma, mast cell tumor, melanoma, nasopharyngeal cancer, pancreatic cancer, peritoneal cancer, kidney cancer, skin cancer, small intestine cancer, or testicular cancer.

68. 64. The method of claim 63, wherein the cancer is leukemia, myeloma, or lymphoma.

69. 69. The method of claim 68, wherein the cancer is acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiple myeloma.

70. 70. The method of any one of claims 1-69, wherein the adoptive T cell therapy agent comprises an exogenous receptor.

71. 71. The method of claim 70, wherein the exogenous cell receptor is a chimeric antigen receptor (CAR) or an exogenous T cell receptor (TCR).

72. 72. The method of claim 71, wherein the chimeric antigen receptor (CAR) or chimeric T cell receptor (TCR) comprises an antigen-binding region that specifically binds to a tumor-associated antigen.

73. The chimeric antigen receptor (CAR) or exogenous T cell receptor (TCR) is selected from the group consisting of CD19, CD123, CD22, CD30, CD171, CS-1, C-type lectin-like molecule-1, CD33, CISH, epidermal growth factor receptor variant III (EGFRvIII), ganglioside G2 (GD2), ganglioside GD3, TNF receptor family member B cell maturation (BCMA), Tn antigen (TnAg) or (GalNAcα-Ser / Thr)), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), Fms-like tyrosine kinase 3 (FLT3), tumor-associated glycoprotein 72 (TAG72), CD38, CD44v6, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EPCAM), B7H3 (CD276), KIT (CD117), interleukin-13 receptor subunit alpha-2, mesothelin, interleukin-11 receptor alpha (IL -11Ra), prostate stem cell antigen (PSCA), protease serine 21, vascular endothelial growth factor receptor 2 (VEGFR2), Lewis (Y) antigen, CD24, platelet-derived growth factor receptor beta (PDGFR-beta), stage-specific embryonic antigen-4 (SSEA-4), CD20, folate receptor alpha, receptor tyrosine-protein kinase ERBB2 (Her2 / neu), mucin 1, cell surface associated (MUC1), epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), prostase, prostatic acid phosphatase (PAP), elongation factor 2 mutated (ELF2M), ephrinB2, fibroblast activation protein alpha (FAP), insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX), proteasome (prosome, macropain) subunit, beta, 9 (LMP2), glycoprotein 100 (gp100), breakpoint cluster region (BCR), and oncogene fusion protein (bcr-a) consisting of Abelson murine leukemia viral oncogene homolog 1 (Abl). bl), tyrosinase, ephrin type A receptor 2 (EphA2), fucosyl GM1, sialyl Lewis adhesion molecule (sLe), ganglioside GM3, transglutaminase 5 (TGS5), high molecular weight melanoma-associated antigen (HMWMAA), o-acetyl-GD2 ganglioside (OAcGD2), folate receptor beta, tumor endothelial marker 1 (TEM1 / CD248), tumor endothelial marker 7-related (TEM7R), claudin 6 (CLDN6), thyroid-stimulating hormone receptor (TSHR), G protein-coupled receptor cleavage RasC group 5, member D (GPRC5D), chromosome X open reading frame 61 (CXORF61), CD97, CD179a, anaplastic lymphoma kinase (ALK), polysialic acid, placenta specific 1 (PLAC1), hexasaccharide moiety of globo H glycoceramide (GloboH), mammary differentiation antigen (NY-BR-1), uroplakin 2 (UPK2), hepatitis A virus cellular receptor 1 (HAVCR1), adrenergic receptor beta 3 (ADRB3), pannexin 3 (PANX3), G-tan Protein-coupled receptor 20 (GPR20), lymphocyte antigen 6 complex, locus K9 (LY6K), olfactory receptor 51E2 (OR51E2), TCR gamma alternative reading frame protein (TARP), Wilms tumor protein (WT1), cancer / testis antigen 1 (NY-ESO-1), cancer / testis antigen 2 (LAGE-1a), melanoma-associated antigen 1 (MAGE-A1), ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML), sperm protein 17 (SPA17), X antigen family, member 1A (XAGE1), angiopoietin-binding cell surface receptor 2 (Tie2), melanoma cancer testis antigen-1 (MAD-CT-1), melanoma cancer testis antigen 2 (MAD-CT-2), Fos-related antigen 1, tumor protein p53 (p53), p53 mutant, prostein, survivin, telomerase, prostate cancer tumor antigen-1, melanoma antigen 1 recognized by T cells, rat sarcoma (Ras) mutant, human telomerase reverse transcriptase (hTERT), sarcoma translocation breakpoints, apoptosis melanoma inhibitor of IL-1 (ML-IAP), ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene), N-acetylglucosaminyltransferase V (NA17), association box protein Pax-3 (PAX3), androgen receptor, cyclin B1, v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN), Ras homolog family member C (RhoC), tyrosinase-related protein 2 (TRP-2), cytochrome P4501B1 (CYP1B1), CCCTC-binding factor (zinc finger protein)-like, T-cell-recognized squamous cell carcinoma antigen 3 (SART3), paired box protein Pax-5 (PAX5), proacrosin-binding protein sp32 (OY-TES1), lymphocyte-specific protein tyrosine kinase (LCK), A-kinase anchoring protein 4 (AKAP-4), synovial sarcoma, X-breakpoint 2 (SSX2), receptor for advanced glycation end products (RAGE-1), renal ubiquitous 1 (RU1), renal ubiquitous 2 (RU2), legumain, human papillomavirus E6 (HPV E6), human papillomavirus E7 (HPV E7), intestinal carboxylesterase, heat shock protein 70-2 mutant (mutated) hsp70-2), CD79a, CD79b, CD72, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), Fc fragment of the IgA receptor (FCAR or CD89), leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2), CD300 molecule-like family member f (CD300LF), C-type lectin domain family 12 member A (CLEC12A), bone marrow stromal cell antigen 2 (BST2), EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2), lymphocyte antigen 75 (LY75), glypican 3 (GPC3), Fc receptor-like 5 (FCRL5), or immunoglobulin lambda-like polypeptide 1 (IGLL1) antigen.

74. 74. The method of any one of claims 1-73, wherein the adoptive T cell therapy (ACT) comprises a plurality of cells that are allogeneic or autologous to the subject.

75. 75. The method of any one of claims 1 to 74, wherein the subject has or is at risk of developing cytokine release syndrome.

76. The cytokine or chemokine is IL-6, IFNγ, TNFα, IFNα, IL-1β, IL-8, IL-10, IL-2, IL-4, IL-5, IL-7, IL-10, IL-13, IL-15, IL-1RA , sIL1RI, sIL1RII, sIL2Rα, sgp130, sIL6R, MCP1, MIP1α, MIP1β, MIG, GCSF, IP10, sTNFRI, sTNFRII, HGF, VEGF, sCD30, or 30. The method of any one of claims 3, 6, 9, 11, 14, 16, or 27, wherein the antibody is GM-CSF.

77. 77. The method of any one of claims 1 to 76, wherein the first agent comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region is an antibody, a functional fragment thereof, or a functional variant thereof.

78. 78. The method of claim 77, wherein the antibody comprises a full length antibody, Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-swap engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

79. 79. The method of claim 77 or 78, wherein the antibody binds to at least one Fc receptor.

80. 72. The method of claim 71, wherein the antibody exhibits at least one effector function.

81. The method of claim 77 or 78, wherein the antibody is a variant that does not bind to at least one of the Fc receptors to which the corresponding wild-type antibody binds.

82. The method of claim 81 , wherein the antibody lacks at least one effector function.

83. The method of any one of claims 1 to 82, wherein the sample is a blood sample or a serum sample.

84. 1. A method of reducing cytokine or chemokine release induced by adoptive T cell therapy in a subject in need thereof, comprising: (a) measuring a first level of a cytokine or chemokine in a first sample from the subject prior to administering the adoptive T cell therapy to the subject; (b) administering the adoptive T cell therapy to the subject, the adoptive T cell therapy comprising a plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region; and (c) measuring a second level of said cytokine or chemokine in a second sample from said subject after administering said adoptive T cell therapy to said subject; (d) comparing the first level with the second level to determine the subject's risk of having or developing at least one symptom associated with an excessive immune response induced by the adoptive T cell therapy; (e) administering to the subject a first agent comprising an agonist comprising a domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region if the subject is determined to have or be at risk for developing the at least one symptom, wherein the agonist ameliorates the at least one symptom; A method comprising:

85. 85. The method of claim 84, wherein the at least one symptom is associated with cytokine release syndrome, macrophage activation syndrome, neurotoxicity, or tumor lysis syndrome.

86. The at least one symptom is hemophagocytic lymphohistiocytosis, fever, nausea, vomiting, chills, hypotension, tachycardia, arrhythmia, cardiomyopathy, acute heart failure, asthenia, headache, rash, dyspnea, encephalopathy, 86. The method of claim 84 or 85, comprising aphasia, tremor, ataxia, hemiplegia, paralysis, dysmetria, seizures, motor weakness, loss of consciousness, cerebral edema, hepatomegaly, hypofibrinogenemia, liver failure, diarrhea, edema, stiffness, arthralgia, myalgia, acute renal failure, splenomegaly, respiratory failure, pulmonary edema, hypoxia, capillary leak syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis (HLH), or tachypnea.

87. 87. The method of any one of claims 1-86, wherein the plurality of T cells expressing an αβ T cell receptor (TCR) comprising a T cell receptor beta variable chain (TCRβV) region of the adoptive cell therapy are expanded ex vivo by contacting the plurality of T cells with an agent comprising a first domain that specifically binds to a T cell receptor beta variable chain (TCRβV) region, thereby generating a first population of T cells.

88. the first agent is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ V24 subfamily, TCRβ V20 subfamily, TCRβ and a domain that specifically binds to a TCRβV region of a first TCRβV belonging to the TCRβ V25 subfamily, or the TCRβ V29 subfamily, and the second agent is selected from the group consisting of TCRβ V6 subfamily, TCRβ V10 subfamily, TCRβ V12 subfamily, TCRβ V5 subfamily, TCRβ V7 subfamily, TCRβ V11 subfamily, TCRβ V14 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V9 subfamily, TCRβ V13 subfamily, TCRβ V4 subfamily, TCRβ V3 subfamily, TCRβ V2 subfamily, TCRβ V16 subfamily, TCRβ V18 subfamily, TCRβ V18 subfamily, TCRβ V19 subfamily, TCRβ V20 subfamily, TCRβ V25 subfamily, or TCRβ V29 subfamily. V15 subfamily, TCRβ V30 subfamily, TCRβ V19 subfamily, TCRβ V27 subfamily, TCRβ V28 subfamily, TCRβ 88. The method of claim 87, wherein the first agent and the second agent each comprise a domain that specifically binds to a second TCRβV region of a TCRβV belonging to a V24 subfamily, a TCRβV20 subfamily, a TCRβV25 subfamily, or a TCRβV29 subfamily, and wherein the first agent and the second agent each specifically bind to a TCRβV belonging to a different subfamily or a different member of the same TCRβV subfamily.

89. 89. The method of claim 87 or 88, wherein said contacting comprises incubating or culturing said plurality of T cells with said first agent.

90. 90. The method of claim 89, wherein said contacting comprises incubating or culturing said plurality of T cells with said first agent for at least about 10 minutes, 20 minutes, 30 minutes, 1 hour, 6 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 5 days, 7 days, 10 days, 14 days, 15 days, or 30 days.

91. 89. The method of claim 87 or 88, wherein said contacting comprises incubating or culturing said plurality of T cells with said first agent for up to about 10 minutes, 20 minutes, 30 minutes, 1 hour, 6 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 5 days, 7 days, 10 days, 12 days, 14 days, 15 days, 21 days, 30 days, 45 days, or 60 days.

92. 89. The method of claim 87 or 88, wherein said contacting comprises incubating or culturing said plurality of T cells with said first agent for about 10-90 minutes, 10-60 minutes, 10-30 minutes, 1-30 days, 1-21 days, 1-14 days, 1-7 days, 1-5 days, 1-3 days, 21-30 days, 14-30 days, 7-30 days, 5-30 days, or 3-30 days.

93. 93. The method of any one of claims 87 to 92, wherein the agent is linked to a solid surface (e.g. a bead).

94. 94. The method of any one of claims 87 to 93, wherein the agent is an antibody, a functional fragment thereof or a functional variant thereof.

95. 95. The method of claim 94, wherein the antibody or functional fragment thereof comprises a full length antibody, Fab, (Fab)2, (Fab')2, Fv, (Fv)2, scFv, diabody, triabody, minibody, scFv-Fc fusion, crossMab, tandem diabody (TandAb), duobody, strand-swap engineered domain body (SEEDbody), dual affinity retargeting molecule (DART), or dual variable domain immunoglobulin or (DVD).

96. The method of claim 94 or 95, wherein the antibody, functional fragment thereof or functional variant thereof is an anti-idiotype antibody domain.

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