Chimeric antigen receptors

专利摘要:
Provided herein are therapeutic polypeptides, e,g., chimeric antigen receptors, able to direct an imune cell, e a T lymphocyte to a target antigen, and able to cause the T cell to proliferate or to kill cells displaying the antigen when the antigen binds to the polypeptide, wherein the polypeptides comprise a transmembrane domain from a T cell coinhibitory protein such as CTLA4 or PDi, Also provided herein are T lymphocytes expressing the polypeptides, and use of such T lymphocytes to treat diseases such as cancer,
公开号:AU2013204922A1
申请号:U2013204922
申请日:2013-04-12
公开日:2014-07-10
发明作者:Stewart Abbot；Tianjian Li；Bitao Liang
申请人:Anthrogenesis Corp；
IPC主号:C07K19-00

专利说明:
ATTORNEY DOCKET NO. 12827-401-007 CHIMERIC ANTIGEN RECEPTORS This application claims priority from US application number 61/740,113 filed on 20 December 2012 and US Application number 61/779,925 filed on 13 March 2013, the contents of which are to be taken as incorporated herein by this reference. 1. FIELD [01] The disclosure herein relates to the field of immunology, and more specifically, to the modification of T lymphocytes or other immune cells. 2. BACKGROUND [02] Cells of the immune system such as T lymphocytes (also referred to as T cells) recognize and interact with specific antigens through receptors or receptor complexes which, upon recognition or an interaction with such antigens, cause activation of the cell. An example of such a receptor is the antigen-specific T lymphocyte receptor complex (TCR/CD3), a complex of eight proteins. The T cell receptor (TCR) is expressed on the surface of T lymphocytes. One component, CD3, which has an invariant structure, is responsible for intracellular signaling following occupancy of the TCR by ligand. The T lymphocyte receptor for antigen-CD3 complex (TCR/CD3) recognizes antigenic peptides that are presented to it by the proteins of the major histocompatibility complex (MHC). Complexes of MHC and peptide are expressed on the surface of antigen presenting cells and other T lymphocyte targets. Stimulation of the TCR/CD3 complex results in activation of the T lymphocyte and a consequent antigen-specific immune response. The TCR/CD3 complex plays a central role in the effector function and regulation of the immune system. [03] T lymphocytes require a second, co-stimulatory signal to become fully active. Without such a signal, T lymphocytes are either non-responsive to antigen binding to the TCR, or become anergic. Such a co-stimulatory signal, for example, is provided by CD28, a T lymphocyte protein, which interacts with CD80 and CD86 on antigen-producing cells. ICOS (Inducible COStimulator), another T lymphocyte protein, provides a co-stimulatory signal when bound to ICOS ligand. CTLA4 (cytotoxic T-Lymphocyte Antigen 4), also known as CD 152, is a receptor expressed on the surface of helper T cells and CD4+ T cells, that downregulates T cell activity. Binding of CTLA4 to its cognate ligands, CD80 and CD86, results in reduced T cell activation 1 and proliferation. PD-I (Programmed Cell Death-1), also known as CD279, is currently understood to negatively regulate T Cell Receptor (TCR) signals, and to broadly negatively regulate immune responses. [04] The essential antigen-binding, signaling, and stimulatory functions of the TCR complex have been reduced by genetic recombination methods to a single polypeptide chain, generally referred to as a Chimeric Antigen Receptor (CAR). See, e.g., Eshhar, U.S. Patent No. 7,741,465; Eshhar, U.S. Patent Application Publication No. 2012/0093842. T lymphocytes bearing such CARs are generally referred to as CAR-T lymphocytes. CARs are constructed specifically to stimulate T cell activation and proliferation in response to a specific antigen to which the CAR binds. 3. SUMMARY [05] In one aspect, provided herein are polypeptides, e.g., chimeric antigen receptors (see, e.g., Eshhar, U.S. Patent No. 7,741,465), that can be expressed by immune system cells, e.g., T lymphocytes (T cells), are membrane-bound in such immune system cells, and which comprise a transmembrane domain from an immune system protein that normally transmits an inhibitory signal to such immune system cells, e.g., a transmembrane domain from CTLA4 (Cytotoxic T Lymphocyte Antigen 4 or Cytotoxic T-Lymphocyte Associated protein 4) or PD-I (Programmed Cell Death-1). [06] In one embodiment, provided herein is a polypeptide comprising (i) a transmembrane domain comprising the transmembrane domain from CTLA4 (e.g., GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493)) or PD-I (e.g., GenBank Accession No. NM_005018.2 (programmed cell death I (Homo sapiens ); Gene ID: 5133)), or a portion thereof, (ii) an intracellular domain (e.g., cytoplasmic domain) of an endogenous protein expressed on the surface of lymphocytes that triggers the activation and/or proliferation of said lymphocytes, and (iii) an extracellular domain that binds to an antigen of interest, wherein if the transmembrane domain is from CTLA4, the intracellular domain and extracellular domain of said polypeptide are not from CTLA4; and if the transmembrane domain is from PD-1, the intracellular domain and extracellular domain of said polypeptide are not from PD-1. In a specific embodiment, the polypeptide is a chimeric antigen receptor (CAR). In a specific embodiment, a T lymphocyte expressing said polypeptide, or any of such polypeptides described herein, is activated or stimulated to proliferate when said 2 NYI-4513920v1 polypeptide binds to said antigen. In a specific embodiment, the polypeptide, when expressed on the surface of a T lymphocyte, directs the T lymphocyte to kill a cell expressing said antigen. [07] In a specific embodiment, provided herein is a polypeptide comprising a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is the polypeptide sequence encoded by exon 3 of a human ctla4 gene (e.g., GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493)). [08] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence PEPCPDSDFLLWILAAVSSGLFFYSFLLTAVSLSKM (in three-letter code, Pro-Glu-Pro-Cys Pro-Asp-Ser-Asp-Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser Phe-Leu-Leu-Thr-Ala-Val-Ser-Leu-Ser-Lys-Met) (SEQ ID NO:1). [09] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the polypeptide sequence encoded by nucleotides 610-722 of GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493). [010] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence PDSDFLLWILAAVSSGLFFYSFLLTAVSL (in three-letter code, Pro-Asp-Ser-Asp-Phe-Leu Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser-Phe-Leu-Leu-Thr-Ala-Val Ser-Leu) (SEQ ID NO:2). [011] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the polypeptide sequence encoded by nucleotides 636-699 of GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493). [012] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence FLLWILAAVSSGLFFYSFLLTAV (in three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser Phe-Leu-Leu-Thr-Ala-Val) (SEQ ID NO:3). [013] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the polypeptide sequence FLLWILAAVSSGLFFYSFLLT (in 3 NYI-4513920v1 three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser Phe-Leu-Leu-Thr) (SEQ ID NO:4). [014] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the polypeptide sequence FLLWILVAVSLGLFFYSFLVSAVSLS (in three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Val Ala-Val-Ser-Leu-Gly-Leu-Phe-Phe-Tyr-Ser-Phe-Leu-Val-Ser-Ala-Val-Ser-Leu-Ser) (SEQ ID NO:5). [015] In another specific embodiment, the PD-i transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence TLVVGVVGGLLGSLVLLVWVLAVICSRAA (in three-letter code, Thr-Leu-Val-Val-Gly-Val Val-Gly-Gly-Leu-Leu-Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val-Leu-Ala-Val-Ile-Cys-Ser-Arg Ala-Ala) (SEQ ID NO:6). [016] In another specific embodiment, the PD-i transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence VGVVGGLLGSLVLLVWVLAVI (in three-letter code, Val-Gly-Val-Val-Gly-Gly-Leu-Leu-Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val Leu-Ala-Val-Ile) (SEQ ID NO:7). [017] In another specific embodiment, the PD-i transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence FQTLVVGVVGGLLGSLVLLVWVLAVI (in three-letter code, Phe-Glu-Thr-Leu-Val-Val-Gly Val-Val-Gly-Gly-Leu-Leu-Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val-Leu-Ala-Val-Ile) (SEQ ID NO:8). [018] In certain embodiments, a nucleotide sequence that encodes one or the polypeptides disclosed herein comprises a nucleotide sequence that encodes any of the amino acid sequences disclosed in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. [019] In a specific embodiment, provided herein is a polypeptide that comprises a transmembrane domain, wherein the transmembrane domain is or comprises at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 consecutive amino acids disclosed in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. In another specific embodiment, provided herein is a nucleic acid that encodes a polypeptide described herein, wherein the nucleic acid comprises a nucleotide sequence that 4 NYI-4513920v1 encodes at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 consecutive amino acids disclosed in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. [020] In certain embodiments, the extracellular domain of any of the polypeptides described herein comprises a receptor, or a portion of a receptor, that binds to an antigen. The extracellular domain may be, e.g., a receptor, or a portion of a receptor, that binds to said antigen. In certain embodiments, the extracellular domain comprises, or is, an antibody or an antigen-binding portion thereof. In a specific embodiment, the extracellular domain comprises, or is, a single chain Fv domain. The single-chain Fv domain can comprise, for example, a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen. [021] The antigen to which the extracellular domain of the polypeptide binds can be any antigen of interest, e.g., an antigen on a tumor cell. The tumor cell may be, e.g., a cell in a solid tumor, or a cell of non-solid tumor, e.g., a cell of a blood cancer. In certain embodiments, the antigen is a tumor-associated antigen or a tumor-specific antigen. In a specific embodiment, the tumor-associated antigen or tumor-specific antigen is, without limitation, Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), CD34, CD45, CD99, CD 117, chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-1), myo-D 1, muscle-specific actin (MSA), neurofilament, neuron specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, the dimeric form of the pyruvate kinase isoenzyme type M2 (tumor M2 PK), CD19, CD22, CD27, CD30, CD70, GD2 (ganglioside G2), EGFRvIII (epidermal growth factor variant III), sperm protein 17 (Sp 17), mesothelin, PAP (prostatic acid phosphatase), prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAPI (six transmembrane epithelial antigen of the prostate 1), an abnormal ras protein, or an abnormal p53 protein. In another specific embodiment, said tumor-associated antigen or tumor-specific antigen is integrin avB3 (CD6 1), galactin, K-Ras (V-Ki-ras2 Kirsten rat sarcoma viral oncogene), or Ral-B. 5 NYI-4513920v1 [022] In certain embodiments, the extracellular domain of the polypeptides described herein is joined to the transmembrane domain of the polypeptide by a linker, spacer or hinge polypeptide/peptide sequence, e.g., a sequence from CD8, CD28, CTLA4 or PD-1. [023] In certain embodiments, the intracellular domain of the polypeptides described herein is or comprises an intracellular domain of a protein that is expressed on the surface of T cells and triggers activation and/or proliferation of said T cells. In a specific embodiment, the intracellular domain is a CD3( intracellular signaling domain. In another specific embodiment, the intracellular domain is from a lymphocyte receptor chain, a TCR/CD3 complex protein, an Fc receptor subunit, or an IL-2 receptor subunit. [024] In certain embodiments, the polypeptides provided herein additionally comprise one or more co-stimulatory domains, e.g., as part of the intracellular domain of the polypeptide. The one or more co-stimulatory domains can be, or can comprise, without limitation, one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD134) polypeptide sequence, a co-stimulatory 4-1BB (CD137) polypeptide sequence, or, a co-stimulatory inducible T-cell costimulatory (ICOS) polypeptide sequence. [025] In a specific embodiment, a polypeptide provided herein comprises, in order, from N terminus to C-terminus: (i) an antigen-binding domain (e.g., an antigen binding domain that binds an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 or CTLA4 hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain. In a specific embodiment, the antigen-binding domain of the polypeptide binds to CD 19. [026] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [027] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on 6 NYI-4513920v1 a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [028] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [029] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [030] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [031] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) an antigen-binding domain (e.g., an antigen binding domain that binds an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain. [032] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide 7 NYI-4513920v1 sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [033] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [034] In another aspect, provided herein are T lymphocytes, e.g., T cells, that comprise, e.g., express on their cell surface, a membrane-bound polypeptide, wherein said polypeptide comprises (i) a transmembrane domain comprising the transmembrane domain from CTLA4 or PD-1, or a portion thereof, (ii) an intracellular domain of an endogenous protein expressed on the surface of lymphocytes and that triggers the activation and/or proliferation of said lymphocytes, and (iii) an extracellular domain that binds to an antigen of interest, wherein if the transmembrane domain is from CTLA4, the intracellular domain and extracellular domain (optionally excluding a CTLA4 linker) of said polypeptide are not from CTLA4; and if the transmembrane domain is from PD-1, the intracellular domain and extracellular domain of said polypeptide are not from PD-1. In a specific embodiment, the polypeptide is a chimeric antigen receptor (CAR). [035] In a specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is the polypeptide sequence encoded by exon 3 of a human CTLA4 gene (e.g., GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493)). [036] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence PEPCPDSDFLLWILAAVSSGLFFYSFLLTAVSLSKM (in three-letter code, Pro-Glu-Pro-Cys Pro-Asp-Ser-Asp-Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser Phe-Leu-Leu-Thr-Ala-Val-Ser-Leu-Ser-Lys-Met) (SEQ ID NO:1). 8 NYl-4513920v1 [037] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is or comprises the polypeptide sequence encoded by nucleotides 610 722 of GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493). [038] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence PDSDFLLWILAAVSSGLFFYSFLLTAVSL (in three-letter code, Pro-Asp-Ser-Asp-Phe-Leu Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser-Phe-Leu-Leu-Thr-Ala-Val Ser-Leu) (SEQ ID NO:2). [039] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is or comprises the polypeptide sequence encoded by nucleotides 636 699 of GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493). [040] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence FLLWILAAVSSGLFFYSFLLTAV (in three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala Val-S er-Ser-Gly-Leu-Phe-Phe-Tyr-Ser-Phe-Leu-Leu-Thr-Ala-Val) (SEQ ID NO:3). [041] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is or comprises the polypeptide sequence FLLWILAAVSSGLFFYSFLLT (in three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala-Val Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser-Phe-Leu-Leu-Thr) (SEQ ID NO:4). [042] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is or comprises the polypeptide sequence FLLWILVAVSLGLFFYSFLVSAVSLS (in three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Val 9 NYI-4513920v1 Ala-Val-Ser-Leu-Gly-Leu-Phe-Phe-Tyr-Ser-Phe-Leu-Val-Ser-Ala-Val-Ser-Leu-Ser) (SEQ ID NO:5). [043] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from PD-1, wherein the PD-I transmembrane domain is or comprises the amino acid sequence TLVVGVVGGLLGSLVLLVWVLAVICSRAA (in three-letter code, Thr-Leu-Val-Val-Gly-Val Val-Gly-Gly-Leu-Leu-Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val-Leu-Ala-Val-Ile-Cys-Ser-Arg Ala-Ala) (SEQ ID NO:6). [044] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from PD-1, wherein the PD-I transmembrane domain is or comprises the amino acid sequence VGVVGGLLGSLVLLVWVLAVI (in three-letter code, Val-Gly-Val-Val-Gly-Gly-Leu-Leu Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val-Leu-Ala-Val-Ile) (SEQ ID NO:7). [045] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain from PD-1, wherein the PD-I transmembrane domain is or comprises the amino acid sequence FQTLVVGVVGGLLGSLVLLVWVLAVI (in three-letter code, Phe-Glu-Thr-Leu-Val-Val-Gly Val-Val-Gly-Gly-Leu-Leu-Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val-Leu-Ala-Val-Ile) (SEQ ID NO:8). [046] In certain embodiments, a nucleotide sequence expressed or encoded by a T lymphocyte provided herein (i.e., a T lymphocyte comprising a polypeptide described herein) comprises a nucleotide sequence that encodes any of the amino acid sequences disclosed in SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. [047] In another specific embodiment, provided herein is a T lymphocyte comprising a polypeptide that comprises a transmembrane domain, wherein the transmembrane domain is or comprises at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 consecutive amino acids disclosed in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. In certain embodiments, provided herein is a T lymphocyte comprising a nucleic acid that encodes a polypeptide described herein, wherein the nucleic acid comprises a nucleotide sequence that encodes at least 10, 11, 12, 13, 14, 15, 16, 17, 10 NYI-4513920v1 18, 19,20 or 21 consecutive amino acids disclosed in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. [048] In certain embodiments, the extracellular domain of a polypeptide expressed by the T lymphocytes provided herein comprises a receptor, or a portion of a receptor, that binds to an antigen of interest. The extracellular domain may be, e.g., a receptor, or a portion of a receptor, that binds to said antigen. In certain embodiments, the extracellular domain comprises, or is, an antibody or an antigen-binding portion thereof. In specific embodiments, the extracellular domain comprises, or is, a single-chain Fv domain. The single-chain Fv domain can comprise, for example, a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen. [049] The antigen to which the extracellular domain of the polypeptide expressed by a T lymphocyte provided herein binds, and therefore to which the T cell is directed by the polypeptide, can be any antigen of interest, e.g., an antigen on a tumor cell. The tumor cell may be, e.g., a cell in a solid tumor, or a cell of a non-solid tumor, e.g., a cell of a blood cancer. In certain embodiments, the antigen is a tumor-associated antigen or a tumor-specific antigen. In certain embodiments, the antigen is one or more of Kappa, Lambda, CD19, CD22, CD27, CD30, CD70, GD2, HER2, CEA, EGFRvIII, Sperm Proteinl7, PSCA, mesothelin, PAP (prostatic acid phosphatase), prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAP 1 (six-transmembrane epithelial antigen of the prostate 1), and/or MUC- 1. In various specific embodiments, without limitation, the tumor-associated antigen or tumor-specific antigen is Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), CD34, CD45, CD99, CD 117, chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP- 15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-1), myo-D 1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, the dimeric form of the pyruvate kinase isoenzyme type M2 (tumor M2-PK), an abnormal ras protein, or an abnormal p53 protein. In another specific embodiment, said tumor-associated antigen or tumor-specific antigen is integrin avB3 (CD61), galactin, K-Ras (V-Ki-ras2 Kirsten rat sarcoma viral oncogene), or Ral-B. 11 NYl-4513920v1 [050] In certain embodiments, the extracellular domain of a polypeptide expressed by a T lymphocyte described herein is joined to said transmembrane domain of the polypeptide by a linker, spacer or hinge polypeptide sequence, e.g., a sequence from CD8, CD28, CTLA4 or PD-1. [051] In certain embodiments, the intracellular domain of a polypeptide expressed by a T lymphocyte described herein is or comprises an intracellular domain of a protein that is normally expressed on the surface of T cells and which triggers activation and/or proliferation of said T cells. In a specific embodiment, the intracellular domain is a CD3( intracellular signaling domain. In another embodiment, the intracellular domain is from a lymphocyte receptor chain, a TCR/CD3 complex protein, an Fc receptor subunit or an IL-2 receptor subunit. [052] In certain embodiments, a polypeptide expressed by a T lymphocyte described herein additionally comprises one or more co-stimulatory domains, e.g., as part of the intracellular domain of the polypeptide. The one or more co-stimulatory domains can be, or comprise, one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD 134) polypeptide sequence, a co-stimulatory 4-1 BB (CD137) polypeptide sequence, or a co-stimulatory inducible T-cell costimulatory (ICOS) polypeptide sequence. [053] In a specific embodiment, the T lymphocytes provided herein express or comprise a polypeptide that comprises, in order, from N-terminus to C-terminus: (i) an antigen-binding domain (e.g., an antigen binding domain that binds an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 or CTLA4 hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain. In a specific embodiment, the antigen-binding domain of the polypeptide binds to CD19. [054] In another specific embodiment, the T lymphocytes provided herein express or comprise a polypeptide that comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [055] In another specific embodiment, the T lymphocytes provided herein express or comprise a polypeptide that comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv 12 NYI-4513920v1 domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [056] In another specific embodiment, the T lymphocytes provided herein express or comprise a polypeptide that comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [057] In another specific embodiment, the T lymphocytes provided herein express or comprise a polypeptide that comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [058] In another specific embodiment, the T lymphocytes provided herein express or comprise a polypeptide that comprises, in order, from N-terminus to C-terminus: (i) an antigen-binding domain (e.g., an antigen binding domain that binds an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain. [059] In another specific embodiment, the T lymphocytes provided herein express or comprise a polypeptide that comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [060] In another specific embodiment, the T lymphocytes provided herein express or comprise a polypeptide that comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell 13 NYI-4513920v1 described above); (ii) a PD-I hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [061] In a specific embodiment, the T lymphocytes provided herein that express or comprise one or more of the polypeptides provided herein, become activated or stimulated to proliferate when said polypeptide binds to the antigen to which the antigen binding domain or single-chain Fv domain of the polypeptide is specific. In another specific embodiment, the T lymphocytes provided herein that express or comprise one or more of the polypeptides provided herein, kill cells that express or comprise the antigen to which the antigen binding domain or single-chain Fv domain of the polypeptide is specific when the T lymphocytes come in contact with said antigen expressing cells. [062] In another aspect, provided herein are methods of treating an individual having a disease or disorder, wherein the disease or disorder is characterized, or is characterizable, by cells expressing an antigen, comprising administering to the individual one or more of the T lymphocytes provided herein, i.e., T lymphocytes that comprise or express a polypeptide described herein. 4. DETAILED DESCRIPTION [063] In one aspect, provided herein are polypeptides, e.g., chimeric antigen receptors (see, e.g., Eshhar, U.S. Patent No. 7,741,465), that can be expressed by immune system cells, e.g., T lymphocytes (T cells), are membrane-bound in such immune system cells, and which comprise a transmembrane domain from an immune system protein that normally transmits an inhibitory signal to such immune system cells, e.g., a transmembrane domain from CTLA4 (Cytotoxic T Lymphocyte Antigen 4 or Cytotoxic T-Lymphocyte Associated protein 4) or PD-I (Programmed Cell Death-1). Further provided herein are nucleic acid sequences encoding the polypeptides described herein. Also provided herein are immune system cells, e.g., T lymphocytes (e.g., T cells), expressing such polypeptides. [064] The polypeptides provided herein comprise an extracellular domain that binds to an antigen, e.g., an antigen on a cell, a transmembrane domain, and an intracellular (cytoplasmic) signaling domain that transmits a primary activation signal to an immune cell. When the polypeptides provided herein are expressed on the surface of, e.g., a T lymphocyte, and when the extracellular domain of the CAR binds to an antigen, the intracellular signaling domain transmits a signal to the T lymphocyte to activate and/or proliferate, and, if the antigen is present on a cell 14 NYI-4513920v1 surface, to kill the cell expressing the antigen. Because T lymphocytes require two signals in order to fully activate, a primary activation signal and a costimulatory signal, in certain embodiments, the polypeptides described herein can comprise a costimulatory domain such that binding of the antigen to the extracellular domain results in transmission of both a primary activation signal and a costimulatory signal. [065] The polypeptides, e.g., CARs, provided herein are functional, immune stimulatory polypeptides that comprise a transmembrane domain from a T cell co-inhibitory protein, e.g., CTLA4 or PD-1. In one aspect, provided herein is a polypeptide comprising (i) a transmembrane domain from CTLA4 or PD-1, (ii) an intracellular domain (e.g., cytoplasmic domain) of an endogenous protein expressed on the surface of lymphocytes and that triggers the activation and/or proliferation of said lymphocytes, and (iii) an extracellular domain that binds to an antigen, wherein if the transmembrane domain is from CTLA4, the intracellular domain and extracellular domain of said polypeptide are not from CTLA4; and if the transmembrane domain is from PD-1, the intracellular domain and extracellular domain of said polypeptide are not from PD-1. In a specific embodiment, a T lymphocyte expressing a polypeptide described herein is activated or stimulated to proliferate when said polypeptide binds to an antigen to which the polypeptide is specific (i.e., an antigen that is bound by the extracellular domain of the polypeptide). In a specific embodiment, the polypeptide, when expressed on the surface of a T lymphocyte, directs the T lymphocyte to kill a cell expressing said antigen. [066] In certain embodiments the polypeptides provided herein comprise a transmembrane domain from CTLA4 or PD-1, or a portion thereof, wherein the CTLA4 or PD-I transmembrane domain is from a mammalian CTLA4 or PD-1, e.g., human, primate, or rodent, e.g., murine CTLA4 or PD-1. In a specific embodiment, the transmembrane domain does not comprise amino acids from the intracellular domain, extracellular domain, or either the intracellular or extracellular domain of CTLA4 or PD-1. Specific, non-limiting examples of CTLA4 or PD-i transmembrane domain sequences are provided below. [067] In a specific embodiment, provided herein is a polypeptide comprising a transmembrane domain from CTLA4, wherein the CTLA4 transmembrane domain is the polypeptide sequence encoded by exon 3 of a human ctla4 gene (e.g., GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493)). 15 NYI-4513920v1 [068] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence PEPCPDSDFLLWILAAVSSGLFFYSFLLTAVSLSKM (in three-letter code, Pro-Glu-Pro-Cys Pro-Asp-Ser-Asp-Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser Phe-Leu-Leu-Thr-Ala-Val-Ser-Leu-Ser-Lys-Met) (SEQ ID NO:1). [069] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the polypeptide sequence encoded by nucleotides 610-722 of GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493). [070] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence PDSDFLLWILAAVSSGLFFYSFLLTAVSL (in three-letter code, Pro-Asp-Ser-Asp-Phe-Leu Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser-Phe-Leu-Leu-Thr-Ala-Val Ser-Leu) (SEQ ID NO:2). [071] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the polypeptide sequence encoded by nucleotides 636-699 of GenBank Accession No. NM_005214.4 (CTLA4 cytotoxic T-lymphocyte-associated protein 4 (Homo sapiens); Gene ID: 1493). [072] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence FLLWILAAVSSGLFFYSFLLTAV (in three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser Phe-Leu-Leu-Thr-Ala-Val) (SEQ ID NO:3). [073] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the polypeptide sequence FLLWILAAVSSGLFFYSFLLT (in three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Ala-Ala-Val-Ser-Ser-Gly-Leu-Phe-Phe-Tyr-Ser Phe-Leu-Leu-Thr) (SEQ ID NO:4). [074] In another specific embodiment, the CTLA4 transmembrane domain of a polypeptide provided herein is or comprises the polypeptide sequence FLLWILVAVSLGLFFYSFLVSAVSLS (in three-letter code, Phe-Leu-Leu-Trp-Ile-Leu-Val Ala-Val-Ser-Leu-Gly-Leu-Phe-Phe-Tyr-Ser-Phe-Leu-Val-Ser-Ala-Val-Ser-Leu-Ser) (SEQ ID NO:5). 16 NYI-4513920v1 [075] In another specific embodiment, the PD-i transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence TLVVGVVGGLLGSLVLLVWVLAVICSRAA (in three-letter code, Thr-Leu-Val-Val-Gly-Val Val-Gly-Gly-Leu-Leu-Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val-Leu-Ala-Val-Ile-Cys-Ser-Arg Ala-Ala) (SEQ ID NO:6). [076] In another specific embodiment, the PD-i transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence VGVVGGLLGSLVLLVWVLAVI (in three-letter code, Val-Gly-Val-Val-Gly-Gly-Leu-Leu-Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val Leu-Ala-Val-Ile) (SEQ ID NO:7). [077] In another specific embodiment, the PD-i transmembrane domain of a polypeptide provided herein is or comprises the amino acid sequence FQTLVVGVVGGLLGSLVLLVWVLAVI (in three-letter code, Phe-Glu-Thr-Leu-Val-Val-Gly Val-Val-Gly-Gly-Leu-Leu-Gly-Ser-Leu-Val-Leu-Leu-Val-Trp-Val-Leu-Ala-Val-Ile) (SEQ ID NO:8). [078] In certain embodiments, a nucleotide sequence that encodes one or the polypeptides disclosed herein comprises a nucleotide sequence that encodes any of the amino acid sequences disclosed in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. [079] In a specific embodiment, provided herein is a polypeptide that comprises a transmembrane domain, wherein the transmembrane domain is or comprises at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 consecutive amino acids disclosed in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. In another specific embodiment, provided herein is a nucleic acid that encodes a polypeptide described herein, wherein the nucleic acid comprises a nucleotide sequence that encodes at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 consecutive amino acids disclosed in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 or SEQ ID NO:8. [080] In constructing the polypeptides provided herein, in certain embodiments, human sequences may be combined with non-human sequences. For example, a polypeptide comprising human extracellular and intracellular domain amino acid sequences may comprise a transmembrane domain from a non-human species; e.g., may comprise a murine CTLA4 17 NYI-4513920v1 transmembrane domain or a murine PD-I transmembrane domain. In a more specific embodiment, the polypeptide comprises human amino acid sequences for the extracellular and intracellular domains, and comprises a transmembrane domain having, or consisting of, the amino acid sequence of SEQ ID NO:5. [081] The extracellular domains of the polypeptides provided herein bind to an antigen of interest. In certain embodiments, the extracellular domain of a polypeptide provided herein comprises a receptor, or a portion of a receptor, that binds to said antigen. The extracellular domain may be, e.g., a receptor, or a portion of a receptor, that binds to said antigen. In certain embodiments, the extracellular domain comprises, or is, an antibody or an antigen-binding portion thereof. In specific embodiments, the extracellular domain comprises, or is, a single chain Fv domain. The single-chain Fv domain can comprise, for example, a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen. [082] The antigen to which the extracellular domain of the polypeptides provided herein binds/recognizes can be any antigen of interest, e.g., can be an antigen on a tumor cell. The tumor cell may be, e.g., a cell in a solid tumor, or cell of a non-solid tumor, e.g., a cell of a blood cancer. The antigen can be any antigen that is expressed on a cell of any tumor or cancer type, e.g., cells of a lymphoma, a lung cancer, a breast cancer, a prostate cancer, an adrenocortical carcinoma, a thyroid carcinoma, a nasopharyngeal carcinoma, a melanoma, e.g., a malignant melanoma, a skin carcinoma, a colorectal carcinoma, a desmoid tumor, a desmoplastic small round cell tumor, an endocrine tumor, an Ewing sarcoma, a peripheral primitive neuroectodermal tumor, a solid germ cell tumor, a hepatoblastoma, a neuroblastoma, a non-rhabdomyosarcoma soft tissue sarcoma, an osteosarcoma, a retinoblastoma, a rhabdomyosarcoma, a Wilms tumor, a glioblastoma, a myxoma, a fibroma, a lipoma, or the like. In more specific embodiments, said lymphoma can be chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstr6m macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, MALT lymphoma, nodal marginal zone B cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma, T lymphocyte prolymphocytic leukemia, T lymphocyte large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T lymphocyte leukemia/lymphoma, extranodal 18 NYI-4513920v1 NK/T lymphocyte lymphoma, nasal type, enteropathy-type T lymphocyte lymphoma, hepatosplenic T lymphocyte lymphoma, blastic NK cell lymphoma, mycosis fungoides, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T lymphocyte lymphoma, peripheral T lymphocyte lymphoma (unspecified), anaplastic large cell lymphoma, Hodgkin lymphoma, or a non-Hodgkin lymphoma. Antigens specific to certain cancers, as well as methods for identifying such antigens, are known in the art. [083] In a specific embodiment, in which the cancer is chronic lymphocytic leukemia (CLL), the B cells of the CLL have a normal karyotype. In other specific embodiments, in which the cancer is chronic lymphocytic leukemia (CLL), the B cells of the CLL carry a 17p deletion, an 11 q deletion, a 12q trisomy, a 13q deletion or a p53 deletion. [084] In certain embodiments, the antigen recognized by the extracellular domain of a polypeptide described herein is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In various specific embodiments, the tumor-associated antigen or tumor-specific antigen is, without limitation, Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma associated antigen (MAGE), CD19, CD22, CD27, CD30, CD34, CD45, CD70, CD99, CD 117, EGFRvIII (epidermal growth factor variant III), mesothelin, PAP (prostatic acid phosphatase), prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAPI (six transmembrane epithelial antigen of the prostate 1), chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-1), myo-D 1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, the dimeric form of the pyruvate kinase isoenzyme type M2 (tumor M2-PK), an abnormal ras protein, or an abnormal p53 protein. [085] In certain embodiments, the TAA or TSA recognized by the extracellular domain of a polypeptide described herein is integrin avp3 (CD61), galactin, or Ral-B. [086] In certain embodiments, the TAA or TSA recognized by the extracellular domain of a polypeptide described herein is a cancer/testis (CT) antigen, e.g., BAGE, CAGE, CTAGE, FATE, 19 NYI-4513920v1 GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88, NY-ESO-1, NY-SAR 35, OY-TES-1, SPANXB1, SPA17, SSX, SYCPi, or TPTE. [087] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of a polypeptide described herein is a carbohydrate or ganglioside, e.g., fuc-GMI, GM2 (oncofetal antigen-immunogenic-1; OFA-I-1); GD2 (OFA-I-2), GM3, GD3, and the like. [088] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of a polypeptide described herein is alpha-actinin-4, Bage-1, BCR-ABL, Bcr-Abl fusion protein, beta-catenin, CA 125, CA 15-3 (CA 27.29BCAA), CA 195, CA 242, CA-50, CAM43, Casp-8, cdc27, cdk4, cdkn2a, CEA, coa- 1, dek-can fusion protein, EBNA, EF2, Epstein Barr virus antigens, ETV6-AMLI fusion protein, HLA-A2, HLA-Al 1, hsp70-2, KIAAO205, Mart2, Mum 1, 2, and 3, neo-PAP, myosin class I, OS-9, pml-RARa fusion protein, PTPRK, K-ras, N-ras, triosephosphate isomerase, Gage 3,4,5,6,7, GnTV, Herv-K-mel, Lage-1, NA-88, NY-Eso I/Lage-2, SP17, SSX-2, TRP2-Int2, , gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, RAGE, GAGE-1, GAGE-2, pi5(58), RAGE, , SCP-1, Hom/Mel-40, PRAME, p53, H Ras, HER-2/neu, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, pI85erbB2, pI80erbB-3, c-met, nm-23HI, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, 13-Catenin, Mum-1, p16, TAGE, PSMA, CT7, telomerase, 43-9F, 5T4, 79ITgp72, 13HCG, BCA225, BTAA,, CD68KPI, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB70K, NY-CO-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72, TLP, or TPS. Other tumor-associated and tumor-specific antigens are known to those in the art. [089] Antibodies, and scFvs, that bind to TSAs and TAAs are known in the art, as are nucleotide sequences that encode them. [090] In certain specific embodiments, the antigen recognized by the extracellular domain of a polypeptide described herein is an antigen not considered to be a TSA or a TAA, but which is nevertheless associated with tumor cells, or damage caused by a tumor. In certain embodiments, for example, the antigen is, e.g., a growth factor, cytokine or interleukin, e.g., a growth factor, cytokine, or interleukin associated with angiogenesis or vasculogenesis. Such growth factors, cytokines, or interleukins can include, e.g., vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), or interleukin-8 (IL-8). Tumors can also create a 20 NYI-4513920v1 hypoxic environment local to the tumor. As such, in other specific embodiments, the antigen is a hypoxia-associated factor, e.g., HIF-la, HIF-1 , HIF-2a, HIF-2p, HIF-3a, or HIF-3p. Tumors can also cause localized damage to normal tissue, causing the release of molecules known as damage associated molecular pattern molecules (DAMPs; also known as alarmins). In certain other specific embodiments, therefore, the antigen is a DAMP, e.g., a heat shock protein, chromatin-associated protein high mobility group box 1 (HMGB 1), Si 00A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B), serum amyloid A (SAA), or can be a deoxyribonucleic acid, adenosine triphosphate, uric acid, or heparin sulfate. [091] In certain embodiments, the extracellular domain of the polypeptides described herein is joined to the transmembrane domain of the polypeptide by a linker, spacer or hinge polypeptide sequence, e.g., a sequence from CD28 or a sequence from CTLA4. [092] In certain embodiments, the intracellular domain of a polypeptide described herein is or comprises an intracellular domain or motif of a protein that is expressed on the surface of T cells and triggers activation and/or proliferation of said T cells. Such a domain or motif is able to transmit a primary antigen-binding signal that is necessary for the activation of a T lymphocyte in response to the antigen's binding to the CAR's extracellular portion. Typically, this domain or motif comprises, or is, an ITAM (immunoreceptor tyrosine-based activation motif). ITAM containing polypeptides suitable for CARs include, for example, the zeta CD3 chain (CD3() or ITAM-containing portions thereof. In a specific embodiment, the intracellular domain is a CD3( intracellular signaling domain. In other specific embodiments, the intracellular domain is from a lymphocyte receptor chain, a TCR/CD3 complex protein, an Fc receptor subunit or an IL-2 receptor subunit. [093] In certain embodiments, the polypeptides provided herein additionally comprise one or more co-stimulatory domains or motifs, e.g., as part of the intracellular domain of the polypeptide. The one or more co-stimulatory domains or motifs can be, or comprise, one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD 134) polypeptide sequence, a co-stimulatory 4-1 BB (CD137) polypeptide sequence, or a co-stimulatory inducible T-cell costimulatory (ICOS) polypeptide sequence, or other costimulatory domain or motif. [094] In a specific embodiment, a polypeptide provided herein comprises, in order, from N terminus to C-terminus: (i) an antigen-binding domain (e.g., an antigen binding domain that 21 NYI-4513920v1 binds an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 or CTLA4 hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain. [095] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) an antigen-binding domain (e.g., an antigen binding domain that binds an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain. [096] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [097] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [098] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [099] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide 22 NYI-4513920v1 sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [0100] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [0101] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) an antigen-binding domain (e.g., an antigen binding domain that binds an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain. [0102] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [0103] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. [0104] In another specific embodiment, a polypeptide provided herein comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a 4-1BB costimulatory domain; and (v) a CD3( intracellular signaling domain. 23 NYI-4513920v1 [0105] In another specific embodiment, the polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CD28 hinge polypeptide sequence; (iii) a PD-i transmembrane domain; (iv) a 4-1BB costimulatory domain; and (v) a CD3( intracellular signaling domain. [0106] In another specific embodiment, the polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a CTLA4 hinge polypeptide sequence; (iii) a PD-i transmembrane domain; (iv) a 4-1BB costimulatory domain; and (v) a CD3( intracellular signaling domain. [0107] In another specific embodiment, the polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a linker, wherein said VL and VH are from an antibody that binds an antigen of interest (e.g., an antigen on a tumor cell, e.g., an antigen on a tumor cell described above); (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a 4-1BB costimulatory domain; and (v) a CD3( intracellular signaling domain. 4.1. Isolated Polypeptides (Chimeric Antigen Receptors) [0108] The T lymphocyte-stimulatory polypeptides provided herein, which comprise a CTLA4 or PD-I transmembrane domain, may be modified by, e.g., acylation, amidation, glycosylation, methylation, phosphorylation, sulfation, sumoylation, ubiquitylation, or the like. The polypeptides may be labeled with a label capable of providing a detectable signal, e.g., with radioisotopes and fluorescent compounds. One or more side chains of the first or second polypeptides may be derivatized, e.g., derivatization of lysinyl and amino terminal residues with succinic or other carboxylic acid anhydrides, or derivatization with, e.g., imidoesters such as methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4 pentanedione; and transaminase-catalyzed reaction with glyoxylate. Carboxyl side groups, aspartyl or glutamyl, may be selectively modified by reaction with carbodiimides (R-N=C=N-R') such as I-cyclohexyl-3-(2 morpholinyl-(4-ethyl)carbodiimide or 1 -ethyl-3 -(4-azonia-4,4-dimethylpentyl)carbodiimide. 24 NYI-4513920v1 4.2. Isolated Nucleic Acids [0109] Provided herein are nucleic acid sequences (polynucleotides) that encode one or more of the polypeptides provided herein. The polynucleotides may be contained within any polynucleotide vector suitable for the transformation of immune cells, e.g., T lymphocytes. For example, T lymphocytes may be transformed using synthetic vectors, lentiviral or retroviral vectors, autonomously replicating plasmids, a virus (e.g., a retrovirus, lentivirus, adenovirus, or herpes virus), or the like, containing polynucleotides encoding the first and second polypeptides (e.g., chimeric receptors). Lentiviral vectors suitable for transformation of T lymphocytes include, but are not limited to, e.g., the lentiviral vectors described in U.S. Patent Nos. 5,994,136; 6,165,782; 6,428,953; 7,083,981; and 7,250,299, the disclosures of which are hereby incorporated by reference in their entireties. HIV vectors suitable for transformation of T lymphocytes include, but are not limited to, e.g., the vectors described in U.S. Patent No. 5,665,577, the disclosure of which is hereby incorporated by reference in its entirety. [0110] Nucleic acids useful in the production of the first and second polypeptides, e.g., within a modified T lymphocyte, include DNA, RNA, or nucleic acid analogs. Nucleic acid analogs can be modified at the base moiety, sugar moiety, or phosphate backbone, and can include deoxyuridine substitution for deoxythymidine, 5-methyl-2'-deoxycytidine or 5-bromo-2' deoxycytidine substitution for deoxycytidine. Modifications of the sugar moiety can include modification of the 2' hydroxyl of the ribose sugar to form 2'-O-methyl or 2'-O-allyl sugars. The deoxyribose phosphate backbone can be modified to produce morpholino nucleic acids, in which each base moiety is linked to a six membered, morpholino ring, or peptide nucleic acids, in which the deoxyphosphate backbone is replaced by a pseudopeptide backbone and the four bases are retained. See, for example, Summerton and Weller (1997) Antisense Nucleic Acid Drug Dev. 7:187-195; and Hyrup et al. (1996) Bioorgan. Med. Chain. 4:5-23. In addition, the deoxyphosphate backbone can be replaced with, for example, a phosphorothioate or phosphorodithioate backbone, a phosphoroamidite, or an alkyl phosphotriester backbone. 4.3. T Lymphocytes [0111] Provided herein are immune cells, e.g., T lymphocytes, comprising the polypeptides provided herein. The T lymphocytes provided herein may be naive T lymphocytes or MHC restricted T lymphocytes. In certain embodiments, the T lymphocytes provided herein are tumor infiltrating lymphocytes (TILs). In certain embodiments, the T lymphocytes provided herein 25 NYI-4513920v1 have been isolated from a tumor biopsy, or have been expanded from T lymphocytes isolated from a tumor biopsy. In certain other embodiments, the T lymphocytes provided herein have been isolated from, or expanded from, T lymphocytes expanded from, peripheral blood, cord blood, or lymph. [0112] In certain embodiments, the immune cells provided herein that comprise a polypeptide provided herein, e.g., modified T lymphocytes, are autologous to an individual to whom the modified T lymphocytes are to be administered. In certain embodiments, the modified T lymphocytes provided herein are allogeneic to an individual to whom the modified T lymphocytes are to be administered. Where allogeneic T lymphocytes are used to prepare modified T lymphocytes, T lymphocytes can be selected that will reduce the possibility of graft versus-host disease (GVHD) in the individual. For example, in certain embodiments, virus specific T lymphocytes can be selected for preparation of modified T lymphocytes; such lymphocytes will be expected to have a greatly reduced native capacity to bind to, and thus become activated by, any recipient antigens. In certain embodiments, recipient-mediated rejection of allogeneic T lymphocytes can be reduced by co-administration to the host of one or more immunosuppressive agents, e.g., cyclosporine, tacrolimus, sirolimus, cyclophosphamide, or the like. [0113] In one embodiment, T lymphocytes are obtained from an individual, optionally expanded, and then transformed with a polynucleotide encoding a CTLA4 or PD-I transmembrane domain containing polypeptide described herein, and optionally expanded. In another embodiment, T lymphocytes are obtained from an individual, optionally then expanded, and then transformed with a polynucleotide encoding a CTLA4 or PD-I transmembrane domain-containing polypeptide described herein, and optionally then expanded at least one more time. Cells containing the polynucleotides may be selected using a selectable marker. [0114] In certain embodiments, the modified T lymphocytes described herein express or comprise native TCR proteins, e.g., TCR-a and TCR-3 that are capable of forming native TCR complexes, in addition to the CTLA4 or PD-I transmembrane domain-containing polypeptide. In certain other embodiments, either or both of the native genes encoding TCR-a and TCR-3 in the modified T lymphocytes are modified to be non-functional, e.g., a portion or all are deleted, a mutation is inserted, etc. 26 NYI-4513920v1 [0115] In certain embodiments, the T lymphocytes described herein are isolated from a tumor lesion, e.g., are tumor-infiltrating lymphocytes; such T lymphocytes are expected to be specific for a TSA or TAA. [0116] In certain embodiments, the signaling motifs of the CTLA4 or PD-i transmembrane domain-containing polypeptide, e.g., CAR, can be used to promote proliferation and expansion of the modified T lymphocytes described herein. For example, unmodified T lymphocytes, and T lymphocytes comprising a polypeptide comprising a CD3( signaling domain and a CD28 co stimulatory domain can be expanded using antibodies to CD3 and CD28, e.g., antibodies attached to beads, or to the surface of a cell culture plate; see, e.g., U.S. Patent Nos. 5,948,893; 6,534,055; 6,352,694; 6,692,964; 6,887,466; and 6,905,681. In certain embodiments, the antigen, to which the extracellular domain of the CTLA4 or PD-I transmembrane domain-containing polypeptide binds, can be used to promote selective expansion of T lymphocytes expressing the polypeptide. For example, in one embodiment, in which the antigen is a TSA, T lymphocytes comprising the polypeptide cultured in the presence of the TSA, e.g., a soluble form of the TSA, resulting in increased proliferation as compared to culturing in the absence of the TSA. [0117] In certain embodiments, T lymphocytes comprising a CTLA4 or PD-I transmembrane domain-containing polypeptide described herein are stimulated to proliferate using an antibody that binds to a signaling domain on the polypeptide coupled with the antigen that can be bound by the extracellular antigen-binding domain of the polypeptide. For example, in embodiments in which the polypeptide's signaling domain is CD3( and the antigen that binds to the polypeptide is a TSA, T lymphocytes comprising the polypeptide are stimulated to proliferate by culturing the cells in the presence of the TSA (e.g., a soluble form of the TSA) in combination with an antibody that binds to CD3(. [0118] In any of the above embodiments, the antigen and/or antibody can exist free in the medium in which the T lymphocytes are cultures, or either or both can be attached to a solid support, e.g., tissue culture plastic surface, beads, or the like. [0119] The T lymphocytes comprising a CTLA4 or PD-i transmembrane domain-containing polypeptide described herein can optionally comprise a "suicide gene" or "safety switch" that enables killing of all or substantially all of the T lymphocytes when desired. For example, the modified T lymphocytes described herein, in certain embodiments, can comprise an HSV thymidine kinase gene (HSV-TK), which causes death of the modified T lymphocytes upon 27 NYI-4513920v1 contact with gancyclovir. In another embodiment, the modified T lymphocytes express or comprise an inducible caspase, e.g., an inducible caspase 9 (icaspase9), e.g., a fusion protein between caspase 9 and human FK506 binding protein allowing for dimerization using a specific small molecule pharmaceutical. See Straathof et al., Blood 105(11):4247-4254 (2005). 4.4. Methods of Using Modified T Lymphocytes [0120] The modified immune cells, e.g., the modified T lymphocytes, provided herein that comprise a CTLA4 or PD-I transmembrane domain-containing polypeptide, e.g., CAR, can be used to treat an individual having one or more types of cells desired to be targeted by T lymphocytes, e.g., one or more types of cells to be killed. In certain embodiments, the cells to be killed are cancer cells, e.g., tumor cells. In certain embodiments, the cancer cells are cells of a solid tumor. In certain embodiments, the cells are cells of a lymphoma, a lung cancer, a breast cancer, a prostate cancer, an adrenocortical carcinoma, a thyroid carcinoma, a nasopharyngeal carcinoma, a melanoma, e.g., a malignant melanoma, a skin carcinoma, a colorectal carcinoma, a desmoid tumor, a desmoplastic small round cell tumor, an endocrine tumor, an Ewing sarcoma, a peripheral primitive neuroectodermal tumor, a solid germ cell tumor, a hepatoblastoma, a neuroblastoma, a non-rhabdomyosarcoma soft tissue sarcoma, an osteosarcoma, a retinoblastoma, a rhabdomyosarcoma, a Wilms tumor, a glioblastoma, a myxoma, a fibroma, a lipoma, or the like. In more specific embodiments, said lymphoma can be chronic lymphocytic leukemia (small lymphocytic lymphoma), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstr6m macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, MALT lymphoma, nodal marginal zone B cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma, T lymphocyte prolymphocytic leukemia, T lymphocyte large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T lymphocyte leukemia/lymphoma, extranodal NK/T lymphocyte lymphoma, nasal type, enteropathy-type T lymphocyte lymphoma, hepatosplenic T lymphocyte lymphoma, blastic NK cell lymphoma, mycosis fungoides, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T lymphocyte lymphoma, peripheral T lymphocyte lymphoma (unspecified), anaplastic large cell lymphoma, Hodgkin lymphoma, or a non-Hodgkin lymphoma. 28 NYI-4513920v1 [0121] Efficacy of the modified T lymphocytes described herein, after administration to an individual having a disease or disorder remediable by T lymphocytes, e.g., an individual having cancer, can be assessed by one or more criteria, specific to the particular disease or disorder, known to those of ordinary skill in the art, to be indicative of progress of the disease or disorder. Generally, administration of the modified T lymphocytes described herein to such an individual is effective when one or more of said criteria detectably, e.g., significantly, moves from a disease state value or range to, or towards, a normal value or range. [0122] The modified T lymphocytes described herein may be formulated in any pharmaceutically-acceptable solution, preferably a solution suitable for the delivery of living cells, e.g., saline solution (such as Ringer's solution), gelatins, carbohydrates (e.g., lactose, amylose, starch, or the like), fatty acid esters, hydroxymethylcellulose, polyvinyl pyrolidine, etc. Such preparations are preferably sterilized prior to addition of the modified T lymphocytes, and may be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, emulsifiers, salts for influencing osmotic pressure, buffers, and coloring. Pharmaceutical carriers suitable for use in formulating the modified T lymphocytes are known in the art and are described, for example, in WO 96/05309. [0123] In certain embodiments, the modified T lymphocytes described herein are formulated into individual doses, wherein said individual doses comprise at least, at most, or about 1x10 4 , 5x10 4 , 1x105,5x105, 1x106,5x106, 1x1O, 5x107, 1x1O8, 5x10, 1x1O9, 5x109, 1x1010, 5x1010, or 1x10 11 modified T lymphocytes. In certain embodiments, the modified T lymphocytes are formulated for intravenous, intraarterial, parenter al, intramuscular, subcutaneous, intrathecal, or intraocular administration, or administration within a particular organ or tissue. 5. EXAMPLES 5.1. Example 1: Treatment of B Cell Lymphoma [0124] An individual presents with B-cell chronic lymphocytic leukemia, a B cell lymphoma. Testing of B cells from the individual determines that the B cells carry a 17p deletion. T lymphocytes are obtained from the individual, transfected with a lentiviral vector comprising a nucleotide sequence that encodes a chimeric antigen receptor (CAR), and expanded using CD3+CD28-coated beads to sufficient numbers for administration. The chimeric receptor comprises an extracellular antigen-binding region that binds to CD 19; a transmembrane domain from CTLA4; an intracellular co-stimulatory domain from CD28; and an intracellular CD3( 29 NYI-4513920v1 domain. The individual is administered between 109 and 1010 of the T lymphocytes in a 200 ml saline solution by intravenous infusion over 30 minutes. The individual is monitored for two weeks afterwards to establish a reduction of at least 90% of CD19+ B cells in the individual's blood. 5.2. Example 2: Treatment of a B Cell Lymphoma [0125] An individual presents with B-cell chronic lymphocytic leukemia, a B cell lymphoma. Testing of B cells from the individual determines that the B cells carry a 17p deletion. About 106 T lymphocytes are obtained from the individual, transfected with a lentiviral vector comprising a nucleotide sequence that encodes a CAR. The CAR comprises an extracellular antigen-binding region that binds to CD 19; a transmembrane domain from PD-1; an intracellular co-stimulatory domain from CD28; and an intracellular CD3( domain. CAR-expressing T cells are administered to the individual without prior expansion of the T cells. The individual is administered between 105 and 106 of the T lymphocytes in 200 ml saline solution by intravenous infusion over 30 minutes. The individual is monitored for two weeks afterwards to establish a reduction of at least 90% of CD19+ B cells in the individual's blood. 5.3. Example 3: Treatment of B Cell Lymphoma [0126] An individual presents with B-cell chronic lymphocytic leukemia, a B cell lymphoma. Testing of B cells from the individual determines that the B cells carry a p53 deletion. T lymphocytes are obtained from the individual, transfected with a lentiviral vector comprising a nucleotide sequence that encodes a CAR, and expanded using CD3+CD28-coated beads to sufficient numbers for administration. The CAR comprises an extracellular antigen-binding region that binds to CD 19; a transmembrane domain from CTLA4; intracellular co-stimulatory domains from each of CD28, 4-1BB, and OX40; and an intracellular CD3( domain. The individual is administered between 109 and 1010 of the T lymphocytes in 200 ml saline solution by intravenous infusion over 30 minutes. The individual is monitored for two weeks afterwards to establish a reduction of at least 90% of CD19+ B cells in the individual's blood. 5.4. Example 4: Treatment of a B Cell Lymphoma An individual presents with B-cell chronic lymphocytic leukemia, a B cell lymphoma. Testing of B cells from the individual determines that the B cells carry a p53 deletion. About 106 T lymphocytes are obtained from the individual, transfected with a lentiviral vector comprising a nucleotide sequence that encodes a CAR. The CAR comprises an extracellular antigen-binding 30 NYI-4513920v1 region that binds to CD 19; a transmembrane domain from PD-1; intracellular co-stimulatory domains from each of CD28, 4-1BB, and OX40; and an intracellular CD3( domain. CAR expressing T cells are administered to the individual without prior expansion of the T cells. The individual is administered between 105 and 106 of the T lymphocytes in 200 ml saline solution by intravenous infusion over 30 minutes. The individual is monitored for two weeks afterwards to establish a reduction of at least 90% of CD19+ B cells in the individual's blood. 5.5. Example 5: Treatment of Prostate Cancer [0127] An individual presents with stage T2 prostate cancer, with no spread to regional or other lymph nodes (NO, MO). Histological grade is determined to be G2. Overall, the individual is determined to have Stage Il prostate cancer. The individual is administered between 10 9 and 1010 modified T lymphocytes that comprise a CAR, in 200 ml saline solution by intravenous infusion over 30 minutes. The CAR comprises an extracellular antigen-binding region that binds to PSCA, a transmembrane domain from CTLA4, an intracellular co-stimulatory domain from CD28, and an intracellular CD3( domain. The individual is re-assessed for prostate cancer stage and spread to lymph nodes, and histology of biopsied prostate tissue is performed, at 30, 60 and 90 days post-administration. 5.6. Example 6: Treatment of Prostate Cancer [0128] An individual presents with stage T2 prostate cancer, with no spread to regional or other lymph nodes (NO, MO). Histological grade is determined to be G2. Overall, the individual is determined to have Stage II prostate cancer. The individual is administered between 109 and 1010 modified T lymphocytes that comprise a CAR, in 200 ml saline solution by intravenous infusion over 30 minutes. The CAR comprises an extracellular antigen-binding region that binds to PSCA, a transmembrane domain from PD-1, an intracellular co-stimulatory domain from CD28, and an intracellular CD3( domain. The individual is re-assessed for prostate cancer stage and spread to lymph nodes, and histology of biopsied prostate tissue is performed, at 30, 60 and 90 days post-administration. 5.7. Example 7: Treatment of Prostate Cancer [0129] An individual presents with stage T2 prostate cancer, with no spread to regional or other lymph nodes (NO, MO). Histological grade is determined to be G2. Overall, the individual is determined to have Stage Il prostate cancer. The individual is administered between 10 9 and 1010 modified T lymphocytes that comprise a CAR, in 200 ml saline solution by intravenous 31 NYI-4513920v1 infusion over 30 minutes. The CAR comprises an extracellular antigen-binding region that binds to PSCA, a transmembrane domain from CTLA-4, intracellular co-stimulatory domains from each of CD28, 4-1BB, and OX40, and an intracellular CD3( domain. The individual is re assessed for prostate cancer stage and spread to lymph nodes, and histology of biopsied prostate tissue is performed, at 30, 60 and 90 days post-administration. 5.8. Example 4: Treatment of Prostate Cancer [0130] An individual presents with stage T2 prostate cancer, with no spread to regional or other lymph nodes (NO, MO). Histological grade is determined to be G2. Overall, the individual is determined to have Stage II prostate cancer. The individual is administered between 109 and 1010 modified T lymphocytes that comprise a CAR, in 200 ml saline solution by intravenous infusion over 30 minutes. The CAR comprises an extracellular antigen-binding region that binds to PSCA, a transmembrane domain from PD-1, intracellular co-stimulatory domains from each of CD28, 4-1BB, and OX40, and an intracellular CD3( domain. The individual is re-assessed for prostate cancer stage and spread to lymph nodes, and histology of biopsied prostate tissue is performed, at 30, 60 and 90 days post-administration. EQUIVALENTS [0131] The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the subject matter provided herein, in addition to those described, will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. [0132] Various publications, patents and patent applications are cited herein, the disclosures of which are incorporated by reference in their entireties. 32 NYI-4513920v1

权利要求:
Claims (80)
[1] 1. A polypeptide comprising (i) a transmembrane domain from CTLA4 or PD-1, (ii) an intracellular domain of an endogenous protein expressed on the surface of lymphocytes that triggers the activation and/or proliferation of said lymphocytes, and (iii) an extracellular domain that binds to an antigen, wherein if the transmembrane domain is from CTLA4, the intracellular domain and extracellular domain of said polypeptide are not from CTLA4; and if the transmembrane domain is from PD-1, the intracellular domain and extracellular domain of said polypeptide are not from PD-1.
[2] 2. The polypeptide of claim 1, wherein said polypeptide is a chimeric antigen receptor (CAR).
[3] 3. The polypeptide of claim 1 or claim 2, wherein a T lymphocyte expressing said polypeptide is activated or stimulated to proliferate when said polypeptide binds to said antigen.
[4] 4. The polypeptide of any of claims 1-3, wherein said polypeptide, when expressed on the surface of a T lymphocyte, directs the T lymphocyte to kill a cell expressing said antigen.
[5] 5. The polypeptide of any of claims 1-4, wherein the CTLA4 transmembrane domain is the polypeptide sequence encoded by exon 3 of a human CTLA4 gene.
[6] 6. The polypeptide of any of claims 1-4, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO: 1.
[7] 7. The polypeptide of any of claims 1-4, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO:2.
[8] 8. The polypeptide of any of claims 1-4, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO:3.
[9] 9. The polypeptide of any of claims 1-4, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO:4.
[10] 10. The polypeptide of any of claims 1-4, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO:5.
[11] 11. The polypeptide of any of claims 1-4, wherein the PD-I transmembrane domain is or comprises the polypeptide sequence of SEQ ID NO:6.
[12] 12. The polypeptide of any of claims 1-4, wherein the PD-I transmembrane domain is or comprises the polypeptide sequence of SEQ ID NO:7. 33 NYI-4513920v1
[13] 13. The polypeptide of any of claims 1-4, wherein the PD-I transmembrane domain is or comprises the polypeptide sequence of SEQ ID NO:8
[14] 14. The polypeptide of any of claims 1-13, wherein said extracellular domain comprises a receptor, or a portion of a receptor, that binds to said antigen.
[15] 15. The polypeptide of any of claims 1-13, wherein said extracellular domain is a receptor, or a portion of a receptor, that binds to said antigen.
[16] 16. The polypeptide of any of claims 1-13, wherein said extracellular domain comprises an antibody or an antigen-binding portion thereof.
[17] 17. The polypeptide of any of claims 1-13, wherein said extracellular domain is an antibody or an antigen-binding portion thereof.
[18] 18. The polypeptide of any of claims 1-13, wherein said extracellular domain comprises a single-chain Fv domain.
[19] 19. The polypeptide of claim 18, wherein said single-chain Fv domain comprises a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen.
[20] 20. The polypeptide of any of claims 1-19, wherein said antigen is an antigen on a tumor cell.
[21] 21. The polypeptide of claim 20, wherein said tumor cell is a cell in a solid tumor.
[22] 22. The polypeptide of claim 20, wherein said tumor cell is a cell of a blood cancer.
[23] 23. The polypeptide of any of claims 1-22, wherein said antigen is a tumor-associated antigen or a tumor-specific antigen.
[24] 24. The polypeptide of claim 23, wherein said tumor-associated antigen or tumor specific antigen is Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma associated antigen (MAGE), CD34, CD45, CD99, CD 117, chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-1), myo-D 1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, the dimeric form of the pyruvate kinase isoenzyme type M2 (tumor M2-PK), CD19, CD22, CD27, CD30, CD70, GD2 34 NYI-4513920v1 (ganglioside G2), EGFRvIII (epidermal growth factor variant III), sperm protein 17 (Sp 17), mesothelin, PAP (prostatic acid phosphatase), prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAP1 (six-transmembrane epithelial antigen of the prostate 1), an abnormal ras protein, an abnormal p53 protein, integrin avB3 (CD6 1), galactin, K-Ras (V-Ki ras2 Kirsten rat sarcoma viral oncogene), or Ral-B.
[25] 25. The polypeptide of any of claims 1-24, wherein said extracellular domain is joined to said transmembrane domain by a linker, spacer or hinge polypeptide sequence.
[26] 26. The polypeptide of claim 25, wherein said linker, spacer or hinge polypeptide sequence is from CD28.
[27] 27. The polypeptide of claim 25, wherein said linker, spacer or hinge polypeptide sequence is from CTLA4.
[28] 28. The polypeptide of claim 25, wherein said linker, spacer or hinge polypeptide is from PD-1.
[29] 29. The polypeptide of any of claims 1-28, wherein said intracellular domain is an intracellular domain of a protein that is expressed on the surface of T cells and triggers activation and/or proliferation of said T cells.
[30] 30. The polypeptide of claim 29, wherein said intracellular domain is a CD3( intracellular signaling domain.
[31] 31. The polypeptide of claim 29, wherein said intracellular domain is from a lymphocyte receptor chain, a TCR/CD3 complex protein, an Fc receptor subunit or an IL-2 receptor subunit.
[32] 32. The polypeptide of any of claims 1-31, wherein said polypeptide additionally comprises one or more co-stimulatory domains.
[33] 33. The polypeptide of claim 32, wherein said one or more co-stimulatory domains comprises one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD 134) polypeptide sequence, a co-stimulatory 4-1BB (CD137) polypeptide sequence, or a co-stimulatory inducible T-cell costimulatory (ICOS) polypeptide sequence.
[34] 34. The polypeptide of any of claims 1-33, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) an antigen-binding domain; (ii) a CD28 or CTLA4 35 NYI-4513920v1 hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain.
[35] 35. The polypeptide of claim 34, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a CD28 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[36] 36. The polypeptide of claim 34, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a CTLA4 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[37] 37. The polypeptide of claim 34, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a CD28 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[38] 38. The polypeptide of claim 34, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a CTLA4 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[39] 39. The polypeptide of claim 34, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[40] 40. The polypeptide of claim 34, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a PD-i 36 NYI-4513920v1 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[41] 41. A T lymphocyte comprising a membrane-bound polypeptide, wherein said polypeptide comprises (i) a transmembrane domain from CTLA4 or PD-I (Programmed Cell Death 1), (ii) an intracellular domain of an endogenous protein expressed on the surface of lymphocytes and that triggers the activation and/or proliferation of said lymphocytes, and (iii) an extracellular domain that binds to an antigen, wherein if the transmembrane domain is from CTLA4, the intracellular domain and extracellular domain of said polypeptide are not from CTLA4; and if the transmembrane domain is from PD-1, the intracellular domain and extracellular domain of said polypeptide are not from PD-1.
[42] 42. The T lymphocyte of claim 41, wherein said polypeptide is a chimeric antigen receptor (CAR).
[43] 43. The T lymphocyte of claim 41 or claim 42, wherein a T lymphocyte expressing said polypeptide is activated or stimulated to proliferate when said polypeptide binds to said antigen.
[44] 44. The T lymphocyte of any of claims 41-43, wherein said polypeptide, when expressed on the surface of the T lymphocyte, directs the T lymphocyte to kill a cell expressing said antigen.
[45] 45. The T lymphocyte of any of claims 41-44, wherein the CTLA4 transmembrane domain is the polypeptide sequence encoded by exon 3 of a human CTLA4 gene.
[46] 46. The T lymphocyte of any of claims 41-44, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO: 1.
[47] 47. The T lymphocyte of any of claims 41-44, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO:2.
[48] 48. The T lymphocyte of any of claims 41-44, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO:3.
[49] 49. The T lymphocyte of any of claims 41-44, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO:4.
[50] 50. The T lymphocyte of any of claims 41-44, wherein the CTLA4 transmembrane domain is or comprises the amino acid sequence of SEQ ID NO: 1. 37 NYI-4513920v1
[51] 51. The T lymphocyte of any of claims 41-44, wherein the PD-I transmembrane domain is or comprises the polypeptide sequence of SEQ ID NO:6.
[52] 52. The T lymphocyte of any of claims 41-44, wherein the PD-I transmembrane domain is or comprises the polypeptide sequence of SEQ ID NO:7.
[53] 53. The T lymphocyte of any of claims 41-44, wherein the PD-I transmembrane domain is or comprises the polypeptide sequence of SEQ ID NO:8.
[54] 54. The T lymphocyte of any of claims 41-53, wherein said extracellular domain comprises a receptor, or a portion of a receptor, that binds to said antigen.
[55] 55. The T lymphocyte of any of claims 41-53, wherein said extracellular domain is a receptor, or a portion of a receptor, that binds to said antigen.
[56] 56. The T lymphocyte of any of claims 41-53, wherein said extracellular domain comprises an antibody or an antigen-binding portion thereof.
[57] 57. The T lymphocyte of any of claims 41-53, wherein said extracellular domain is an antibody or an antigen-binding portion thereof.
[58] 58. The T lymphocyte of any of claims 41-53, wherein said extracellular domain comprises a single-chain Fv domain.
[59] 59. The T lymphocyte of claim 58, wherein said single-chain Fv domain comprises a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen.
[60] 60. The T lymphocyte of any of claims 41-59, wherein said antigen is an antigen on a tumor cell.
[61] 61. The T lymphocyte of claim 60, wherein said tumor cell is a cell in a solid tumor.
[62] 62. The T lymphocyte of claim 60, wherein said tumor cell is a cell of a blood cancer.
[63] 63. The T lymphocyte of any of claims 41-62, wherein said antigen is a tumor associated antigen or a tumor-specific antigen.
[64] 64. The T lymphocyte of claim 63, wherein said tumor-associated antigen or tumor specific antigen is Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma associated antigen (MAGE), CD34, CD45, CD99, CD 117, chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 38 NYI-4513920v1 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-1), myo-D 1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, the dimeric form of the pyruvate kinase isoenzyme type M2 (tumor M2-PK), an abnormal ras protein, an abnormal p53 protein, CD19, CD22, CD27, CD30, CD70, GD2 (ganglioside G2), EGFRvIII (epidermal growth factor variant III), sperm protein 17 (Sp17), mesothelin, PAP (prostatic acid phosphatase), prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAPI (six transmembrane epithelial antigen of the prostate 1), an abnormal ras protein, an abnormal p53 protein, integrin av33 (CD61), galactin, K-Ras (V-Ki-ras2 Kirsten rat sarcoma viral oncogene), or Ral-B..
[65] 65. The T lymphocyte of any of claims 41-64, wherein said extracellular domain is joined to said transmembrane domain by a linker, spacer or hinge polypeptide sequence.
[66] 66. The T lymphocyte of claim 65, wherein said linker, spacer or hinge polypeptide sequence is from CD28.
[67] 67. The T lymphocyte of claim 65, wherein said linker, spacer or hinge polypeptide sequence is from CTLA4.
[68] 68. The T lymphocyte of claim 65, wherein said linker, spacer or hinge polypeptide sequence is from PD-1.
[69] 69. The T lymphocyte of any of claims 41-68, wherein said intracellular domain is an intracellular domain of a protein that is expressed on the surface of T cells and triggers activation and/or proliferation of said T cells.
[70] 70. The T lymphocyte of claim 69, wherein said intracellular domain is a CD3( intracellular signaling domain.
[71] 71. The T lymphocyte of claim 69, wherein said intracellular domain is from a lymphocyte receptor chain, a TCR/CD3 complex protein, an Fc receptor subunit or an IL-2 receptor subunit.
[72] 72. The T lymphocyte of any of claims 41-71, wherein said polypeptide additionally comprises one or more co-stimulatory domains.
[73] 73. The T lymphocyte of claim 72, wherein said one or more co-stimulatory domains comprises one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD 134) polypeptide sequence, a co-stimulatory 39 NYI-4513920v1 4-1BB (CD137) polypeptide sequence, or a co-stimulatory inducible T-cell costimulatory (ICOS) polypeptide sequence.
[74] 74. The T lymphocyte of any of claims 41-73, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) an antigen-binding domain; (ii) a CD28 or CTLA4 hinge polypeptide sequence; (iii) a CTLA4 or PD-I transmembrane domain; (iv) a costimulatory domain; and (v) an intracellular signaling domain.
[75] 75. The T lymphocyte of claim 74, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a CD28 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[76] 76. The T lymphocyte of claim 74, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a CTLA4 hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[77] 77. The T lymphocyte of claim 74, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a CD28 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[78] 78. The T lymphocyte of claim 74, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a CTLA4 hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain.
[79] 79. The T lymphocyte of claim 74, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a PD-I hinge polypeptide sequence; (iii) a CTLA4 transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. 40 NYI-4513920v1
[80] 80. The T lymphocyte of claim 74, wherein said polypeptide comprises, in order, from N-terminus to C-terminus: (i) a single-chain Fv domain comprising a VL linked to VH by a flexible linker, wherein said VL and VH are from an antibody that binds said antigen; (ii) a PD-I hinge polypeptide sequence; (iii) a PD-I transmembrane domain; (iv) a CD28 costimulatory domain; and (v) a CD3( intracellular signaling domain. 41 NYI-4513920v1

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

US4554101A|1981-01-09|1985-11-19|New York Blood Center, Inc.|Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity|

---

US4798824A|1985-10-03|1989-01-17|Wisconsin Alumni Research Foundation|Perfusate for the preservation of organs|

---

US4873192A|1987-02-17|1989-10-10|The United States Of America As Represented By The Department Of Health And Human Services|Process for site specific mutagenesis without phenotypic selection|

---

WO1989006692A1|1988-01-12|1989-07-27|Genentech, Inc.|Method of treating tumor cells by inhibiting growth factor receptor function|

---

US5720937A|1988-01-12|1998-02-24|Genentech, Inc.|In vivo tumor detection assay|

---

US5906936A|1988-05-04|1999-05-25|Yeda Research And Development Co. Ltd.|Endowing lymphocytes with antibody specificity|

---

US6534055B1|1988-11-23|2003-03-18|Genetics Institute, Inc.|Methods for selectively stimulating proliferation of T cells|

---

US6905680B2|1988-11-23|2005-06-14|Genetics Institute, Inc.|Methods of treating HIV infected subjects|

---

US5665577A|1989-02-06|1997-09-09|Dana-Farber Cancer Institute|Vectors containing HIV packaging sequences, packaging defective HIV vectors, and uses thereof|

---

DE3920358A1|1989-06-22|1991-01-17|Behringwerke Ag|BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE|

---

US5283173A|1990-01-24|1994-02-01|The Research Foundation Of State University Of New York|System to detect protein-protein interactions|

---

WO1992008796A1|1990-11-13|1992-05-29|Immunex Corporation|Bifunctional selectable fusion genes|

---

US6319494B1|1990-12-14|2001-11-20|Cell Genesys, Inc.|Chimeric chains for receptor-associated signal transduction pathways|

---

US5843728A|1991-03-07|1998-12-01|The General Hospital Corporation|Redirection of cellular immunity by receptor chimeras|

---

US5190556A|1991-03-19|1993-03-02|O.B. Tech, Inc.|Cord cutter sampler|

---

US5851795A|1991-06-27|1998-12-22|Bristol-Myers Squibb Company|Soluble CTLA4 molecules and uses thereof|

---

GB9114948D0|1991-07-11|1991-08-28|Pfizer Ltd|Process for preparing sertraline intermediates|

---

US8211422B2|1992-03-18|2012-07-03|The United States Of America, As Represented By The Secretary, Department Of Health And Human Services|Chimeric receptor genes and cells transformed therewith|

---

IL104570D0|1992-03-18|1993-05-13|Yeda Res & Dev|Chimeric genes and cells transformed therewith|

---

US5552267A|1992-04-03|1996-09-03|The Trustees Of Columbia University In The City Of New York|Solution for prolonged organ preservation|

---

US5858358A|1992-04-07|1999-01-12|The United States Of America As Represented By The Secretary Of The Navy|Methods for selectively stimulating proliferation of T cells|

---

DK0656946T4|1992-08-21|2010-07-26|Univ Bruxelles|Immunoglobulins without light chains|

---

US6005079A|1992-08-21|1999-12-21|Vrije Universiteit Brussels|Immunoglobulins devoid of light chains|

---

US5629327A|1993-03-01|1997-05-13|Childrens Hospital Medical Center Corp.|Methods and compositions for inhibition of angiogenesis|

---

DK0698097T3|1993-04-29|2001-10-08|Unilever Nv|Production of antibodies or fragments thereof derived from Camelidae heavy chain immunoglobulins|

---

EP0804590A1|1993-05-21|1997-11-05|Targeted Genetics Corporation|Bifunctional selectable fusion genes based on the cytosine deaminase gene|

---

US5698579A|1993-07-02|1997-12-16|Celgene Corporation|Cyclic amides|

---

US5372581A|1993-07-21|1994-12-13|Minneapolis Children's Services Corporation|Method and apparatus for placental blood collection|

---

CA2143491C|1994-03-01|2011-02-22|Yasumasa Ishida|A novel peptide related to human programmed cell death and dna encoding it|

---

US6352694B1|1994-06-03|2002-03-05|Genetics Institute, Inc.|Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells|

---

US7175843B2|1994-06-03|2007-02-13|Genetics Institute, Llc|Methods for selectively stimulating proliferation of T cells|

---

US6309853B1|1994-08-17|2001-10-30|The Rockfeller University|Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof|

---

US5827642A|1994-08-31|1998-10-27|Fred Hutchinson Cancer Research Center|Rapid expansion method for in vitro propagation of T lymphocytes|

---

US5712149A|1995-02-03|1998-01-27|Cell Genesys, Inc.|Chimeric receptor molecules for delivery of co-stimulatory signals|

---

US6103521A|1995-02-06|2000-08-15|Cell Genesys, Inc.|Multispecific chimeric receptors|

---

US5783404A|1995-04-13|1998-07-21|Amgen Inc.|Methods and compositions for determining HER-2/neu expression using monoclonal antibodies|

---

US6692964B1|1995-05-04|2004-02-17|The United States Of America As Represented By The Secretary Of The Navy|Methods for transfecting T cells|

---

US7067318B2|1995-06-07|2006-06-27|The Regents Of The University Of Michigan|Methods for transfecting T cells|

---

US6013516A|1995-10-06|2000-01-11|The Salk Institute For Biological Studies|Vector and method of use for nucleic acid delivery to non-dividing cells|

---

US5948893A|1996-01-17|1999-09-07|The United States Of America As Represented By The Secretary Of The Navy|Murine hybridoma and antibody binding to CD28 receptor secreted by the hybridoma and method of using the antibody|

---

US5635517B1|1996-07-24|1999-06-29|Celgene Corp|Method of reducing TNFalpha levels with amino substituted 2--1-oxo-and 1,3-dioxoisoindolines|

---

CA2261762C|1996-07-24|2008-06-17|Celgene Corporation|Substituted 2phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels|

---

US6281230B1|1996-07-24|2001-08-28|Celgene Corporation|Isoindolines, method of use, and pharmaceutical compositions|

---

AU729247B2|1996-08-12|2001-01-25|Celgene Corporation|Novel immunotherapeutic agents and their use in the reduction of cytokine levels|

---

US5798368A|1996-08-22|1998-08-25|Celgene Corporation|Tetrasubstituted 2--1-oxoisoindolines and method of reducing TNFα levels|

---

US6541212B2|1997-03-10|2003-04-01|The Regents Of The University Of California|Methods for detecting prostate stem cell antigen protein|

---

US5874448A|1997-11-18|1999-02-23|Celgene Corporation|Substituted 2--isoindolines and method of reducing TNFα levels|

---

US5994136A|1997-12-12|1999-11-30|Cell Genesys, Inc.|Method and means for producing high titer, safe, recombinant lentivirus vectors|

---

FR2777909B1|1998-04-24|2002-08-02|Pasteur Institut|USE OF TRIPLEX-STRUCTURED DNA SEQUENCES FOR THE TRANSFER OF NUCLEOTID SEQUENCES IN CELLS, RECOMBINANT VECTORS CONTAINING THESE TRIPLEX SEQUENCES|

---

US6410319B1|1998-10-20|2002-06-25|City Of Hope|CD20-specific redirected T cells and their use in cellular immunotherapy of CD20+ malignancies|

---

WO2000063268A1|1999-04-16|2000-10-26|Wm. Marsh Rice University|Poly cross linked with poly|

---

JP2002541845A|1999-04-16|2002-12-10|セルテックセラピューティックスリミテッド|Synthetic transmembrane component|

---

GB9908816D0|1999-04-16|1999-06-09|Celltech Therapeutics Ltd|Biological product|

---

AT528406T|1999-04-29|2011-10-15|Gbp Ip Llc|METHOD AND DEVICE FOR PRODUCING SAFE, RECOMBINANT HIGH TITAN LENTIVIRUS VECTORS|

---

US6355699B1|1999-06-30|2002-03-12|Ethicon, Inc.|Process for manufacturing biomedical foams|

---

US7572631B2|2000-02-24|2009-08-11|Invitrogen Corporation|Activation and expansion of T cells|

---

US6797514B2|2000-02-24|2004-09-28|Xcyte Therapies, Inc.|Simultaneous stimulation and concentration of cells|

---

US6867041B2|2000-02-24|2005-03-15|Xcyte Therapies, Inc.|Simultaneous stimulation and concentration of cells|

---

AU4328801A|2000-02-24|2001-09-03|Xcyte Therapies Inc|Simultaneous stimulation and concentration of cells|

---

JP2002045174A|2000-07-31|2002-02-12|Inst Of Physical & Chemical Res|Method for proliferating natural killer cell|

---

GB0025307D0|2000-10-16|2000-11-29|Celltech Chiroscience Ltd|Biological products|

---

US7229960B2|2000-11-03|2007-06-12|University Of Vermont And State Agricultural College|Methods and compositions for inhibiting GRB7|

---

AT338124T|2000-11-07|2006-09-15|Hope City|CD19-SPECIFIC TARGETED IMMUNOCELLS|

---

US8057788B2|2000-12-06|2011-11-15|Anthrogenesis Corporation|Placental stem cell populations|

---

EP2336301B1|2001-02-14|2014-07-30|Anthrogenesis Corporation|Post-partum mammalian placenta, its use and placental stem cells therefrom|

---

EP2206772A3|2000-12-06|2010-08-04|Robert J. Hariri|Method of collecting placental stem cells|

---

US7091353B2|2000-12-27|2006-08-15|Celgene Corporation|Isoindole-imide compounds, compositions, and uses thereof|

---

US20030045552A1|2000-12-27|2003-03-06|Robarge Michael J.|Isoindole-imide compounds, compositions, and uses thereof|

---

US7070995B2|2001-04-11|2006-07-04|City Of Hope|CE7-specific redirected immune cells|

---

US20090257994A1|2001-04-30|2009-10-15|City Of Hope|Chimeric immunoreceptor useful in treating human cancers|

---

US7514537B2|2001-04-30|2009-04-07|City Of Hope|Chimeric immunoreceptor useful in treating human gliomas|

---

EP1385946B1|2001-05-01|2009-12-23|National Research Council Of Canada|A system for inducible expression in eukaryotic cells|

---

AUPR617901A0|2001-07-06|2001-08-02|Pacmab Pty Ltd|Method for treating multiple myeloma|

---

US7670781B2|2002-01-03|2010-03-02|The Trustees Of The University Of Pennsylvania|Activation and expansion of T-cells using an agent that provides a primary activation signal and another agent that provides a co-stimulatory signal|

---

US20030187515A1|2002-03-26|2003-10-02|Hariri Robert J.|Collagen biofabric and methods of preparing and using the collagen biofabric|

---

US7498171B2|2002-04-12|2009-03-03|Anthrogenesis Corporation|Modulation of stem and progenitor cell differentiation, assays, and uses thereof|

---

US7446190B2|2002-05-28|2008-11-04|Sloan-Kettering Institute For Cancer Research|Nucleic acids encoding chimeric T cell receptors|

---

JP2004113062A|2002-09-25|2004-04-15|Teruyuki Nagamune|Animal cell having chimera receptor and its utilization|

---

US7541440B2|2002-09-30|2009-06-02|Immunomedics, Inc.|Chimeric, human and humanized anti-granulocyte antibodies and methods of use|

---

CN101972478B|2002-10-08|2012-10-31|免疫医疗公司|Antibody therapy|

---

GB0225279D0|2002-10-30|2002-12-11|Celltech R&D Ltd|Biological products|

---

US20070155663A1|2003-03-24|2007-07-05|Rudolf Richter|Use of chemokine receptor agonists for stem cell transplantation|

---

US7595379B2|2003-05-30|2009-09-29|Agensys, Inc.|Antibodies and related molecules that bind to PSCA proteins|

---

US7541442B2|2003-05-30|2009-06-02|Agensys, Inc.|Antibodies and related molecules that bind to PSCA proteins|

---

US20050118185A1|2003-06-18|2005-06-02|Cell Center Cologne Gmbh|Recombinant immunoreceptors|

---

KR101581040B1|2003-06-27|2015-12-30|암젠 프레몬트 인코포레이티드|Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof|

---

US7902338B2|2003-07-31|2011-03-08|Immunomedics, Inc.|Anti-CD19 antibodies|

---

JP4733635B2|2003-07-31|2011-07-27|イミューノメディクス、インコーポレイテッド|Anti-CD19 antibody|

---

US7435596B2|2004-11-04|2008-10-14|St. Jude Children's Research Hospital, Inc.|Modified cell line and method for expansion of NK cell|

---

DK1720569T3|2004-02-27|2015-02-02|Immune System Therapeutics Ltd|Targets for B-cell disorders|

---

JP2005336062A|2004-05-24|2005-12-08|Mitsubishi Chemicals Corp|Homing inducer of t cell to intestinal tissue|

---

FR2872170B1|2004-06-25|2006-11-10|Centre Nat Rech Scient Cnrse|NON-INTERACTIVE AND NON-REPLICATIVE LENTIVIRUS, PREPARATION AND USES|

---

US7147626B2|2004-09-23|2006-12-12|Celgene Corporation|Cord blood and placenta collection kit|

---

WO2007044033A2|2004-12-07|2007-04-19|University Of Pittsburgh Of The Commonwealth System Of Higher Education|Therapeutic and diagnostic cloned mhc-unrestricted receptor specific for the muc1 tumor associated antigen|

---

US8444973B2|2005-02-15|2013-05-21|Duke University|Anti-CD19 antibodies and uses in B cell disorders|

---

US8088908B2|2005-05-10|2012-01-03|City Of Hope|Humanized anti-prostate stem cell antigen monoclonal antibody|

---

US9598669B2|2005-12-29|2017-03-21|Anthrogenesis Corporation|Composition for collecting placental stem cells and methods of using the composition|

---

AU2007211334A1|2006-02-01|2007-08-09|Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College|Polypeptide-nucleic acid conjugate for immunoprophylaxis or immunotherapy for neoplastic or infectious disorders|

---

CN101563104A|2006-02-01|2009-10-21|约翰霍普金斯大学|Polypeptide-nucleic acid conjugate for immunoprophylaxis or immunotherapy for neoplastic or infectious disorders|

---

WO2007146968A2|2006-06-12|2007-12-21|Trubion Pharmaceuticals, Inc.|Single-chain multivalent binding proteins with effector function|

---

US20100105136A1|2006-10-09|2010-04-29|The General Hospital Corporation|Chimeric t-cell receptors and t-cells targeting egfrviii on tumors|

---

EP2126054B1|2007-01-31|2016-07-06|Yeda Research And Development Company Limited|Redirected, genetically-engineered t regulatory cells and their use in suppression of autoimmune and inflammatory disease|

---

WO2008150853A1|2007-05-29|2008-12-11|Trustees Of Dartmouth College|Compositions and methods for producing adaptive regulatory t cells|

---

AU2008261644B2|2007-06-12|2014-04-03|Case Western Reserve University|Targeted cell death|

---

EP2006376A1|2007-06-21|2008-12-24|Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH|Fusion protein comprising a caspase domain and a nuclear hormone receptor binding domain and methods and uses thereof|

---

KR20200136051A|2007-09-26|2020-12-04|안트로제네시스 코포레이션|Angiogenic cells from human placental perfusate|

---

KR101648589B1|2007-09-28|2016-08-17|안트로제네시스 코포레이션|Tumor suppression using human placental perfusate and human placenta-derived intermediate natural killer cells|

---

WO2010003002A2|2008-07-02|2010-01-07|Board Of Regents, The University Of Texas System|Modulation of follicular helper t cells|

---

ES2553421T3|2008-08-26|2015-12-09|City Of Hope|Method and compositions for enhanced functioning of the T-cell anti-tumor effector|

---

JP6133538B2|2008-09-22|2017-05-24|ベイラー カレッジ オブ メディスンＢａｙｌｏｒ Ｃｏｌｌｅｇｅ Ｏｆ Ｍｅｄｉｃｉｎｅ|Methods and compositions for generating an immune response by inducing CD40 and pattern recognition receptor adapters|

---

MX2011008843A|2009-02-23|2011-12-14|Glenmark Pharmaceuticals Sa|Humanized antibodies that bind to cd19 and their uses.|

---

EP3141562A1|2009-03-10|2017-03-15|Biogen MA Inc.|Anti-bcma antibodies|

---

US20120207744A1|2009-03-19|2012-08-16|Mendlein John D|Reprogramming compositions and methods of using the same|

---

IN2012DN01663A|2009-09-16|2015-06-05|Immunomedics Inc||

---

WO2011035018A2|2009-09-18|2011-03-24|Fate Therapeutics, Inc.|Suicide ready cells|

---

CA2776143A1|2009-10-01|2011-04-07|The United States Of America, As Represented By The Secretary, Departmen T Of Health And Human Services|Anti-vascular endothelial growth factor receptor-2 chimeric antigen receptors and use of same for the treatment of cancer|

---

WO2011059836A2|2009-10-29|2011-05-19|Trustees Of Dartmouth College|T cell receptor-deficient t cell compositions|

---

AU2013274416B2|2012-06-11|2019-07-04|Wilson Wolf Manufacturing Corporation|Improved methods of cell culture for adoptive cell therapy|

---

PL2536706T3|2010-02-11|2017-10-31|Celgene Corp|Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same|

---

TW201134488A|2010-03-11|2011-10-16|Ucb Pharma Sa|PD-1 antibodies|

---

US20110287038A1|2010-04-16|2011-11-24|Kevin Slawin|Method for treating solid tumors|

---

WO2011146862A1|2010-05-21|2011-11-24|Bellicum Pharmaceuticals, Inc.|Methods for inducing selective apoptosis|

---

AU2011268110B2|2010-06-19|2016-05-19|Memorial Sloan-Kettering Cancer Center|Anti-GD2 antibodies|

---

JP5996533B2|2010-07-13|2016-09-21|アントフロゲネシス コーポレーション|How to generate natural killer cells|

---

EP2614143B1|2010-09-08|2018-11-07|Baylor College Of Medicine|Immunotherapy of non-small lung cancer using genetically engineered gd2-specific t cells|

---

WO2012050374A2|2010-10-13|2012-04-19|Innocell, Inc.|Immunotherapy for solid tumors|

---

NZ728530A|2010-10-27|2017-06-30|Baylor College Medicine|Chimeric cd27 receptors for redirecting t cells to cd70-positive malignancies|

---

EP3305798A1|2010-12-09|2018-04-11|The Trustees of The University of Pennsylvania|Use of chimeric antigen receptor-modified t cells to treat cancer|

---

EP2665521A4|2011-01-18|2014-09-03|Univ Pennsylvania|Compositions and methods for treating cancer|

---

MX359513B|2011-03-23|2018-10-01|Hutchinson Fred Cancer Res|METHOD and COMPOSITIONS FOR CELLULAR IMMUNOTHERAPY.|

---

WO2012138858A1|2011-04-08|2012-10-11|Baylor College Of Medicine|Reversing the effects of the tumor microenvironment using chimeric cytokine receptors|

---

ES2696000T3|2011-04-08|2019-01-11|Us Health|Receptors of epimeric growth factor receptor anti-variant III antigens and use thereof for the treatment of cancer|

---

US20130071414A1|2011-04-27|2013-03-21|Gianpietro Dotti|Engineered cd19-specific t lymphocytes that coexpress il-15 and an inducible caspase-9 based suicide gene for the treatment of b-cell malignancies|

---

EP2756521A4|2011-09-16|2015-04-22|Univ Pennsylvania|Rna engineered t cells for the treatment of cancer|

---

CN103946242A|2011-10-20|2014-07-23|美国卫生和人力服务部|Anti-cd22 chimeric antigen receptors|

---

WO2013063419A2|2011-10-28|2013-05-02|The Trustees Of The University Of Pennsylvania|A fully human, anti-mesothelin specific chimeric immune receptor for redirected mesothelin-expressing cell targeting|

---

ES2861435T3|2011-11-03|2021-10-06|Univ Pennsylvania|Specific compositions of isolated B7-H4 and methods of using them|

---

WO2013070468A1|2011-11-08|2013-05-16|The Trustees Of The University Of Pennsylvania|Glypican-3-specific antibody and uses thereof|

---

JP6850528B2|2012-02-13|2021-03-31|シアトル チルドレンズ ホスピタル ドゥーイング ビジネス アズ シアトル チルドレンズ リサーチ インスティテュート|Bispecific chimeric antigen receptor and its therapeutic use|

---

CN103483452B|2012-06-12|2021-08-13|上海细胞治疗集团有限公司|Dual signal independent chimeric antigen receptors and uses thereof|

---

ES2872967T3|2012-06-29|2021-11-03|Celgene Corp|Methods to determine drug efficacy using IKZF3 |

---

RU2015108761A|2012-08-13|2016-10-10|Антродженезис Корпорейшн|NATURAL KILLER CELLS AND THEIR APPLICATION|

---

ES2871349T3|2012-09-04|2021-10-28|Inven2 As|Selective and controlled expansion of educated NK cells|

---

CN112430580A|2012-10-02|2021-03-02|纪念斯隆-凯特琳癌症中心|Compositions and methods for immunotherapy|

---

US10117896B2|2012-10-05|2018-11-06|The Trustees Of The University Of Pennsylvania|Use of a trans-signaling approach in chimeric antigen receptors|

---

AU2013204922B2|2012-12-20|2015-05-14|Celgene Corporation|Chimeric antigen receptors|

---

SG10201810087QA|2013-02-06|2018-12-28|Celgene Corp|Modified t lymphocytes having improved specificity|

---

US9434935B2|2013-03-10|2016-09-06|Bellicum Pharmaceuticals, Inc.|Modified caspase polypeptides and uses thereof|

---

SG11201506974XA|2013-03-14|2015-10-29|Bellicum Pharmaceuticals Inc|Methods for controlling t cell proliferation|

---

ES2837628T3|2013-03-15|2021-07-01|Celgene Corp|Modified T lymphocytes|

---

US9745368B2|2013-03-15|2017-08-29|The Trustees Of The University Of Pennsylvania|Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy|

---

US9393268B2|2013-03-15|2016-07-19|Thomas Jefferson University|Cell-based anti-cancer compositions with reduced toxicity and methods of making and using the same|

---

DK3004329T3|2013-06-05|2020-05-18|Bellicum Pharmaceuticals Inc|METHODS FOR INDUCTION OF PARTIAL APOPTOSIS USING CASPASE POLYPEPTIDES|

---

WO2015127351A1|2014-02-24|2015-08-27|Celgene Corporation|Methods of using an activator of cereblon for neural cell expansion and the treatment of central nervous system disorders|

---

RU2020139890A|2014-04-14|2022-01-18|Арвинас Оперэйшнз, Инк.|IMIDE MODULATORS OF PROTEOLYSIS AND METHODS FOR THEIR APPLICATION|

---

CA2954534A1|2014-07-07|2016-01-14|Targazyme, Inc.|Manufacture and cryopreservation of fucosylated cells for therapeutic use|

---

KR20170045244A|2014-08-12|2017-04-26|안트로제네시스 코포레이션|Car-t lymphocytes engineered to home to lymph node b cell zone, skin, or gastrointestinal tract|

---

WO2016109668A1|2014-12-31|2016-07-07|Anthrogenesis Corporation|Methods of treating hematological disorders, solid tumors, or infectious diseases using natural killer cells|

---

WO2016138034A1|2015-02-24|2016-09-01|The Regents Of The University Of California|Binding-triggered transcriptional switches and methods of use thereof|

---

EP3528851A4|2016-10-20|2020-06-03|Celgene Corporation|Cereblon-based heterodimerizable chimeric antigen receptors|

---

MA46723A|2016-11-04|2019-09-11|Bluebird Bio Inc|T CAR ANTI-BCMA LYMPHOCYTES COMPOSITIONS|

---

AU2019301126A1|2018-07-11|2021-02-04|Celgene Corporation|Uses of anti-BCMA chimeric antigen receptors|AU2013204922B2|2012-12-20|2015-05-14|Celgene Corporation|Chimeric antigen receptors|

---

DK2958943T3|2013-02-20|2019-12-09|Univ Pennsylvania|Treatment of cancer using humanized anti-EGFRvIII chimeric antigen receptor|

---

JP6857028B2|2013-03-15|2021-04-14|メモリアル スローン ケタリング キャンサー センター|Compositions and methods for immunotherapy|

---

ES2837628T3|2013-03-15|2021-07-01|Celgene Corp|Modified T lymphocytes|

---

KR20210040467A|2013-05-14|2021-04-13|보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템|Human application of engineered chimeric antigen receptort-cells|

---

CA2913052A1|2013-05-24|2014-11-27|Board Of Regents, The University Of Texas System|Chimeric antigen receptor-targeting monoclonal antibodies|

---

CN110938655A|2014-04-25|2020-03-31|蓝鸟生物公司|MND promoter chimeric antigen receptor|

---

AU2015269219B2|2014-06-06|2020-12-24|Memorial Sloan-Kettering Cancer Center|Mesothelin-targeted chimeric antigen receptors and uses thereof|

---

MX2017000646A|2014-07-15|2017-04-27|Juno Therapeutics Inc|Engineered cells for adoptive cell therapy.|

---

MA42895A|2015-07-15|2018-05-23|Juno Therapeutics Inc|MODIFIED CELLS FOR ADOPTIVE CELL THERAPY|

---

RU2751660C2|2014-07-21|2021-07-15|Новартис Аг|Treatment of malignant neoplasm using humanized chimeric antigen receptor against bcma|

---

TWI718992B|2014-07-21|2021-02-21|瑞士商諾華公司|Treatment of cancer using a cll-1 chimeric antigen receptor|

---

WO2016014789A2|2014-07-24|2016-01-28|Bluebird Bio, Inc.|Bcma chimeric antigen receptors|

---

WO2016026143A1|2014-08-22|2016-02-25|Huiru Wang|Saccharide-based biomarkers and therapeutics|

---

AU2015310897B2|2014-09-04|2020-03-19|Cellectis|Trophoblast glycoproteinspecific chimeric antigen receptors for cancer immunotherapy|

---

AU2015316480B2|2014-09-15|2021-02-04|Molmed Spa|Chimeric antigen receptors|

---

KR20170075785A|2014-11-05|2017-07-03|보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템|Gene modified immune effector cells and engineered cells for expansion of immune effector cells|

---

KR20170090501A|2014-12-12|2017-08-07|블루버드 바이오, 인코포레이티드.|Bcma chimeric antigen receptors|

---

EP3250605A1|2015-01-26|2017-12-06|Cellectis|Anti-hsp70 specific chimeric antigen receptorsfor cancer immunotherapy|

---

KR101755431B1|2015-02-02|2017-07-12|단국대학교 산학협력단|CTLA-4 targeting trans-splicing ribozyme for delivering chimeric antigen receptor and use thereof|

---

WO2016127257A1|2015-02-12|2016-08-18|University Health Network|Chimeric antigen receptors|

---

CA2977106A1|2015-02-27|2016-09-01|Icell Gene Therapeutics Llc|Chimeric antigen receptorstargeting hematologic malignancies, compositions and methods of use thereof|

---

BR112017018770A2|2015-03-02|2018-04-17|Innovative Cellular Therapeutics CO., LTD.|reduced immune tolerance induced by pd-l1|

---

JP2018510652A|2015-03-18|2018-04-19|ベイラー カレッジ オブ メディスンＢａｙｌｏｒ Ｃｏｌｌｅｇｅ Ｏｆ Ｍｅｄｉｃｉｎｅ|HER2 / ERBB2 chimeric antigen receptor|

---

CN107614531A|2015-03-18|2018-01-19|纪念斯隆凯特琳癌症中心|CD99 composition and method is targetted in hematopoiesis and lymphoid malignancy|

---

US11173179B2|2015-06-25|2021-11-16|Icell Gene Therapeutics Llc|Chimeric antigen receptortargeting multiple antigens, compositions and methods of use thereof|

---

US20180187149A1|2015-06-25|2018-07-05|Icell Gene Therapeutics Llc|CHIMERIC ANTIGEN RECEPTORS , COMPOSITIONS AND METHODS OF USE THEREOF|

---

EP3474867A4|2016-06-24|2020-05-20|iCell Gene Therapeutics LLC|Chimeric antigen receptors , compositions and methods thereof|

---

MX2018000278A|2015-06-29|2018-03-08|Univ Johns Hopkins|Immune checkpoint chimeric antigen receptors therapy.|

---

MX2018001502A|2015-08-05|2018-08-01|Yoo Young Pharm Co Ltd|Chimeric antigen receptor, and t cells in which chimeric antigen receptor is expressed.|

---

GB201518816D0|2015-10-23|2015-12-09|Autolus Ltd|Receptor|

---

EP3371227B1|2015-11-04|2022-02-23|City of Hope|Chimeric antigen receptors targeting her2|

---

TWI634125B|2016-01-21|2018-09-01|輝瑞股份有限公司|Chimeric antigen receptors targeting epidermal growth factor receptor variant iii|

---

CN105567640A|2016-01-27|2016-05-11|苏州佰通生物科技有限公司|Chimeric antigen receptor adipose-derived stem cell and preparation method thereof|

---

CN108779160A|2016-02-05|2018-11-09|希望之城公司|Using engineering T cell to treat the cancer in central nervous system|

---

WO2017139975A1|2016-02-19|2017-08-24|Huiru Wang|Antibodies against n-acetylglucosamine and n-acetyl-galactosamine|

---

CA3017036A1|2016-03-23|2017-09-28|Helmholtz Zentrum Munchen - Deutsches Forschungszentrum Fur Gesundheit Und Umwelt |Fusion proteins of pd-1 and 4-1bb|

---

CN106279432B|2016-08-10|2019-09-20|深圳市再生之城生物医药技术有限公司|A kind of VC-CAR molecule and the application in removing HIV-1 infection cell|

---

MX2019007404A|2016-12-23|2019-09-27|Macrogenics Inc|Adam9-binding molecules, and methods of use thereof.|

---

WO2019008001A1|2017-07-04|2019-01-10|Curevac Ag|Novel nucleic acid molecules|

---

CN107400168B|2017-07-18|2020-02-07|深圳市免疫基因治疗研究院|Chimeric antigen receptor based on CD117 and application thereof|

---

CN112601546A|2018-06-12|2021-04-02|普瑞迈博生物技术有限公司|PLAP-CAR-Effector cells|

---

US20210395329A1|2018-06-29|2021-12-23|City Of Hope|Cd6 targeted chimeric antigen receptors for treatent of certain autoimmune disorders|

---

WO2020261231A1|2019-06-27|2020-12-30|Eutilex Co., Ltd.|Chimeric antigen receptor with 4-1bb costimulatory domain|

---

CN109096405B|2018-09-20|2021-07-09|杭州普略生物科技有限公司|Chimeric antigen receptor taking GD2 as target and pharmaceutical composition|

---

TW202100747A|2018-12-07|2021-01-01|中國大陸商亘喜生物科技（上海）有限公司|Compositions and methods for immunotherapy|

---

US20220056092A1|2018-12-11|2022-02-24|Obsidian Therapeutics, Inc.|Membrane bound il12 compositions and methods for tunable regulation|

---

WO2020185632A1|2019-03-08|2020-09-17|Obsidian Therapeutics, Inc.|Human carbonic anhydrase 2 compositions and methods for tunable regulation|

---

WO2020252404A1|2019-06-12|2020-12-17|Obsidian Therapeutics, Inc.|Ca2 compositions and methods for tunable regulation|

---

CA3140668A1|2019-06-12|2020-12-17|Obsidian Therapeutics, Inc.|Ca2 compositions and methods for tunable regulation|

---

WO2021040736A1|2019-08-30|2021-03-04|Obsidian Therapeutics, Inc.|Tandem cd19 car-based compositions and methods for immunotherapy|

---

CN110590960B|2019-09-26|2020-08-28|武汉波睿达生物科技有限公司|Chimeric antigen receptor with CD99 as target and application thereof|

法律状态:
2015-09-10| FGA| Letters patent sealed or granted (standard patent)|

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2018-11-01| PC| Assignment registered|Owner name: CELGENE CORPORATION Free format text: FORMER OWNER(S): ANTHROGENESIS CORPORATION |

优先权:

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申请号 | 申请日 | 专利标题

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US201261740113P| true| 2012-12-20|2012-12-20||

---

US61/740,113||2012-12-20||

---

US201361779925P| true| 2013-03-13|2013-03-13||

---

US61/779,925||2013-03-13||AU2015210373A| AU2015210373B2|2012-12-20|2015-08-05|Chimeric antigen receptors|

---

AU2017204617A| AU2017204617B2|2012-12-20|2017-07-06|Chimeric antigen receptors|