WO2024099990A1

WO2024099990A1 - TGF-ß SWITCH RECEPTOR CAR T CELLS

Info

Publication number: WO2024099990A1
Application number: PCT/EP2023/080884
Authority: WO
Inventors: Jordan HARTLEY; Hinrich Abken
Original assignee: Leibniz-Institut Für Immuntherapie (Lit)
Priority date: 2022-11-07
Filing date: 2023-11-06
Publication date: 2024-05-16

Abstract

The present invention provides recombinant T cells comprising switch receptors that protect the T cell from TGF-ß mediated repression and the same time produce an intracellular IL2 receptor signal, thereby increasing the functional efficacy of T cells triggered by a chimeric antigen receptor or T cell receptor co-expressed in the same T cell.

Description

TGF- ^ Switch Receptor CAR T cells Field of the invention The present invention provides recombinant T cells comprising switch receptors that protect the T cell from TGF- ^ repression and the same time produce an intracellular IL2 signal, thereby increasing the efficacy of a chimeric antigen receptor co-expressed in the same T cell. Background T cell based immunotherapy has emerged as promising therapy in the treatment of cancer. In particular, chimeric antigen receptor (CAR) T cell therapy offers new avenues in the treatment of cancerous diseases, such as lymphoid malignancies. Conventional CAR T cells are genetically engineered T cells that contain an artificial chimeric antigen receptor that initiates an immune response against cells recognized by the CAR. However, the tumor microenvironment (TME) is a strong barrier for effective CAR T cell therapy. A hostile TME and the cancer cell itself often protects tumor cells from the immune system. One of the most relevant components are soluble immunosuppressive factors, such as TGF- ^ ^, a soluble immunosuppressive cytokine commonly present in the TME (Trends Cancer (2019) 5: 351–64). TGF- ^1 is released as an inactive complex and is activated by proteases such as matrix metalloprotease (MMP)-9 and MMP-2 (Genes Dev (2000) 14: 163–76). Active TGF- ^1 binds to TGF- ^ receptor II (TRII) on the T cell surface, thereby activating the TRII intracellular kinase domain, which recruits and phosphorylates TRI. The resulting heterodimeric complex consists of TRI and TRII and induces the phosphorylation of R-SMADs, transcription factors which are translocated to the nucleus where they associate with DNA-binding co-factors and transcriptional co-activators and/or co-repressors, eventually resulting in cell cycle inhibition (Nat Rev Immunol (2007) 7: 443–53). TGF- ^ promotes tumor invasion and metastasis and inhibits T cell activation and proliferation (Int J Cancer (2007) 121: 2119–24; Proc Natl Acad Sci USA (2005) 102: 419–24; Annu Rev Immunol (2006) 24: 99–146). Hence, there is still a strong need to improve T cell based immunotherapies of cancer in order to circumvent repression in the tumor tissue due to the high TGF- ^1 concentrations on the cancer cell surface, the tumor tissue and the TME. Various strategies have been employed to circumvent the T cell inhibitory effects of TGF- ^ in cancer therapy. This includes the expression of a dominant-negative TRII (dnTRII) to create T cells that are insensitive to TGF- ^. dnTRII is a truncated TRII that lacks the intracellular domains necessary for downstream signaling. Therefore, it acts as a decoy and renders effector T cells resistant to TGF- ^ ^ but leaves their proliferation, cytokine secretion, and cytolytic functions unchanged (Mol Cell Biol (1993) 13: 7239–47; J Immunother (2006) 29: 250–60; Blood (2002) 99: 3179–87), thereby enhancing anti-tumor immunity (Mol Ther (2018) 26: 1855–66; J Clin Oncol (2018) 36: 1128). Switch receptors are chimeric molecules that have been created to reverse the outcome of their original signaling pathways and transform (or “switch”) the signal by way of a chimeric intracellular signaling domain. For instance, a switch receptor binds a suppressive factor and provides a stimulatory signal to the cell; or vice versa binds an activating factor and provides a suppressive signal. Activating switch receptors exploit inhibitory molecules to stimulate T lymphocytes by fusing the extracellular portion of an inhibitory receptor with a signaling domain that provides an immune- activating function (for a review see Immunotherapy (2017) 9: 1339–49). Several switch receptors are reported. Molecular Therapy (2017) 25: 249–58 describes a switch receptor containing an IL4R ^ binding domain and an IL7R ^ signaling domain. Front Immunol (2019) 10:1691 describes a switch receptor containing an IL4R ^ binding domain and a IL7Ra/IL21R signaling domain. J Biol Chem (2010) 285: 25538-44 describes a switch receptor containing an IL4R ^ binding domain and an IL2R ^ signaling domain. Journal for ImmunoTherapy of Cancer (2021) 9: e003176 describes a switch receptor containing a TIM-3 binding domain and a CD28 signaling domain. Cancer Res (2016) 76: 1578–90 describes a switch receptor containing a PD1 binding domain and a CD28 signaling domain. Int J Mol Sci (2021) 22:8706 describes a switch receptor containing a TGFβRII binding domain and an IL7 signaling domain. The latter switch receptor is therefore the only switch receptor that makes use of a TGFβRII binding domain. The signal is however converted into the IL7 signaling pathway. The present disclosure describes novel switch receptors that contain a TGFβRII binding domain and an IL2 receptor- ^ (IL2R ^ ^ signaling domain. In the activation of effector and repressor T cells downstream IL2 signaling through the IL2R ^ signaling domain is superior over the IL7 pathway since IL2 acts on both T cells subsets and does not need a “help” of an additional cytokine signal like IL7 plus IL15 in order to trigger T cell amplification and cytotoxic properties such as the upregulation of perforin and CD107a. Switch receptors according to this disclosure are superior to other approaches for the treatment of T cell based immunotherapies, such as the treatment of cancer or auto-immune diseases. These switch receptors protect effector T cell from TGF- ^ repression and the same time produce an intracellular IL2 signal through the linked IL2R ^-chain to trigger T cell activation. The protection from TGF- ^ repression is more powerful the higher the TGF- ^ concentration is. These switch receptors also provide a positive stimulatory signal to regulatory T cells upon TGF- ^ ^binding, thereby promoting their survival and amplification. Summary of the invention The present disclosure relates to recombinant switch receptors comprising of a polypeptide extracellular domain which specifically binds TGF, a transmembrane domain, and an IL-2 receptor signaling domain. The present disclosure relates to recombinant switch receptors comprising a. an extracellular domain comprising a polypeptide which specifically binds TGF, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. Said polypeptide which specifically binds TGF may bind to any member of the TGF ^ family. In certain embodiments, said polypeptide which specifically binds TGF, specifically binds TGF ^1. In other embodiments, said polypeptide which specifically binds TGF, specifically binds TGF ^2. In yet other embodiments, said polypeptide which specifically binds TGF, specifically binds TGF ^1 and TGF ^ ^. Said polypeptide may comprise a natural binding domain that is specific for TGF ^1 or an antibody, an antibody fragment, or a protein scaffold which specifically binds TGF ^1. Said natural binding domain that is specific for TGF ^1 may be a binding domain of TGFR ^II. Said binding domain of TGFR ^II may comprise a polypeptide of SEQ No.3. Said IL-2 receptor signaling domain may be an IL-2 receptor signaling domain of IL-2R ^. Said IL- 2 receptor signaling domain may comprise a polypeptide of SEQ No.9. Said transmembrane domain may be a transmembrane domain of PDGFRB. Said transmembrane domain may comprise a polypeptide of SEQ No.6. The present disclosure also relates to a T cell comprising aforementioned switch receptors. Said T cell may further comprise a chimeric antigen receptor or a T cell receptor. Said chimeric antigen receptor may comprise a. an extracellular domain b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. Said the extracellular domain of said chimeric antigen receptor may comprise an antigen-binding region with specificity for a tumor antigen. Said tumor antigen may be CEA. Said antigen-binding region may be a scFv comprising a polypeptide of SEQ No.23. Said one or more cytoplasmic signaling domains of said chimeric antigen receptor may be a cytoplasmic costimulatory signaling domain and/or a cytoplasmic T cell receptor complex associated signaling domain. Said cytoplasmic costimulatory signaling domain may be 4-1BB. Said cytoplasmic signaling domain may comprise a polypeptide of SEQ No. 12. Said cytoplasmic T cell receptor complex associated signaling domain may be CD3, preferably CD3 ^. Said cytoplasmic T cell receptor complex associated signaling domain may comprise a polypeptide of SEQ No.15. Said transmembrane domain of said chimeric antigen receptor may be a CD4 transmembrane domain. Said transmembrane domain may be a transmembrane domain comprising a polypeptide of SEQ No.19. The present disclosure also relates pharmaceutical compositions comprising aforementioned switch receptors, and optionally a pharmaceutically acceptable carrier. The present disclosure also relates pharmaceutical compositions comprising aforementioned T cells, and optionally a pharmaceutically acceptable carrier. The present disclosure also relates to aforementioned switch receptors, aforementioned T cells or aforementioned pharmaceutical compositions for use in medicine. Said use in medicine may be the treatment of a disease or disorder, preferably the treatment of cancer. The present disclosure also relates to a recombinant T cell comprising i) a chimeric antigen receptor or a T cell receptor, and ii) a recombinant switch receptor, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. The present disclosure also relates to a recombinant T cell comprising i) a chimeric antigen receptor comprising a polypeptide of amino acid sequence of SEQ ID No.28, and ii) a recombinant switch receptor comprising a polypeptide of amino acid sequence of SEQ No.27. Figure legends Figure 1 illustrates the domain structure of the CAR alone (labeled as “Standard”), the construct containing the CAR and a dominant negative receptor (labeled as “DNR”), and the construct containing the CAR and a switch receptor (labeled as “SWR”). P2A designates the P2A of self-cleavage site. All constructs contain human signaling domains for functioning in human T cells. Figure 2 illustrates the architecture of a T cell containing a CAR and a switch receptor (SWR). Figure 3 shows representative dot plots confirming that human T cells retrovirally transduced with the respective CAR constructs express the CAR and the switch receptor SWR. CAR expression was detected by flow cytometry using a PE-conjugated anti-IgG antibody that recognizes the CAR extracellular IgG1 spacer domain. For the identification of T cells, a BV421-conjugated anti-human CD3 antibody was used. The SWR was detected using the APC-conjugated anti-TGFβRII antibody recognizing the TGF ^ ^binding domain. Top panels: 4-1BB-ζ and 4-1BB-ζ-SWR CAR was expressed on human CD3+ T cell surface. Human T cells were retrovirally transduced with respective CAR by spinfection. CAR expression was detected by flow cytometry using the PE-conjugated anti-IgG antibody (Southern Biotech, Cat. No. 2043-09) which is specific for the extracellular spacer in the CAR; for the T cells the BV421-conjugated anti-CD3 antibody (BioLegend, Cat. No.300434) was used. The percentage indicates the total number of CAR+ T cells. Bottom panels: SWR expression after gating on 4-1BB-ζ CAR T cells. SWR was detected by staining for TGF-βRII using APC-conjugated anti- human TGF-βRII antibody (BioLegend, Cat. No.399706). T cells expressing the CAR also express the SWR. NT, non-transduced non-modified T cells. Figure 4 shows that T cells transduced with the construct encoding the CAR and the switch receptor showed no reduction in specific cytotoxicity in the presence of TGF-β1, whereas T cells transduced with the construct encoding the CAR alone did show a reduction in specific cytotoxicity in the presence of TGF-β1. CAR T cells (1 x 10⁵ T cells per well) were incubated with CEA+ HT-29 cells (2 x 10⁴ per well) in the presence or absence of TGF-β1 (0, 100 ng/ml). The specific cytotoxicity after 2 days was determined by a XTT-based viability assay (“Cell proliferation kit II” Roche, cat no 11465015001). The assay was repeated with T cells from three donors. Data represent the mean of triplicates ± SD. Statistical analyses were performed using a one-tailed paired t test (*p <0.05). Figure 5 shows that T cells transduced with the construct encoding the anti-CEA CAR and the switch receptor (SWR) proliferate in the presence of TGF-β1, whereas T cells transduced with the construct encoding the CAR alone did not (A) Human T cells were engineered to express 4-1BB-ζ CAR with and without switch receptor and labelled with “Cell Proliferation Dye eFluor 450” (Invitrogen). CAR T cells (1 x 10⁵) were incubated on a 96-well plate coated with anti-idiotypic mAb BW2064/36 (1.5 µg/ml coating concentration) as surrogate antigen for CEA in the presence and absence of TGF-β1 (0, 10 or 100 ng/ml) for 5 days. Proliferation was recorded by flow cytometry, PE-conjugated anti-IgG antibody (Southern Biotech, Cat. No.2043-09) that detects the extracellular IgG spacer of the CAR was used to detect CAR T cells;dilution of the dye measured CAR T cell proliferation. Data represent the mean of triplicates ± SEM from 3 donors. Statistical analyses were performed using a two-way ANOVA test (**p<0.005; ns, not significant). (B) Representative histograms of dye dilution of CAR+ cells under different conditions; w/o, CAR T cells without CAR stimulation. Figure 6 shows that the SWR protects different signaling CAR T cells from repression through TGF- ^. T cells were engineered with the respective anti-CEA CAR with the 4-1BB- ^, CD28 ^lck- ^, and OX40- ^ intracellular signaling chain, each CAR with or without co-expressed SWR. Cells were labelled with “Cell Proliferation Dye eFluor 450” (Invitrogen). CAR T cells (10⁵ T cells/well) were stimulated through their CAR by incubating for 5 days on a 96-well plate coated with the anti-idiotypic mAb BW2064/36 (1.5 µg/ml coating concentration). Cells were incubated in the presence or absence of TGF-β1 (0, 10 or 100 ng/ml). CAR T cell amplification was recorded by flow cytometry measuring the dye dilution; CAR T cells identified by staining for the IgG spacer region within the extracellular CAR domain using the PE- conjugated anti-IgG antibody (Southern Biotech). Data represent the mean of triplicates ± SEM with T cells from three different blood donors. Statistical analyses were performed using a two-way ANOVA test (*p <0.05; **p<0.005; ns, not significant). Figure 7 shows that Switch Receptor (SWR) CAR T cells display better cytolytic properties in the presence of TGF-β.4-1BB-ζ CAR T cells with specificity for CEA and with and without switch receptor (5 x 10⁴ cells) were incubated in the presence (+) and absence (-) of TGF-β1 (100 ng/ml) on a 96-well plate coated with anti-idiotypic mAb BW2064/36 (1.5 µg/ml) as surrogate antigen for CEA for 24 hours. CAR T cells were detected by staining with the PE-conjugated anti-IgG antibody (Southern Biotech). (A) Perforin MFI Fold change of CAR T cells, perforin was detected using APC-conjugated anti-perforin antibody (clone B-D48, BioLegend). (B) CD107a expression of activated CAR T cells, indicating cytolytic activities, was detected by incubation with the “Protein Transport Inhibitor Cocktail” (Invitrogen Life technologies) and a VioBlue-conjugated anti-CD107a (LAMP-1) antibody (clone H4A3, Miltenyi Biotec). (C) 4-1BB-ζ CAR T cells with and without switch receptor (2 x 10⁴ cells) were incubated in a 1:1 ratio (E:T) with CEA+ N87 tumor cells in the presence (+) and absence of TGF- β1. Culture supernatant was collected after 3 days and IFN-γ in the culture supernatant was detected by ELISA using matched-pairs capture and detection antibodies (BD Pharmingen). Data represent the mean of triplicates ± SEM. Statistical analyses were performed using an unpaired t test *p<0.05; ns, not significant. Figure 8 shows that the switch receptor (SWR) of the present disclosure sustains amplification of CAR T cells significantly better than the conventional dominant negative receptor (DNR) in the presence of TGF-β1. T cells were engineered with the anti-CEA 4-1BB-ζ CAR and additionally with the SWR or the DNR. T cells were labelled with “Cell Proliferation Dye eFluor 450” and stimulated through their CAR (10⁵ T cells/well) for 5 days with the immobilized mAb BW2064/36 in the presence or absence of TGF-β1 (0, 10 or 100 ng/ml). CAR T cell amplification was recorded by flow cytometry measuring the dilution of the cell proliferation dye and gating on CAR T cells that are detected by staining with the anti-IgG antibody (Southern Biotech) that recognizes the CAR extracellular spacer domain. Data represent the mean of triplicates ± SEM using T cells from three donors. Statistical analyses were performed using a two-way ANOVA test; *p <0.05; **p<0.005; ns, not significant. Figure 9 shows the experimental overview of the in vitro tumor cell re-challenging assay. Figure 10 shows the results of a repetitive stimulation assay of CAR T cells with switch receptor (SWR) or dominant negative receptor (DNR) in the absence or presence of added TGFβ1 (10 ng/ml). CAR T cell counts are shown in the left panel, tumor cell counts in the right panel. CAR T cell count after each round of tumor re-challenging. CAR T cells (1 x 10⁵) were incubated with CEA+ N87 cells (1 x 10⁵) (ATCC; No. CRL-5822), producing TGF- ^1 and TGF- ^2 at very low levels, in the presence (10 ng/ml) or absence (w/o) of added TGF-β1. After 3 days all cells were harvested and added to freshly seeded N87 cells (1 x 10⁵). The process was repeated for 3 rounds. During each harvest, cell counts determined via flow cytometry using “AccuCheck Counting Beads” (ThermoFisher). Living CAR T cells were identified using PE-conjugated anti-IgG antibody, BV421-conjugated anti-human CD3 antibody and “Fixable Viability Dye eFluor 780” (ThermoFisher). Tumor cells were counted after each round of re-challenging. N87 cell numbers were determined by flow cytometry using “AccuCheck Counting Beads”, “Fixable Viability Dye eFluor 780” and antigen negative back gating. Data represent the mean of triplicates ± SEM. The assay was repeated with T cells from 3 blood donors. Statistical analyses were performed using an unpaired t test (*p<0.05; **p<0.005 ns., not significant). Figure 11 shows that SWR CAR T cells outperform DNR CAR T cells in the treatment of solid cancer with high TGF- ^ load. CEA+ NCI-N87 cancer cells were engineered to express high levels of TGF-β1 and s.c. inoculated into NXG mice at day 0 (2x10⁶ cells/mouse). Human T cells were engineered with the anti-CEA CAR with or without SWR or DNR, respectively, and inoculated by injection into the retrobulbar venous plexus (10⁶ cells per mouse, 5 mice per group) at day 7 (ACT, adoptive cell transfer). Tumor growth was monitored by digital caliper measurements three times per week (n = 5 mice). Data show the mean values ± SEM. Figure 12 shows a Kaplan-Meier survival curve of mice bearing NCI-N87-TGF-β1 tumors treated with CAR modified T cells (1 x 10⁶, n = 5 mice per group). Tumor cell inoculation was performed at day 0; adoptive cell transfer with CAR T cells was performed at day 7. Comparison of survival data was done using Gehan-Breslow-Wilcoxon test. *p<0.05; ns, not significant. Figure 13 shows the fold increase in tumor size calculated on day 7, 10 and 14 after adoptive transfer of CAR modified T cells (n = 5 mice per group). Statistical analysis was done using unpaired t test, *p<0.05; **p<0.005; ***p<0.0005; ns, not significant. Definitions The term "cell" as used herein includes a single cell as well as a plurality of cells. The term "host cell" as used herein refers to a cell comprising a nucleic acid and/or a vector. In the context of the present disclosure, the term host cell refers to a cell comprising a nucleic acid and/or a vector encoding for chimeric antigen receptor and/or a switch receptor. Preferred host cells of the present invention are eukaryotic host cells, such as immune cells, preferably T cells. The term "T cell" as used herein refers to a type of lymphocyte that plays a central role in cell- mediated immunity. T cells, also referred to as T lymphocytes, can be distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T cell receptor (TCR) on the cell surface. There are several subsets of T cells with distinct functions, including but not limited to, T helper cells, cytotoxic T cells, memory T cells, regulatory T cells and natural killer T cells. In some embodiments, the T cell is an engineered T cell. The terms "polynucleotide" and/or "nucleic acid sequence" and/or "nucleic acid" as used herein refer to a sequence of nucleoside or nucleotide monomers consisting of bases, sugars and intersugar (backbone) linkages. The term includes DNA and RNA and can be either double stranded or single stranded, and represents the sense or antisense strand. The term also includes modified or substituted sequences comprising non-naturally occurring monomers or portions thereof. The nucleic acid sequences of the present application may be deoxyribonucleic acid sequences (DNA) or ribonucleic acid sequences (RNA) and may include naturally occurring bases including adenine, guanine, cytosine, thymidine and uracil. The sequences may also contain modified bases. Examples of such modified bases include aza and deaza adenine, guanine, cytosine, thymidine and uracil; and xanthine and hypoxanthine. The nucleic acids of the present disclosure may be isolated from biological organisms, formed by laboratory methods of genetic recombination or obtained by chemical synthesis or other known protocols for creating nucleic acids. The terms "isolated polynucleotide" or "isolated nucleic acid" as used herein refer to a nucleic acid substantially free of cellular material or culture medium when produced by recombinant DNA techniques, or chemical precursors, or other chemicals when chemically synthesized. The term “recombinant” as used in recombinant protein, recombinant protein domain, recombinant nucleic acid, and the like, means that said polypeptides, proteins or nucleic acids, are produced by the use of recombinant DNA technologies well known by the practitioner skilled in the relevant art. For example, a recombinant DNA molecule (e.g. produced by gene synthesis) encoding a polypeptide can be cloned into a bacterial expression plasmid (e.g. pQE30, Qiagen). When such a constructed recombinant expression plasmid is inserted into a host cell (e.g. E. coli), this host cell can produce the polypeptide encoded by this recombinant DNA. The correspondingly produced polypeptide is called a recombinant polypeptide or recombinant protein. The term "vector" as used herein refers to a polynucleotide that can be used to deliver a nucleic acid to the inside of a cell. In one embodiment, a vector is an expression vector comprising expression control sequences (for example, a promoter) operatively linked to a nucleic acid to be expressed in a cell. Vectors known in the art include, but are not limited to, plasmids, phages, cosmids and viruses. The term "polypeptide" or "protein" as used herein describes a chain of amino acids. A polypeptide or protein of this disclosure can be a peptide, which usually describes a chain of amino acids of from two to about 30 amino acids. The term protein as used herein also describes a chain of amino acids having more than 30 amino acids and can be a fragment or domain of a protein or a full length protein. Furthermore, as used herein, the term protein can refer to a linear chain of amino acids or it can refer to a chain of amino acids that has been processed and folded into a functional protein. It is understood, however, that 30 is an arbitrary number with regard to distinguishing peptides and proteins and the terms can be used interchangeably for a chain of amino acids. The proteins of the present disclosure can be obtained by isolation and purification of the proteins from cells where they are produced naturally, by enzymatic (e.g., proteolytic) cleavage, and/or recombinantly by expression of nucleic acid encoding the proteins or fragments of this disclosure. The proteins and/or fragments of this disclosure can also be obtained by chemical synthesis or other known protocols for producing proteins and fragments. The term "isolated polypeptide" refers to a polypeptide substantially free of cellular material or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. A part of a protein or a polypeptide, which individually has, or is able to acquire a defined three- dimensional arrangement by forming secondary or tertiary structures, is termed “protein domain” or “domain”. Such protein domains are well known to the practitioner skilled in the art. The terms “binds”, “is specific” and “specifically binds” as used herein refers to a molecule, for example an antibody, an antibody fragment, an antigen-binding region, a chimeric antigen receptor or protein scaffold, which recognizes a specific antigen or target molecule, but does not substantially recognize or bind other molecules in a sample. An antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more further species. Such cross-species reactivity does not itself alter the classification of an antibody as specific. In this context, the term “binding domain” refers to the domain of a protein or a polypeptide which is responsible for binding to a specific molecule or other protein or polypeptide. Furthermore, certain binding domains are known to bind to more than one ligand. For example, the extracellular domain of TGF ^RII which binds TGF ^1, also binds to TGF ^2 and TGF ^3. In the present disclosure, the inventors made use of the specificity of TGF ^RII to TGF ^1, which is abundant in tumors, specifically solid tumors. As used herein, the term "switch receptor" refers to a molecule designed to switch a negative signal transduction signal into a positive signal. In some embodiments, the switch receptor is a chimeric protein comprising a first protein or fragment thereof binding a negatively signalling protein, and a second protein or fragment thereof associated with a positive signalling. Accordingly, a switch receptor, when expressed in a cell, converts a negative signal into a positive signal in the cell. The terms “chimeric antigen receptor” and “CAR” are used interchangeably and refer to a chimeric polypeptide comprising multiple functional domains arranged from amino to carboxy terminus in the sequence: (a) an extracellular domain (ECD) comprising an antigen binding domain, (b) a transmembrane domain; and (c) one or more cytoplasmic signaling domains. The CAR may further comprise a signal peptide sequence which is conventionally removed during post- translational processing and presentation of the CAR on the cell surface of a cell transformed with an expression vector comprising a nucleic acid sequence encoding the CAR. The term “antibody” as used herein refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, which interacts with an antigen. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FR’s arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The term “antibody” includes for example, monoclonal antibodies, human antibodies, humanized antibodies, camelised, cameloid or camel-derived antibodies and chimeric antibodies. The antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass. Both the light and heavy chains are divided into regions of structural and functional homology. The term “antibody fragment” as used herein refers to one or more portions of an antibody that retain the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing spatial distribution) an antigen. Examples of binding fragments include, but are not limited to, a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as “single chain fragment of variable region”, “single chain Fv” or “scFv”; see e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci.85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antibody fragment”. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No.6,703,199, which describes fibronectin polypeptide monobodies). Antibody fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1 -VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen-binding sites (Zapata et al., (1995) Protein Eng.8: 1057-1062; and U.S. Pat. No.5,641 ,870). The term “scaffold” or "protein scaffold" means a protein with exposed surface areas in which amino acid insertions, substitutions or deletions are highly tolerable. Examples of protein scaffolds that can be used to generate binding domains of the present invention are antibodies or fragments thereof such as single-chain Fv or Fab fragments, T cell receptor such as single chain T cell receptors, protein A from Staphylococcus aureus, the bilin binding protein from Pieris brassicae or other lipocalins, ankyrin repeat proteins, monobodies, human fibronectin, or antibodies from camelids, such as nanobodies. Protein scaffolds are known to the person skilled in the art (Curr Opin Biotechnol 22:849-857 (2011); Ann Rev Pharmacol Toxicol 60:391-415 (2020)). In certain embodiments of the present disclosure the protein scaffold is a polypeptide. In certain embodiments of the present disclosure the protein scaffold is a monomeric polypeptide. In certain embodiments of the present disclosure, the protein scaffold is an antibody fragment. In certain embodiments of the present disclosure the protein scaffold is a scFv. In certain embodiments of the present disclosure the protein scaffold is an a single chain T cell receptor. In certain embodiments of the present disclosure the protein scaffold is a peptide. The term “antigen-binding region” is art recognized and refers to a domain or amino acid stretch of a protein, such as an antibody, an antibody fragment or a protein scaffold, which is responsible for the specific interaction of such protein to a target antigen. The terms “recipient”, “individual”, “subject”, “host”, and “patient”, are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. As used herein, the terms “treatment,” “treating,” and the like, in some embodiments, refer to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of affecting a partial or complete cure for a disease and/or symptoms of the disease. The terms include treatment of a disease or disorder (e.g. inflammation) in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g, including diseases that may be associated with or caused by a primary disease; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease. The treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including the results of an examination by a physician. Accordingly, the term "treating" includes the administration of the compounds or agents of the present invention to prevent, delay, alleviate, arrest or inhibit development of the symptoms or conditions associated with diseases (e.g. inflammation). The term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject. The terms “costimulatory molecule" or “costimulatory receptor” as used herein refers to a cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response in the T cell, such as, but not limited to, activation or proliferation. A co-stimulatory receptor may be expressed on cells other than T cells, such as NK cells or macrophages. A costimulatory molecule can be represented in the following protein families: TNF receptor proteins, Immunoglobulin like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), Toll-like receptors and NK cell receptors. Costimulatory molecules include, but are not limited to 4-IBB (CD137), BAFFR, OX40, CD27, CD28, CD40, 2B4, GITR, HVEM, OX40, RELT, TACI, TROY, TWEAK, KIR receptors, TLR1 to TLR9 receptors, IL- 2, IL-7 and IL-15 receptors. The terms “costimulatory signaling domain” or “costimulatory domain” as used herein refer to the domain of a costimulatory molecule or costimulatory receptor responsible for mediating a costimulatory response by the T cell. The intracellular signaling domain can comprise the entire intracellular portion, or the entire native intracellular signaling domain, of the molecule from which it is derived, or a functional fragment or derivative thereof. The terms “T cell receptor signaling domain” or “TCR signaling domain” as used herein refers to cytoplasmic signaling sequence that acts in a stimulatory manner to induce immune effector functions. In some embodiments, the TCR signaling domain contains a signaling motif known as Immunoreceptor Tyrosine-based Activation Motif, or ITAM. In some embodiments, the primary intracellular signaling domain comprises a functional signaling domain of a protein selected from the group consisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCER1G) , FcR beta (Fc ^RI ^) , CD79a, CD79b, Fc ^RII ^, DAP10, and DAP12. A preferred TCR signaling domain is a TCR signaling domain selected from CD3 zeta, CD3 gamma, CD3 delta or CD3 epsilon. A particularly preferred TCR signaling domain is CD3 zeta, CD3 gamma, CD3 delta and CD3 epsilon. The terms “is”, “are”, “is derived from” and “are derived from” in the context of a polypeptide or domain of a polypeptide refers to the amino acid sequence of said polypeptide or domain of a polypeptide and indicates that the amino acid sequence is either identical to the native version of said polypeptide or domain of a polypeptide, or a variant of said polypeptide or domain of a polypeptide which is functionally indistinguishable form from the native version of said polypeptide or domain of a polypeptide. The term “TGF ^1” as used herein refers to a protein also known as TGFB1 or Transforming Growth Factor Beta 1. TGF ^1 (UniProt P01137) has the following amino acid sequence: MPPSGLRLLPLLLPLLWLLVLTPGRPAAGLSTCKTIDMELVKRKRIEAIRGQILSKLRLA SPPSQGEVPPGPLPEAVLALYNSTRDRVAGESAEPEPEPEADYYAKEVTRVLMVETHNEI YDKFKQSTHSIYMFFNTSELREAVPEPVLLSRAELRLLRLKLKVEQHVELYQKYSNNSWR YLSNRLLAPSDSPEWLSFDVTGVVRQWLSRGGEIEGFRLSAHCSCDSRDNTLQVDINGFT TGRRGDLATIHGMNRPFLLLMATPLERAQHLQSSRHRRALDTNYCFSSTEKNCCVRQLYI DFRKDLGWKWIHEPKGYHANFCLGPCPYIWSLDTQYSKVLALYNQHNPGASAAPCCVPQA LEPLPIVYYVGRKPKVEQLSNMIVRSCKCS (SEQ ID No. 1). TGF ^1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. The term “TGF ^RII” as used herein refers to a protein also known as TGFBR2 or Transforming Growth Factor Beta Receptor 2. TGF ^RII (UniProt P37173) has the following amino acid sequence: MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFST CDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPK CIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAI SVIIIFYCYRVNRQQKLSSTWETGKTRKLMEFSEHCAIILEDDRSDISSTCANNINHNTE LLPIELDTLVGKGRFAEVYKAKLKQNTSEQFETVAVKIFPYEEYASWKTEKDIFSDINLK HENILQFLTAEERKTELGKQYWLITAFHAKGNLQEYLTRHVISWEDLRKLGSSLARGIAH LHSDHTPCGRPKMPIVHRDLKSSNILVKNDLTCCLCDFGLSLRLDPTLSVDDLANSGQVG TARYMAPEVLESRMNLENVESFKQTDVYSMALVLWEMTSRCNAVGEVKDYEPPFGSKVRE HPCVESMKDNVLRDRGRPEIPSFWLNHQGIQMVCETLTECWDHDPEARLTAQCVAERFSE LEHLDRLSGRSCSEEKIPEDGSLNTTK (SEQ ID No. 2). TGF ^RII is a serine/threonine kinase receptor that belongs to the TGFβ receptor family. TGF ^1 is a ligand of TGF ^RII. The extracellular domain of TGF ^RII which specifically binds TGF ^1 has the following sequence: MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFST CDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPK CIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPD (SEQ ID No. 3) The nucleic acid encoding the extracellular domain of TGF ^RII of the switch receptor exemplified in the present disclosure has the following sequence: ATGGGCAGGGGCCTGCTGAGGGGCCTGTGGCCCCTGCACATCGTGCTGTGGACCAGGATCGCCAGC ACCATCCCCCCCCACGTGCAGAAGAGCGTGAACAACGACATGATCGTGACCGACAACAACGGCGCC GTGAAGTTCCCCCAGCTGTGCAAGTTCTGCGACGTGAGGTTCAGCACCTGCGACAACCAGAAGAGC TGCATGAGCAACTGCAGCATCACCAGCATCTGCGAGAAGCCCCAGGAGGTGTGCGTGGCCGTGTGG AGGAAGAACGACGAGAACATCACCCTGGAGACCGTGTGCCACGACCCCAAGCTGCCCTACCACGAC TTCATCCTGGAGGACGCCGCCAGCCCCAAGTGCATCATGAAGGAGAAGAAGAAGCCCGGCGAGACC TTCTTCATGTGCAGCTGCAGCAGCGACGAGTGCAACGACAACATCATCTTCAGCGAGGAGTACAAC ACCAGCAACCCCGAC (SEQ ID No. 4) The term “PDGFRB” as used herein refers to a protein also known as platelet-derived growth factor receptor (UniProt P09619): MRLPGAMPALALKGELLLLSLLLLLEPQISQGLVVTPPGPELVLNVSSTFVLTCSGSAPV VWERMSQEPPQEMAKAQDGTFSSVLTLTNLTGLDTGEYFCTHNDSRGLETDERKRLYIFV PDPTVGFLPNDAEELFIFLTEITEITIPCRVTDPQLVVTLHEKKGDVALPVPYDHQRGFS GIFEDRSYICKTTIGDREVDSDAYYVYRLQVSSINVSVNAVQTVVRQGENITLMCIVIGN EVVNFEWTYPRKESGRLVEPVTDFLLDMPYHIRSILHIPSAELEDSGTYTCNVTESVNDH QDEKAINITVVESGYVRLLGEVGTLQFAELHRSRTLQVVFEAYPPPTVLWFKDNRTLGDS SAGEIALSTRNVSETRYVSELTLVRVKVAEAGHYTMRAFHEDAEVQLSFQLQINVPVRVL ELSESHPDSGEQTVRCRGRGMPQPNIIWSACRDLKRCPRELPPTLLGNSSEEESQLETNV TYWEEEQEFEVVSTLRLQHVDRPLSVRCTLRNAVGQDTQEVIVVPHSLPFKVVVISAILA LVVLTIISLIILIMLWQKKPRYEIRWKVIESVSSDGHEYIYVDPMQLPYDSTWELPRDQL VLGRTLGSGAFGQVVEATAHGLSHSQATMKVAVKMLKSTARSSEKQALMSELKIMSHLGP HLNVVNLLGACTKGGPIYIITEYCRYGDLVDYLHRNKHTFLQHHSDKRRPPSAELYSNAL PVGLPLPSHVSLTGESDGGYMDMSKDESVDYVPMLDMKGDVKYADIESSNYMAPYDNYVP SAPERTCRATLINESPVLSYMDLVGFSYQVANGMEFLASKNCVHRDLAARNVLICEGKLV KICDFGLARDIMRDSNYISKGSTFLPLKWMAPESIFNSLYTTLSDVWSFGILLWEIFTLG GTPYPELPMNEQFYNAIKRGYRMAQPAHASDEIYEIMQKCWEEKFEIRPPFSQLVLLLER LLGEGYKKKYQQVDEEFLRSDHPAILRSQARLPGFHGLRSPLDTSSVLYTAVQPNEGDND YIIPLPDPKPEVADEGPLEGSPSLASSTLNEVNTSSTISCDSPLEPQDEPEPEPQLELQV EPEPELEQLPDSGCPAPRAEAEDSFL (SEQ ID No. 5). The transmembrane domain of PDGFRB which is used for exemplification of the present disclosure has the following sequence: VVISAILALVVLTIISLIILI (SEQ ID No. 6) The nucleic acid encoding the transmembrane domain of PDGFRB of the switch receptor exemplified in the present disclosure has the following sequence: GTGGTGATCAGCGCCATCCTGGCCCTGGTGGTGCTGACCATCATCAGCCTGATCATCCTGATC (SEQ ID No. 7) The term “IL-2R ^” as used herein refers to a protein also known as IL2RB, Interleukin 2 Receptor Subunit Beta or CD122. IL-2R ^ (UniProt P14784) has the following amino acid sequence: MAAPALSWRLPLLILLLPLATSWASAAVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQ VHAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMA IQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEE APLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDT IPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDV QKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFT NQGYFFFHLPDALEIEACQVYFTYDPYSEEDPDEGVAGAPTGSSPQPLQPLSGEDDAYCT FPSRDDLLLFSPSLLGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVP DLVDFQPPPELVLREAGEEVPDAGPREGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQ ELQGQDPTHLV (SEQ ID No. 8). IL-2Rb forms part of the IL2 receptor, which is involved in T cell-mediated immune responses. The IL-2 receptor may consist of different forms. Depending on its composition different signaling cascades are triggered. The term “IL-2 receptor signaling domain” as used herein refers to the signaling chains IL-2R ^ and IL-2R ^ of the IL-2 receptor complex. The IL-2R ^ chain couples to the Janus kinase-signal transducer and activator of transcription (JAK-1), and the IL2R ^ chain couples to JAK-3. Engagement of the IL-2 receptor results in the activation of the JAKs and the phosphorylation of the IL-2R ^ and IL-2R ^. IL-2R ^ phosphorylation results in the recruitment of STAT5A, STAT5B and STAT3 and SHC1. Once recruited to the receptor, these proteins are phosphorylated by JAK kinases. pSTAT5 allows dimerization, nuclear translation and transcriptional initiation of specific target genes (Annu Rev Immunol.2018 Apr 26; 36: 411–433). The present disclosure makes use of the intracellular signaling domain of IL-2R ^ which has the following sequence: NCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPL EVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFTYD PYSEEDPDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSRDDLLLFSPSLLGGPSPPSTAP GGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPDAGP REGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV (SEQ ID No. 9). The nucleic acid encoding the intracellular signaling domain of IL-2R ^ of the switch receptor exemplified in the present disclosure has the following sequence: AACTGCAGGAACACCGGCCCCTGGCTGAAGAAGGTGCTGAAGTGCAACACCCCCGACCCCAGCAAG TTCTTCAGCCAGCTGAGCAGCGAGCACGGCGGCGACGTGCAGAAGTGGCTGAGCAGCCCCTTCCCC AGCAGCAGCTTCAGCCCCGGCGGCCTGGCCCCCGAGATCAGCCCCCTGGAGGTGCTGGAGAGGGAC AAGGTGACCCAGCTGCTGCTGCAGCAGGACAAGGTGCCCGAGCCCGCCAGCCTGAGCAGCAACCAC AGCCTGACCAGCTGCTTCACCAACCAGGGCTACTTCTTCTTCCACCTGCCCGACGCCCTGGAGATC GAGGCCTGCCAGGTGTACTTCACCTACGACCCCTACAGCGAGGAGGACCCCGACGAGGGCGTGGCC GGCGCCCCCACCGGCAGCAGCCCCCAGCCCCTGCAGCCCCTGAGCGGCGAGGACGACGCCTACTGC ACCTTCCCCAGCAGGGACGACCTGCTGCTGTTCAGCCCCAGCCTGCTGGGCGGCCCCAGCCCCCCC AGCACCGCCCCCGGCGGCAGCGGCGCCGGCGAGGAGAGGATGCCCCCCAGCCTGCAGGAGAGGGTG CCCAGGGACTGGGACCCCCAGCCCCTGGGCCCCCCCACCCCCGGCGTGCCCGACCTGGTGGACTTC CAGCCCCCCCCCGAGCTGGTGCTGAGGGAGGCCGGCGAGGAGGTGCCCGACGCCGGCCCCAGGGAG GGCGTGAGCTTCCCCTGGAGCAGGCCCCCCGGCCAGGGCGAGTTCAGGGCCCTGAACGCCAGGCTG CCCCTGAACACCGACGCCTACCTGAGCCTGCAGGAGCTGCAGGGCCAGGACCCCACCCACCTGGTG (SEQ ID No. 10). The term “4-1BB” as used herein refers to a protein also known as CD137 or TNFRSF9 or TNF Receptor Superfamily Member 9.4-1BB (UniProt Q07011) has the following amino acid sequence: MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQR TCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDC CFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPARE PGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDG CSCRFPEEEEGGCEL (SEQ ID No. 11). The present disclosure makes use of the intracellular domain of 4-1BB which has the following sequence: KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID No. 12). The nucleic acid encoding the intracellular domain of 4-1BB of the CAR exemplified in the present disclosure has the following sequence: AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAA CTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGCGAA CTG (SEQ ID No. 13). The term “CD3 ^” as used herein refers to a protein also known as CD247. CD3 ^ (UniProt P20963) has the following amino acid sequence: MKWKALFTAAILQAQLPITEAQSFGLLDPKLCYLLDGILFIYGVILTALFLRVKFSRSAD APAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMA EAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID No. 14). The present disclosure makes use of the intracellular domain of CD3 ^ which has the following sequence: LRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID No. 15). The nucleic acid encoding the intracellular domain of CD3 ^ of the CAR exemplified in the present disclosure has the following sequence: CTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTAT AACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCT GAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGAT AAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGAT GGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTG CCCCCTCGC (SEQ ID No. 16). The term “CEA” as used herein refers to a protein also known as CEACAM5, Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 or CD66e. CEA (UniProt P06731) has the following amino acid sequence: MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQ HLFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFY TLHVIKSDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWV NNQSLPVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAP TISPLNTSYRSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQ AHNSDTGLNRTTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNN QSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDDPTI SPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEKNSGLYTCQAN NSASGHSRTTVKTITVSAELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVNGQS LPVSPRLQLSNGNRTLTLFNVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTPIISP PDSSYLSGANLNLSCHSASNPSPQYSWRINGIPQQHTQVLFIAKITPNNNGTYACFVSNL ATGRNNSIVKSITVSASGTSPGLSAGATVGIMIGVLVGVALI (SEQ ID No. 17). The term “CD4” as used herein refers to a protein also known as IMD79 or OKT4D. CD4 (UniProt P01730) has the following amino acid sequence: MNRGVPFRHLLLVLQLALLPAATQGKKVVLGKKGDTVELTCTASQKKSIQFHWKNSNQIK ILGNQGSFLTKGPSKLNDRADSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQL LVFGLTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSG TWTCTVLQNQKKVEFKIDIVVLAFQKASSIVYKKEGEQVEFSFPLAFTVEKLTGSGELWW QAERASSSKSWITFDLKNKEVSVKRVTQDPKLQMGKKLPLHLTLPQALPQYAGSGNLTLA LEAKTGKLHQEVNLVVMRATQLQKNLTCEVWGPTSPKLMLSLKLENKEAKVSKREKAVWV LNPEAGMWQCLLSDSGQVLLESNIKVLPTWSTPVQPMALIVLGGVAGLLLFIGLGIFFCV RCRHRRRQAERMSQIKRLLSEKKTCQCPHRFQKTCSPI (SEQ ID No. 18). The transmembrane domain of CD4 which is used for exemplification of the present disclosure has the following sequence: QPMALIVLGGVAGLLLFIGLGIFFCVR (SEQ ID No. 19) The nucleic acid encoding the transmembrane domain of CD4 of the CAR exemplified in the present disclosure has the following sequence: CAGCCAATGGCCCTGATTGTGCTGGGGGGCGTCGCCGGCCTCCTGCTTTTCATTGGGCTAG GCATCTTCTTCTGTGTCAGG (SEQ ID No. 20) The term “P2A” as used herein refers to a peptide sequence which is capable of self-cleavage. P2A belongs to the family of 2A peptides, which all are capable of self-cleavage.2A peptides share a common core sequence motif. Any 2A peptide may be used in the context of the present disclosure. The amino acid sequence of P2A used herein is as follows: GSGATNFSLLKQAGDVEENPGP (SEQ ID No.21). Other commonly used 2A peptides are T2A, E2A and F2A. The nucleic acid encoding P2A peptide of the present disclosure has the following sequence: GGATCTGGAGCCACGAACTTCTCTCTGTTAAAGCAAGCAGGAGACGTGGAAGAAAACCCCGGTCCT (SEQ ID No.22). The anti-CEA scFv used for exemplification of the present disclosure has the following sequence: GVHSQVQLQESGPGLVRPSQTLSLTCTVSGFTISSGYSWHWVRQPPGRGLEWIGYIQYSG ITNYNPSLKSRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAREDYDYHWYFDVWGQGTTV TVSSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGDRVTITCSTSSSVSYMHWYQQKPGK APKLLIYSTSNLASGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQWSSYPTFGQGTK VEIKV (SEQ ID No. 23). The nucleic acid encoding the anti-CEA scFv has the following sequence: GGTGTCCACTCCCAGGTCCAACTGCAGGAGTCAGGTCCAGGTCTTGTGAGACCTAGCCAGA CCCTGAGCCTGACCTGCACCGTGTCTGGCTTCACCATCAGCAGTGGTTATAGCTGGCACTG GGTGAGACAGCCACCTGGACGAGGTCTTGAGTGGATTGGATACATACAGTACAGTGGTATC ACTAACTACAACCCCTCTCTCAAAAGTAGAGTGACAATGCTGGTAGACACCAGCAAGAACC AGTTCAGCCTGAGACTCAGCAGCGTGACAGCCGCCGACACCGCGGTCTATTATTGTGCAAG AGAAGACTATGATTACCACTGGTACTTCGATGTCTGGGGCCAAGGGACCACGGTCACCGTC TCCTCAGGAGGTGGTGGATCGGGCGGTGGCGGGTCGGGTGGCGGCGGATCTGACATCCAGC TGACCCAGAGCCCAAGCAGCCTGAGCGCCAGCGTGGGTGACAGAGTGACCATCACCTGTAG TACCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGCCAGGTAAGGCTCCAAAG CTGCTGATCTACAGCACATCCAACCTGGCTTCTGGTGTGCCAAGCAGATTCAGCGGTAGCG GTAGCGGTACCGACTTCACCTTCACCATCAGCAGCCTCCAGCCAGAGGACATCGCCACCTA CTACTGCCATCAGTGGAGTAGTTATCCCACGTTCGGCCAAGGGACCAAGGTGGAGATCAAA GTG (SEQ ID No. 24). The human IgG hinge-CH2-CH3 region used for exemplification of the present disclosure has the following sequence: DPAEPKSPDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKK (SEQ ID No. 25). The nucleic acid encoding the human IgG hinge-CH2-CH3 region has the following sequence: GATCCCGCCGAGCCCAAATCTCCTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGAT CTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCT GAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAA ACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCC GGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAG CGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCA GGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAAAA (SEQ ID No. 26). The full length of the switch receptor exemplified in the present disclosure has the following amino acid sequence: MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTC DNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCI MKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDVVISAILALVVLTIISLIILINCR NTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLE RDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFTYDPYSEE DPDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSRDDLLLFSPSLLGGPSPPSTAPGGSGAG EERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPDAGPREGVSFP WSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLVS (SEQ ID No. 27). The full length of the anti-CEA CAR exemplified in the present disclosure has the following amino acid sequence: GVHSQVQLQESGPGLVRPSQTLSLTCTVSGFTISSGYSWHWVRQPPGRGLEWIGYIQYSGI TNYNPSLKSRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAREDYDYHWYFDVWGQGTTVTV SSGGGGSGGGGSGGGGSDIQLTQSPSSLSASVGDRVTITCSTSSSVSYMHWYQQKPGKAPK LLIYSTSNLASGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCHQWSSYPTFGQGTKVEIK VGSDPAEPKSPDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKAGDPQ PMALIVLGGVAGLLLFIGLGIFFCVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE EEGGCELQLLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRR KNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID No. 28). Embodiments of the invention The present disclosure relates to novel engineered or recombinant T cells which comprise a switch receptor (SWR) and an antigen-specific T cell receptor, such as a chimeric antigen receptor (CAR), a T cell receptor (TCR), or an engineered antigen-specific T cell comprising a switch receptor and a natural T cell receptor, such as a T cell isolated from blood. The switch receptor contains a TGFβRII binding domain and an IL2R ^ signaling domain. These switch receptors protect the T cell from TGF- ^ repression and the same time produce an intracellular IL2 signal through the linked IL2R ^-chain. Such switch receptors may be combined or co-expressed with essentially any recombinant receptor. These switch receptors are superior to other approaches for the treatment of T cell based immunotherapies, such as the treatment of cancer or auto-immune diseases. These switch receptors protect the T cell from TGF- ^ repression and the same time produce an intracellular IL2 signal through the linked IL2R ^-chain. The protection from TGF- ^ repression is equally powerful in higher TGF- ^ concentrations. These switch receptors also provide a positive stimulatory signal to regulatory T cells upon TGF- ^ ^binding, thereby promoting their amplification. For experimental purposes, the chimeric antigen receptor used in the present disclosure comprises an extracellular scFv which specifically binds to CEA, and cytoplasmic signaling domains comprising 4-1BB and CD3 ^. Switch receptors In certain embodiments the switch receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain comprising a polypeptide which specifically binds TGF, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. The extracellular domain comprised in said switch receptors may contain any polypeptide which binds TGF ^1. Said extracellular domain may also bind TGF ^2 and TGF ^3. In certain embodiments of the present disclosure, said polypeptide which specifically binds TGF comprises a natural binding domain that is specific for TGF ^1. Such natural binding domain may be a binding domain of any protein found in nature, preferably in a human, that specifically binds to TGF ^1. This includes natural ligands of TGF ^1, such as TGFR ^I, TGFR ^II or a combination of TGFR ^I and TGFR ^II. Therefore, in certain embodiments the switch receptors of the present disclosure comprise a. an extracellular domain comprising a natural ligand of TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In certain embodiments of the present disclosure, said polypeptide which specifically binds TGF comprises a natural binding domain that is specific for TGF ^2. Such natural binding domain may be a binding domain of any protein found in nature, preferably in a human, that specifically binds to TGF ^2. This includes natural ligands of TGF ^2, such as TGFR ^I, TGFR ^II or a combination of TGFR ^I and TGFR ^II. Therefore, in certain embodiments the switch receptors of the present disclosure comprise a. an extracellular domain comprising a natural ligand of TGF ^2, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In certain embodiments of the present disclosure, said polypeptide which specifically binds TGF comprises a natural binding domain that is specific for TGF ^1 and TGF ^2. Such natural binding domain may be a binding domain of any protein found in nature, preferably in a human, that specifically binds to TGF ^1 and TGF ^2. This includes natural ligands of TGF ^1 and TGF ^2, such as TGFR ^I, TGFR ^II or a combination of TGFR ^I and TGFR ^II. Therefore, in certain embodiments the switch receptors of the present disclosure comprise a. an extracellular domain comprising a natural ligand of TGF ^1 and TGF ^2, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising a binding domain of TGFR ^I, TGFR ^II or a combination of TGFR ^I and TGFR ^II which specifically bind TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In preferred embodiments, said binding domain is TGFR ^II. In other preferred embodiments, said binding domain comprises a polypeptide of SEQ No.3. In certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising a binding domain of TGFR ^I, TGFR ^II or a combination of TGFR ^I and TGFR ^II which specifically bind TGF ^ ^, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In other embodiments of the present disclosure, said polypeptide which specifically binds TGF ^1 is an antibody, an antibody fragment, or a protein scaffold which specifically binds TGF ^1. This includes any known antibody, antibody fragment, or protein scaffold which specifically binds TGF ^1. Such antibodies, an antibody fragments, or a protein scaffolds may also be generated by selection of novel antibodies, antibody fragments, or protein scaffolds of appropriate libraries by known standard molecular biology technologies, or by modifying or improving known antibodies, antibody fragments, or protein scaffolds. An antibody or an antibody fragment that binds TGF ^1 may be or may be derived from fresolimumab, livmoniplimab, metelimumab , SRK-181, NIS793 or SHR1701 (BioDrugs 2022; 36(2): 153–180). Therefore, in certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising an antibody, an antibody fragment, or a protein scaffold which specifically binds TGF, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In certain embodiments, said extracellular domain comprises an antibody, more preferably an antibody fragment, and most preferably a scFv. In certain embodiments, said antibody, said antibody fragment or said scFv is or is derived from fresolimumab, livmoniplimab, metelimumab, SRK-181, NIS793 or SHR1701 (BioDrugs 2022; 36(2): 153–180). The IL-2 receptor signaling domain comprised in said switch receptors may contain is polypeptide domain which induced an IL-2 receptor signaling. Such domains include the IL-2 receptor signaling domain of IL-2R ^ ^ Therefore, in certain embodiments the switch receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain comprising a polypeptide which specifically binds TGF, b. a transmembrane domain, and c. the IL-2 receptor signaling domain of IL-2R ^. In preferred embodiments, said IL-2 receptor signaling domain is the IL-2 receptor signaling domain of IL-2R ^. In other preferred embodiments, said the IL-2 receptor signaling domain comprises a polypeptide of SEQ No.9. In certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising a binding domain of TGFR ^II which specifically binds TGF, b. a transmembrane domain, and c. an IL-2 receptor signaling domain of IL-2R ^ ^. In certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising a polypeptide of SEQ No.3 which specifically binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain of IL-2R ^ ^. In certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising a binding domain of TGFR ^II which specifically binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain of IL-2R ^ ^comprising a polypeptide of SEQ No.9. In certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising a polypeptide of SEQ No.3 which specifically binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain of IL-2R ^ ^comprising a polypeptide of SEQ No.9. Principally any transmembrane domain can be used for the switch receptors comprised in the recombinant T cell of the present disclosure. Experimentally, the transmembrane domain of PDGFRB was used. Therefore, in certain embodiments the switch receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain comprising a polypeptide which specifically binds TGF, b. the transmembrane domain of PDGFRB, and c. an IL-2 receptor signaling domain. In certain embodiments the switch receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain comprising a polypeptide which specifically binds TGF, b. the transmembrane domain of PDGFRB comprising a polypeptide of SEQ No.6, and c. an IL-2 receptor signaling domain. In certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising a polypeptide of SEQ No.3 which specifically binds TGF, b. the transmembrane domain of PDGFRB, and c. an IL-2 receptor signaling domain of IL-2R ^ ^. In certain embodiments, said transmembrane domain of PDGFRB comprises a polypeptide of SEQ No.6. In certain embodiments of the present disclosure, the switch receptors comprise a. an extracellular domain comprising a binding domain of TGFR ^II which specifically binds TGF, b. the transmembrane domain of PDGFRB, and c. an IL-2 receptor signaling domain of IL-2R ^ ^comprising a polypeptide of SEQ No.9. In certain embodiments said transmembrane domain of PDGFRB comprises a polypeptide of SEQ No.6. In certain embodiments, the switch receptors of the present disclosure comprise a. an extracellular domain comprising a polypeptide of SEQ No.3 which specifically binds TGF, b. the transmembrane domain of PDGFRB, and c. an IL-2 receptor signaling domain of IL-2R ^ ^comprising a polypeptide of SEQ No.9. In certain embodiments said transmembrane domain of PDGFRB comprises a polypeptide of SEQ No.6. In certain embodiments, the switch receptors of the present disclosure comprise a polypeptide comprising an amino acid sequence of SEQ No.27. Antigen receptors The antigen receptor used in conjunction with the switch receptors of the present disclosure may be any antigen-specific T cell receptor, such as a chimeric antigen receptor (CAR) or a T cell receptor (TCR). The antigen receptor may also be a natural T cell receptor comprised in a T cell isolated from the blood or organ tissue or tumor. Such T cell may be engineered to additionally carry a switch receptor according to the present disclosure. Chimeric antigen receptors The chimeric antigen receptor comprised in said T cell of the present disclosure can be any chimeric antigen receptor known in the art. The switch receptors co-expressed in the T cell comprising the chimeric antigen receptor protect the T cell from TGF- ^ repression, thereby increasing the therapeutic potency of the T cell. A CAR is a modularly composed, recombinant one-polypeptide-chain trans-membrane receptor molecule that mediates target recognition by its extracellular part and cellular activation by the intracellular part. The targeting specificity is mostly provided by an antibody-derived binding domain, mostly a single chain fragment of a variable region (scFv) antibody that is linked by a spacer to a transmembrane domain to anchor the receptor in the cell membrane. The CAR intracellular signaling domain is mostly derived from the T cell receptor (TCR) CD3 ^ chain to provide the primary signal for T cell activation. Alternatively, the Fc ^ receptor-I (Fc ^RI) ^ chain or kinases downstream in the TCR signaling machinery are used. Thereby the CAR initiates T cell activation upon engagement of target by feeding into the TCR downstream signaling machinery. The first generation of CARs harbors only the primary signal while CARs of the second generation additionally harbor a costimulatory domain, for instance derived from CD28, 4-1BB, OX40, CD27, or ICOS. Both signals are required for complete T cell activation (J Immunol (1998) 161:2791–7; Cancer Res. (2001) 61:1976– 82; Eur J Immunol. (1991) 21:1775–8). Third generation CARs combine two costimulatory domains. CAR T cells that are engineered with an additional transgenic „payload“ are called TRUCKs (“T cells redirected for unrestricted cytokine-induced killing”) or the fourth generation of CARs (Expert Opin Biol Ther. (2015) 15:1145–54; Cancer Res. (2011) 71:5697–706). The modular composition of the CAR prototype allows multiple combinations and variants of domains; for details (Rec. Res. Cancer Res. 214, 93 – 128 (2020); Holzinger, A., Abken, H., Chimeric antigen receptor (CAR) redirected T cells. In: Introduction to Antibody Engineering, Ed. Florian Rüker and Gordana Wozniak-Knopp, Springer (2020), p.251 – 302). In certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. The extracellular domain of said chimeric antigen receptor preferably comprises an antigen- binding domain. Preferably said antigen-binding domain is an antibody, an antibody fragment or a protein scaffold. Most preferably, said antigen-binding domain is an antibody fragment, such as an scFv. Therefore, in certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antibody, an antibody fragment or a protein scaffold, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. Preferably, said extracellular domain comprises an antibody fragment. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising a scFv , b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. The antigen-binding domain of the extracellular domain of the chimeric antigen receptor may be specific for any antigen. Preferably, said antigen-binding domain specifically binds to a tumor antigen. Any antigen exposed on the surface of the target cell may be used in the context of the present disclosure, including cancer associated antigens, virally or microbially encoded antigens exposed on the surface of infected cells, auto-antigens or others. For exemplification, the present disclosure utilizes an antigen-binding domain which specifically binds to carcinoembryonic antigen (CEA, CD66e). Therefore, in certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain which specifically binds a tumor antigen, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain which specifically binds CEA, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain which specifically binds to a polypeptide comprising an amino acid sequence of SEQ No.17, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an scFv which specifically binds CEA, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an scFv specifically binds to a polypeptide comprising an amino acid sequence of SEQ No.17, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an scFv comprising an amino acid sequence of SEQ No.23, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. The chimeric antigen receptor used in the context of the present disclosure may also utilize any cytoplasmic signaling domain that is commonly used for chimeric antigen receptors. The cytoplasmic signaling domain may be a costimulatory signaling domain. The cytoplasmic signaling domain may also be a T cell receptor signaling domain. The chimeric antigen receptor used in the context of the present disclosure may also contain more than one cytoplasmic signaling domain. In certain embodiments, the chimeric antigen receptor used in the context of the present disclosure contains one cytoplasmic signaling domain. In certain embodiments, the chimeric antigen contains two cytoplasmic signaling domain. In certain embodiments, the chimeric antigen contains more than two cytoplasmic signaling domain. In certain embodiments, the chimeric antigen contains two cytoplasmic signaling domain, wherein one of said two cytoplasmic signaling domains is a costimulatory signaling domain and the other of said two cytoplasmic signaling domains is a T cell receptor signaling domain. A non-limiting list of costimulatory molecules includes 4-IBB (CD137), BAFFR, OX40, CD27, CD28, CD40, 2B4, GITR, HVEM, OX40, RELT, TACI, TROY, TWEAK, KIR receptors, TLR1 to TLR9 receptors, IL- 2, IL-7 and IL-15 receptors. The chimeric antigen receptor of the present invention therefore comprises a costimulatory signaling domain of a polypeptide selected from the list of 4-IBB (CD137), BAFFR, OX40, CD27, CD28, CD40, 2B4, GITR, HVEM, OX40, RELT, TACI, TROY, TWEAK, KIR receptors, TLR1 to TLR9 receptors, IL-2, IL-7 and IL-15 receptors. Preferably, the costimulatory signaling domain is a costimulatory signaling domain of 4-IBB (CD137). Also preferably, the costimulatory signaling domain comprises an amino acid sequence of SEQ No.12. A non-limiting list of proteins comprising a T cell receptor signaling domain includes CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCER1G) , FcR beta (Fc Epsilon Rib) , CD79a, CD79b, Fcgamma RIIa, DAP10, and DAP12. A preferred TCR signaling domain is a TCR signaling domain selected from CD3 zeta, CD3 gamma, CD3 delta and CD3 epsilon. Preferred TCR signaling domain are CD3 zeta, CD3 gamma, CD3 delta and CD3 epsilon. A particularly preferred TCR signaling domain is CD3 zeta. Also preferred, is a costimulatory signaling domain comprising an amino acid sequence of SEQ No.15. Therefore, in certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain which specifically binds a tumor antigen, b. a transmembrane domain, and c. a costimulatory signaling domain and a T cell receptor signaling domain. In certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain which specifically binds a tumor antigen, b. a transmembrane domain, and c. a 4-1BB costimulatory signaling domain and a CD3zeta T cell receptor signaling domain. In certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain which specifically binds a tumor antigen, b. a transmembrane domain, and c. a costimulatory signaling domain comprising SEQ ID No. 12 and a T cell receptor signaling domain comprising SEQ ID No.15. In certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain which specifically binds CEA, b. a transmembrane domain, and c. a 4-1BB costimulatory signaling domain and a CD3zeta T cell receptor signaling domain. In certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an antigen-binding domain which specifically binds CEA, b. a transmembrane domain, and c. a costimulatory signaling domain comprising SEQ ID No. 12 and a T cell receptor signaling domain comprising SEQ ID No.15. In certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprises a. an extracellular domain comprising an scFv comprising an amino acid sequence of SEQ No.23, b. a transmembrane domain, and c. a costimulatory signaling domain comprising SEQ ID No. 12 and a T cell receptor signaling domain comprising SEQ ID No.15. Principally any transmembrane domain can be used for the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure. Experimentally, the transmembrane domain of CD4 was used. Therefore, in certain embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain, b. a CD4 transmembrane domain, and c. one or more cytoplasmic signaling domains. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain, b. a transmembrane domain comprising the amino acid sequence of SEQ ID No.19, and c. one or more cytoplasmic signaling domains. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain comprising an scFv which specifically binds CEA, b. a CD4 transmembrane domain, and c. one or more cytoplasmic signaling domains. Preferably said scFv which specifically binds CEA comprises an amino acid sequence of SEQ No.23. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain comprising an scFv which specifically binds CEA, b. a transmembrane domain comprising the amino acid sequence of SEQ ID No.19, and c. one or more cytoplasmic signaling domains. Preferably said scFv which specifically binds CEA comprises an amino acid sequence of SEQ No.23. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain, b. a CD4 transmembrane domain, and c. a 4-1BB costimulatory signaling domain and a CD3zeta T cell receptor signaling domain. Preferably, said costimulatory signaling domain comprises an amino acid sequence of SEQ ID No. 12 and said T cell receptor signaling domain comprises an amino acid sequence of SEQ ID No.15. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain, b. a transmembrane domain comprising the amino acid sequence of SEQ ID No.19, and c. a 4-1BB costimulatory signaling domain and a CD3zeta T cell receptor signaling domain. Preferably, said costimulatory signaling domain comprises an amino acid sequence of SEQ ID No. 12 and said T cell receptor signaling domain comprises an amino acid sequence of SEQ ID No.15. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain comprising an scFv which specifically binds CEA, b. a transmembrane domain comprising the amino acid sequence of SEQ ID No.19, and c. a 4-1BB costimulatory signaling domain and a CD3zeta T cell receptor signaling domain. Preferably said scFv which specifically binds CEA comprises an amino acid sequence of SEQ No.23, said costimulatory signaling domain comprises an amino acid sequence of SEQ ID No. 12 and said T cell receptor signaling domain comprises an amino acid sequence of SEQ ID No.15. In other embodiments, the chimeric antigen receptors comprised in the recombinant T cell of the present disclosure comprise a. an extracellular domain comprising an scFv comprising an amino acid sequence of SEQ No.23 which specifically binds CEA, b. a transmembrane domain comprising the amino acid sequence of SEQ ID No.19, and c. a 4-1BB costimulatory signaling domain comprising an amino acid sequence of SEQ ID No. 12 and a CD3zeta T cell receptor signaling domain comprising an amino acid sequence of SEQ ID No.15. In other embodiments, the chimeric antigen receptor comprised in the recombinant T cell of the present disclosure comprises a polypeptide comprising an amino acid sequence of SEQ ID No.28. T cell receptors Alternatively, the switch receptors of the present disclosure can also be used in a T cell comprising a T cell receptor. Said T cell receptor may comprise an antigen-binding region with specificity for a tumor antigen. Said T cell receptor may comprise additional intracellular domains in analogy to the chimeric antigen receptors described herein above. Said T cell receptor may also be a natural T cell receptor. For example, a T cell bearing a suitable T cell receptor may be isolated from blood, and then be engineered to additionally carry a switch receptor according to the present disclosure. T cells The present disclosure is based on T cells that comprise an antigen receptor and a switch receptor as disclosed herein. Principally any T cell can be used in the context of the present disclosure. Preferably, said T cell is a recombinant T cell. The T cells may be obtained from any source, such as a blood bank or a donor. Any subset of T cells can be used, including but not limited to CD4+, CD8+ T cells, Treg cells, ^ ^ T cells, NK-T cells, and also NK cells, macrophages or other immune cells. In certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor or a T cell receptor, and ii) a recombinant switch receptor, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In certain embodiments, said chimeric antigen receptor comprises a. an extracellular domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains. Therefore, in certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an extracellular domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains, and, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In certain embodiments, said polypeptide which specifically binds TGF comprises a natural binding domain that is specific for TGF ^1 and/or TGF ^2, or an antibody, an antibody fragment, or a protein scaffold which specifically binds TGF ^1 and/or TGF ^2. In other embodiments, said natural binding domain that is specific for TGF ^1 is the binding domain of TGFR ^II, preferably wherein said a binding domain of TGFR ^II comprises a polypeptide of SEQ No.3. Therefore, in certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an extracellular domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains, and. wherein said recombinant switch receptor comprises a. an extracellular domain comprising a natural binding domain that is specific for TGF ^1 or an antibody, an antibody fragment, or a protein scaffold which specifically binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. Preferably, said natural binding domain that is specific for TGF ^1 is a binding domain of TGFR ^II. More preferably, said a binding domain of TGFR ^II comprises a polypeptide of SEQ No.3. In certain embodiments, said IL-2 receptor signaling domain is an IL-2 receptor signaling domain of IL-2R ^ ^ preferably said IL-2 receptor signaling domain comprises a polypeptide of SEQ No.9. Therefore, in certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an extracellular domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains, and. wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain of IL-2R ^. Preferably, said IL-2 receptor signaling domain comprises a polypeptide of SEQ No.9 In certain embodiments, the transmembrane domain of said switch receptor is a transmembrane domain of PDGFRB, preferably said transmembrane domain comprises a polypeptide of SEQ No.6. Therefore, in certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an extracellular domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, b. a transmembrane domain of PDGFRB, and c. an IL-2 receptor signaling domain. Preferably said transmembrane domain comprises a polypeptide of SEQ No.6. In certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an extracellular domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, preferably a binding domain of TGFR ^II, and more preferably a binding domain comprising a polypeptide of SEQ No.3, b. a transmembrane domain of PDGFRB, preferably a transmembrane domain comprising a polypeptide of SEQ No.6, and c. an IL-2 receptor signaling domain, preferably the IL-2 receptor signaling domain of IL- 2R ^ ^ ^more preferably aIL-2 receptor signaling domain comprising a polypeptide of SEQ No.9. In certain embodiments, the extracellular domain of said chimeric antigen receptor comprises an antigen-binding region with specificity for a tumor antigen. In certain embodiments, said tumor antigen is CEA. In other embodiments, said antigen-binding region is a scFv comprising a polypeptide of SEQ No.23. Therefore, in certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an antigen-binding region with specificity for a tumor antigen, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. Preferably, the antigen-binding region of said chimeric antigen receptor is specific for CEA. More preferably, the antigen-binding region of said chimeric antigen receptor comprises a polypeptide of SEQ No.23. In certain embodiments, the one or more cytoplasmic signaling domains of said chimeric antigen receptor are a cytoplasmic costimulatory signaling domain and a cytoplasmic T cell receptor complex associated signaling domain. In certain embodiments, said cytoplasmic costimulatory signaling domain is 4-1BB and said cytoplasmic T cell receptor complex associated signaling domain is CD3, preferably CD3zeta. More preferably, said cytoplasmic signaling domain comprises a polypeptide of SEQ No.12 and said T cell receptor signaling domain comprises a polypeptide of SEQ No.15. Therefore, in certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an extracellular domain, b. a transmembrane domain, and c. a cytoplasmic costimulatory signaling domain and a cytoplasmic T cell receptor complex associated signaling domain, and, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. Preferably, said cytoplasmic costimulatory signaling domain is 4-1BB and said cytoplasmic T cell receptor complex associated signaling domain is CD3, preferably CD3zeta. More preferably, said cytoplasmic signaling domain comprises a polypeptide of SEQ No. 12 and said T cell receptor signaling domain comprises a polypeptide of SEQ No.15. In certain embodiments, the transmembrane domain of said chimeric antigen receptor comprises a CD4 transmembrane domain. Preferably a transmembrane domain comprises a polypeptide of SEQ No.19. Therefore, in certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an extracellular domain, b. a CD4 transmembrane domain, and c. one or more cytoplasmic signaling domains, and, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. Preferably, the transmembrane domain of said chimeric antigen receptor comprises a polypeptide of SEQ No.19. In certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an antigen-binding region with specificity for CEA, preferably wherein said antigen- binding region comprises a polypeptide of SEQ No.23, b. a CD4 transmembrane domain, preferably, wherein said transmembrane domain comprises a polypeptide of SEQ No.19, c. a cytoplasmic costimulatory signaling domain and a cytoplasmic T cell receptor complex associated signaling domain, preferably wherein said cytoplasmic costimulatory signaling domain is 4-1BB and said cytoplasmic T cell receptor complex associated signaling domain is CD3, more preferably wherein said cytoplasmic signaling domain comprises a polypeptide of SEQ No. 12 and said T cell receptor signaling domain comprises a polypeptide of SEQ No.15, and, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, b. a transmembrane domain, and c. an IL-2 receptor signaling domain. In certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an antigen-binding region with specificity for CEA, preferably wherein said antigen- binding region comprises a polypeptide of SEQ No.23, b. a CD4 transmembrane domain, preferably, wherein said transmembrane domain comprises a polypeptide of SEQ No.19, c. a cytoplasmic costimulatory signaling domain and a cytoplasmic T cell receptor complex associated signaling domain, preferably wherein said cytoplasmic costimulatory signaling domain is 4-1BB and said cytoplasmic T cell receptor complex associated signaling domain is CD3, more preferably wherein said cytoplasmic signaling domain comprises a polypeptide of SEQ No. 12 and said T cell receptor signaling domain comprises a polypeptide of SEQ No.15, and, wherein said recombinant switch receptor comprises a. an extracellular domain comprising a polypeptide which binds TGF ^1, preferably a binding domain of TGFR ^II, and more preferably a binding domain comprising a polypeptide of SEQ No.3, b. a transmembrane domain of PDGFRB, preferably a transmembrane domain comprising a polypeptide of SEQ No.6, and c. an IL-2 receptor signaling domain, preferably the IL-2 receptor signaling domain of IL- 2R ^ ^ ^more preferably aIL-2 receptor signaling domain comprising a polypeptide of SEQ No.9. In certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an antigen-binding region with specificity for CEA, b. a CD4 transmembrane domain, c. a 4-1BB cytoplasmic costimulatory signaling domain and a CD3 cytoplasmic T cell receptor complex associated signaling domain, and, wherein said recombinant switch receptor comprises a. an extracellular binding domain of TGFR ^II, b. a transmembrane domain of PDGFRB, and c. an IL-2 receptor signaling domain of IL-2R ^. In certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an antigen-binding region with specificity for CEA comprising a polypeptide of SEQ No. 23, b. a transmembrane domain, c. a cytoplasmic costimulatory signaling domain comprising a polypeptide of SEQ No.12 and a T cell receptor signaling domain comprising a polypeptide of SEQ No.15, and, wherein said recombinant switch receptor comprises a. an extracellular binding domain of TGFR ^II comprising a polypeptide of SEQ No.3, b. a transmembrane domain, and c. an IL-2 receptor signaling domain of IL-2R ^ ^comprising a polypeptide of SEQ No.9. In certain embodiments, the present disclosure relates to a recombinant T cell comprising i) a chimeric antigen receptor, and ii) a recombinant switch receptor, wherein said chimeric antigen receptor comprises a. an antigen-binding region with specificity for CEA comprising a polypeptide of SEQ No. 23, b. a CD4 transmembrane domain comprising a polypeptide of SEQ No.19, c. a cytoplasmic costimulatory signaling domain comprising a polypeptide of SEQ No.12 and a T cell receptor signaling domain comprising a polypeptide of SEQ No.15, and, wherein said recombinant switch receptor comprises a. an extracellular binding domain of TGFR ^II comprising a polypeptide of SEQ No.3, b. a transmembrane domain of PDGFRB comprising a polypeptide of SEQ No.6, and c. an IL-2 receptor signaling domain of IL-2R ^ ^comprising a polypeptide of SEQ No.9. Nucleic acids, vectors and host cells The chimeric antigen receptors and the switch receptors of the present disclosure are encoded by nucleic acids. The chimeric antigen receptors and the switch receptors may be encoded by the same nucleic acid molecule or by separate nucleic acid molecules. Therefore, the in certain embodiments the present disclosure relates to nucleic acids encoding the chimeric antigen receptors of the present disclosure. In other embodiments the present disclosure relates to nucleic acids encoding the switch receptors of the present disclosure. In other embodiments the present disclosure relates to nucleic acids encoding the chimeric antigen receptors and the switch receptors of the present disclosure. In cases where the nucleic acid molecule comprises both, the chimeric antigen receptor and the switch receptor, the part encoding the chimeric antigen receptor and the part encoding the switch receptor may be separated by certain elements, such as an element that is capable of self-cleavage, for example a P2A peptide. Therefore, in certain embodiments the present disclosure relates to a nucleic acid encoding a chimeric antigen receptors and a switch receptors according to the present disclosure, wherein nucleic acid encoding the chimeric antigen receptor and the nucleic acid encoding the switch receptor are separated by a peptide that is capable of self-cleavage. In other embodiments the present disclosure relates to a nucleic acid encoding a chimeric antigen receptors and a switch receptors according to the present disclosure, wherein nucleic acid encoding the chimeric antigen receptor and the nucleic acid encoding the switch receptor are separated by a P2A peptide. In certain embodiments the present disclosure relates a vector comprising a nucleic acid encoding a chimeric antigen receptors and a switch receptors of the present disclosure. The nucleic acid encoding the chimeric antigen receptor and the nucleic acid encoding the switch receptor may be on the same vector or on different vectors. In certain embodiments the present disclosure relates to a host cell comprising a nucleic acid or a vector encoding a chimeric antigen receptor and a switch receptor of to the present disclosure. In preferred embodiments, said host cell is a eukaryotic host cell. In other preferred embodiments, said eukaryotic host cell is a T cell, preferably a CD4+ or a CD8+ T cell. Therefore, in certain embodiments the present disclosure relates to a eukaryotic host cell comprising a nucleic acid or a vector encoding a chimeric antigen receptors and a switch receptors according to the present disclosure. In other embodiments the present disclosure relates to a T cell comprising a nucleic acid or a vector encoding a chimeric antigen receptors and a switch receptors according to the present disclosure. In certain embodiments said T cell is a CD4+ T cell. In other embodiments said T cell is a CD8+ T cell. In certain embodiments the present disclosure relates to a switch receptor comprising an extracellular domain comprising a polypeptide which specifically binds TGF, a transmembrane domain, and an IL-2 receptor signaling domain, wherein said extracellular domain comprising a polypeptide which specifically binds TGF ^1 is encoded by a nucleic acid comprising SEQ ID No.4. In certain embodiments the present disclosure relates to a switch receptor comprising an extracellular domain comprising a polypeptide which specifically binds TGF, a transmembrane domain, and an IL-2 receptor signaling domain, wherein said transmembrane domain is encoded by a nucleic acid comprising SEQ ID No.7. In certain embodiments the present disclosure relates to a switch receptor comprising an extracellular domain comprising a polypeptide which specifically binds TGF, a transmembrane domain, and an IL-2 receptor signaling domain, wherein said IL-2 receptor signaling domain is encoded by a nucleic acid comprising SEQ ID No.10. In certain embodiments the present disclosure relates to a switch receptor comprising an extracellular domain comprising a polypeptide which specifically binds TGF, a transmembrane domain, and an IL-2 receptor signaling domain, wherein said extracellular domain comprising a polypeptide which specifically binds TGF is encoded by a nucleic acid comprising SEQ ID No. 4, wherein said transmembrane domain is encoded by a nucleic acid comprising SEQ ID No. 7, and wherein said IL-2 receptor signaling domain is encoded by a nucleic acid comprising SEQ ID No.10. In certain embodiments the present disclosure relates to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain and one or more cytoplasmic signaling domains, wherein said extracellular domain is encoded by a nucleic acid comprising SEQ ID No.24. In certain embodiments the present disclosure relates to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain and one or more cytoplasmic signaling domains, wherein said transmembrane domain is encoded by a nucleic acid comprising SEQ ID No.20. In certain embodiments the present disclosure relates to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain and one or more cytoplasmic signaling domains, wherein on of said cytoplasmic signaling domains is encoded by a nucleic acid comprising SEQ ID No.13. In certain embodiments the present disclosure relates to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain and one or more cytoplasmic signaling domains, wherein on of said cytoplasmic signaling domains is encoded by a nucleic acid comprising SEQ ID No.16. In certain embodiments the present disclosure relates to a chimeric antigen receptor comprising an extracellular domain, a IgG hinge-CH2-CH3 region a transmembrane domain and one or more cytoplasmic signaling domains, wherein said IgG hinge-CH2-CH3 region is encoded by a nucleic acid comprising SEQ ID No.26. In certain embodiments the present disclosure relates to a chimeric antigen receptor comprising an extracellular domain, a IgG hinge-CH2-CH3 region a transmembrane domain and one or more cytoplasmic signaling domains, wherein said extracellular domain is encoded by a nucleic acid comprising SEQ ID No. 24, wherein said IgG hinge-CH2-CH3 region is encoded by a nucleic acid comprising SEQ ID No. 26, wherein said transmembrane domain is encoded by a nucleic acid comprising SEQ ID No.20, and wherein said cytoplasmic signaling domains are encoded by a nucleic acid comprising SEQ ID No.13 and SEQ ID No.16. Pharmaceutical compositions and therapeutic use The T cells comprising the chimeric antigen receptors and the switch receptors of the present disclosure can be used therapeutically for the prevention and treatment of diseases and disorders. For such therapeutic use, said T cells may be part of a pharmaceutical composition comprising said recombinant T cells and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier may be a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting cells of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or some combination thereof. Each component of the carrier must be "pharmaceutically acceptable" in that it must be compatible with the other ingredients of the formulation. It also must be suitable for contact with any tissue, organ, or portion of the body that it may encounter, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits. The administration of the recombinant T cells of the present disclosure may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. The compositions described herein may be administered to a patient subcutaneously, intradermaly, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous or intralymphatic injection, or intraperitoneally. In an embodiment, the cell compositions of the present invention are preferably administered by intravenous injection. In certain embodiments, the present disclosure provides recombinant T cells or a pharmaceutical composition comprising recombinant T cell, and optionally a pharmaceutically acceptable carrier, for use in the treatment of a disease or disorder, wherein said recombinant T cells or said pharmaceutical composition comprising said recombinant T cells comprise a chimeric antigen receptor and a switch receptor as disclosed herein. In certain embodiments, the present disclosure provides recombinant T cells or a pharmaceutical composition comprising recombinant T cell, and optionally a pharmaceutically acceptable carrier, for use in the prevention of a disease or disorder, wherein said recombinant T cells or said pharmaceutical composition comprising said recombinant T cells comprise a chimeric antigen receptor and a switch receptor as disclosed herein. The most effective results in terms of efficacy of treatment or prevention in a given subject will vary depending upon a variety of factors, including but not limited to the characteristics of the recombinant T cells (including longevity, activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of any pharmaceutically acceptable carrier or carriers in any composition used, and the route of administration. A therapeutically effective dose of recombinant T cells also depends on the number of the switch receptor or any other co-expressed receptor on the surface of the T cells (e.g., the affinity and density of the cell surface receptors expressed on the cell), the type of target cell, the nature of the disease or pathological condition being treated, or a combination of all. In certain embodiments said disease or disorder is an acute or chronic inflammatory disorder or cancer. In preferred embodiments said disease or disorder is cancer. In certain embodiments said cancer is, but not limited to, a carcinoma of the gastrointestinal tract, adrenal glands, the nervous system, the connective tissue, the liver, kidney, lung or the hematopoietic system. In other embodiments said disease or disorder is a viral or a microbial infection, an autoimmune disease, transplant rejection, graft-versus-host disease, or a chronic inflammatory disease. Examples Example 1: Switch receptors, dominant negative receptors and CARs The constructs used are shown in Figure 1. The exemplary CAR used consists of an anti-CEA single chain antibody (SEQ ID No. 23), a human IgG hinge-CH2-CH3 region (SEQ ID No. 25), a CD4 transmembrane domain (SEQ ID No. 19), a 4-1BB signaling domain (SEQ ID No.12) and a CD3zeta signaling domain (SEQ ID No.15). The full length amino acid sequence of the CAR is shown in SEQ ID No.28. T cells were transduced with a construct only encoding this CAR (labeled as “Standard” in Figure 1), or with constructs also encoding either a dominant negative receptor (labeled as “DNR” in Figure 1) or a switch receptor (labeled as “SWR” in Figure 1). The dominant negative receptor contains a TGFRII ^ extracellular domain and a PDGFRB transmembrane domain. The switch receptor contains a TGFRII ^ extracellular domain (SEQ ID No.3), a PDGFRB transmembrane domain (SEQ ID No.6) and a IL-2 receptor ^-chain signaling domain (SEQ ID No.9). The amino acid sequence of the switch receptor is shown in SEQ ID No.27. The CAR and the dominant negative receptor, as well as the CAR and the switch receptor are separated on the constructs by a P2A peptide which is capable of self-cleavage. The architecture of the T cell containing the CAR and a switch receptor are depicted in Figure 2. Example 2: Transduction of T cells Human T cells were isolated from the peripheral blood of a healthy donor by density gradient centrifugation and were retrovirally transduced by “spinfection” with the constructs of Example 1 according to standard methods (see e.g. Hum Gene Ther Meth (2017) 28: 302-309). After transduction, expression was detected by flow cytometry using a PE-conjugated anti-IgG antibody which is specific for the extracellular spacer in the CAR. For the identification of T cells, an BV421- conjugated anti-human CD3 antibody was used. Results are shown in Figure 3. It was confirmed that the CAR is expressed on CD3-positive T cells . Flow cytometry analyses shown by representative dot plots (bottom) confirm the expression of TGFβRII, as part of the SWR, in CAR-positive T cells transduced together with the SWR, but not in T cells transduced with the CAR alone. Example 3: Switch Receptor CARs overcome TGF-β mediated repression in cytotoxic activities of T cells It was investigated whether human peripheral blood T cells engineered with a standard CAR or with a CAR with switch receptor of the present disclosure could overcome TGF-β mediated repression in cytotoxic activities of T cells. CAR T cells (1 x 10⁵ T cells per well) were incubated with CEA+ HT-29 cells (2 x 10⁴ per well) in the presence or absence of TGF-β1 (0, 100 ng/ml) and the specific cytotoxicity determined after 2 days Results are shown in Figure 4. T cells transduced with the construct encoding the CAR and the switch receptor showed no reduction in specific cytotoxicity in the presence of TGF-β1, whereas T cells transduced with the construct encoding the CAR alone showed reduced specific cytotoxicity in the presence of TGF-β1. Of note, the specific cytotoxicity of CAR T cells with the SWR in total is lower than of CAR T cells without SWR which is often observed when any co-expressed receptor is coexpressed with the CAR. Example 4: Switch Receptor prevents CAR T cells from repression in proliferation in the presence of TGF-β It was addressed whether proliferation of CAR T cells with the switch receptor (SWR) according to the present invention is repressed in presence of increasing concentrations of TGF- ^. T cells from the peripheral blood were transduced with the construct encoding the anti-CEA CAR and the SWR, or the CAR alone. T cells were labelled with “Cell Proliferation Dye eFluor 450” (Invitrogen) and CAR T cells were stimulated through their CAR by incubation with the antibody BW2064/36 in the presence and absence of TGF-β1. ) BW2064/36 antibody is an anti-idiotypic antibody against the anti-CEA scFv binding domain of the CAR (Bosslet et al 1985; Immunohistochemical localization and molecular characteristics of three monoclonal antibody-defined epitopes detectable on carcinoembryonic antigen (CEA). Int J Cancer. 1985 Jul 15;36(1):75-84.) and thereby served as a surrogate antigen for CEA to stimulate the CAR. Proliferation was recorded by flow cytometric recording the dye dilution in CAR T cells after 5 days (Figure 5). It was demonstrated that T cells transduced with the construct encoding the CAR and the switch receptor, but not T cells transduced with the construct encoding the CAR alone, proliferate in presence of TGF- ^ und thereby overcome TGF-β mediated repression. CAR T cells with the SWR proliferated in presence of TGF- ^ in the same degree as in absence of TGF- ^ while CAR T cells without SWR were repressed in proliferation by TGF- ^. Proliferation was triggered through the CAR since CAR T cells without stimulation through BW2064/36 as surrogate for CEA did not proliferate. Example 5: Switch Receptor prevents CARs with different signaling chains from repression in the presence of TGF-β It was investigated whether the switch receptor of the present disclosure conveys TGF- ^ resistance to T cells with CARs with different signaling chains. T cells were engineered with the respective CAR with the 4-1BB- ^, CD28 ^lck- ^, and OX40- ^ intracellular signaling chain; the CARs have the same extracellular domain and recognize CEA. These CARs are sensitive to repression by TGF- ^ (Golumba-Nagy, V., Kuehle, J., Hombach, A.A., Abken, H., T cells with CD28- ^ CAR resist TGF- ^ repression through IL-2 signaling which can be mimicked by an engineered IL-7/IL-2R ^ autocrine loop. Mol. Ther.26, 2218 – 2230 (2018). CAR T cells with or without co-expressed SWR were labelled with “Cell Proliferation Dye eFluor 450” (Invitrogen). CAR T cells were stimulated through their CAR by incubating for 5 days on immobilized BW2064/36 antibody as surrogate antigen for CEA. Cells were incubated in the presence or absence of TGF- ^. CAR T cell amplification was recorded by flow cytometry measuring the dye dilution; CAR T cells were identified by staining for the CAR (Figure 6). Data show that T cells with the 4-1BB-z, CD28 ^lck- ^, and OX40- ^ ^CAR, respectively, were repressed by TGF- ^ in proliferation while the respective CAR T cells with the co-expressed SWR were not. Example 6: Switch receptor CARs prevent repression of perforin, cytolytic activity and IFN- ^ release by TGF-β The regulation of perforin as an essential mediator of cytolytic acivities was measured to investigate the cytolytic capacities of CAR T cells in the presence of TGF ^. Perforin is a glycoprotein responsible for the formation of pores in the membrane of target cells. Perforin regulation has also been known to be associated with IL-2 receptor signaling. Therefore, an impact on the level of perforin in the presence of TGF ^ shows an additional function of the switch receptor. CAR T cells were stimulated through their CAR by incubating with antigen in the presence (+) or absence (-) of TGF-β1 for 24 hours. Alternatively, CAR T cells were incubated on plates without antigen leaving CAR T cells unstimulated. For recording T cell functional activities, the level of perforin expression, CD107a expression and the release of IFN-g into the culture supernatant were monitored.Results are shown in Figure 7. It was demonstrated that T cells transduced with the construct encoding the CAR and the switch receptor increase perforin expression upon CAR stimulation compared to non-stimulated CAR T cells. Moreover, CAR T cells with co-expressed SWR increased perforin in presence of TGF- ^ which is not the case for CAR T cells without SWR. CD107a, a marker for lytic degranulation, was increased in CAR T cells with SWR in presence of TGF- ^, but not in CAR T cells without SWR. IFN- ^, a cytokine released by activated T cells, was increased in the supernatant of CAR T cells with the SWR compared to CAR T cells without SWR upon stimulation through CAR cognate antigen; IFN- ^ release was not repressed in the presence of TGF- ^. Example 7: Switch receptor CARs proliferate better in the presence of TGF-β compared to CAR T cells with a conventional dominant negative receptor The switch receptor (SWR) was experimentally compared to conventional dominant negative (DNR) receptor for the capacity to promote T cell proliferation. Human peripheral blood T cells were engineered with a CAR and a co-expressed dominant negative receptor or with a CAR and a coexpressed switch receptor of the present disclosure and were labelled with Cell Proliferation Dye eFluor 450 (Invitrogen). CAR T cells were stimulated for 5 days through their CAR by incubation with immobilized surrogate antigen. Cells were incubated in the presence or absence of TGF-β1 (0, 10 or 100 ng/ml). CAR T cell proliferation was recorded via flow cytometry measuring the dilution of the cell proliferation dye. CAR T cells were identified by staining for the CAR. Results are shown in Figure 8. It was demonstrated that the switch receptor of the present disclosure improves T cell proliferation (as a marker for T cell functional capacities) significantly better than the conventional dominant negative receptor in the presence of TGF-β1. Example 8: Switch Receptor shows superiority in converting TGF-β resistance compared to the Dominant Negative Receptor under conditions of repetitive CAR stimulation. Switch receptors were experimentally compared to conventional dominant negative receptors with respect to CAR T cell mediated cellular cytotoxicity in presence of TGF- ^ under “stress conditions” of repetitive stimulation with tumor cells. Anti-CEA CAR T cells with switch receptor (SWR) or dominant negative receptor (DNR) were co- cultured with antigen positive tumor cells in the presence and absence of TGFβ1. As tumor cells, the CEA+ N87 cell line was used (ATCC; No. CRL-5822). CAR T cells were harvested and seeded onto fresh tumor cells for a total number of 3 rounds with each round of 72 hours. During each harvest round a small sample is taken for flow cytometry analysis to measure CAR T cell amplification and the number of tumor cells to monitor cytotoxicity. The experimental overview of the tumor re- challenging assay is shown in Figure 9; results are shown in Figure 10. In the presence of TGFβ1 the number of CAR T cells without SWR or DNR declines rapidly. The number of CAR T cells is higher in rounds 2 and 3 of stimulation in presence of TGF- ^ only when the switch receptor is present. This is not the case for CAR T cells in Rounds 2 and 3 in the presence of the dominant negative receptor (DNR). CAR T cells comprising the switch receptor of the present disclosure more efficiently eliminate tumor cells in Rounds 2 and 3 in the presence of TGF ^ compared to CAR T cells with the dominant negative receptor or CAR T cells alone. Of note, the N87 cell line used expresses low amounts of TGF ^1 on surface and also secretes low amounts of TGF ^1 and TGF ^2 (Infect Immun (2011) 79: 2737-45). This explains the reduction in killing by the CAR T cells without SWR or DNR when no additional TGF ^ is added. Example 9: In vivo efficacy of CAR T cells with SWR CEA+ NCI-N87 cancer cells were engineered to express high levels of TGF-β1. T cells were engineered with the anti-CEA CAR plus SWR or DNR. NCI-N87-TGF-β1 cells tumor cells were inoculated by s.c. injection at day 0 and tumors were treated at day 7 by intravenous injection of CAR modified T cells (1 x 10⁶, n = 5 mice per group) with SWR or DWR into the retrobulbar venous plexus. Tumor growth was monitored by digital caliper measurements three times per week. Data are based on n = 5 mice per group and shown in Figure 11. Figure 12 shows a Kaplan-Meier survival curve of mice bearing NCI-N87-TGF-β1 tumors treated with CAR modified T cells; Figure 13 shows the fold increase in tumor size calculated on day 7, 10 and 14 after adoptive transfer of CAR modified T cells. CAR T cells with SWR were superior in controlling tumor growth compared to CAR T cells with DNR or CAR T cells without any co-receptor. Superior tumor control is shown by prolonged survival of mice. Of note, the TGF- ^1 modified N87 cells used in this example expresses high amounts of TGF ^1 on surface and secretes high amounts of TGF ^1 representing the situation of a highly aggressive tumor.

Claims

Claims 1. A recombinant T cell comprising i) a chimeric antigen receptor or a T cell receptor, and ii) a recombinant switch receptor, wherein said recombinant switch receptor comprises d. an extracellular domain comprising a polypeptide which binds TGF, e. a transmembrane domain, and f. an IL-2 receptor signaling domain.

2. The recombinant T cell according to claim 1, wherein said chimeric antigen receptor comprises a. an extracellular domain, b. a transmembrane domain, and c. one or more cytoplasmic signaling domains.

3. The recombinant T cell according to claim 1 or 2, wherein said polypeptide which specifically binds TGF comprises a natural binding domain that is specific for TGF or an antibody, an antibody fragment, or a protein scaffold which specifically binds TGF.

4. The recombinant T cell to claim 3, wherein said natural binding domain that is specific for TGF is a binding domain of TGFR ^II, preferably wherein said a binding domain of TGFR ^II comprises a polypeptide of SEQ No.3.

5. The recombinant T cell according to any one of the preceding claims, wherein said IL-2 receptor signaling domain is an IL-2 receptor signaling domain of IL-2R ^ ^ preferably said IL-2 receptor signaling domain comprises a polypeptide of SEQ No.9. 6. The recombinant T cell according to any one of the preceding claims, wherein the transmembrane domain of said switch receptor is a transmembrane domain of PDGFRB, preferably said transmembrane domain comprises a polypeptide of SEQ No.

6.

7. The recombinant T cell according to any one of claims 2-6, wherein the extracellular domain of said chimeric antigen receptor comprises an antigen-binding region with specificity for a tumor antigen.

8. The recombinant T cell according to claim 7, wherein said tumor antigen is CEA, and preferably wherein said antigen-binding region is a scFv comprising a polypeptide of SEQ No.23.

9. The recombinant T cell according to any one of claims 2-8, wherein the one or more cytoplasmic signaling domains of said chimeric antigen receptor are a cytoplasmic costimulatory signaling domain and/or a cytoplasmic T cell receptor complex associated signaling domain.

10. The recombinant T cell according to claim 9, wherein said cytoplasmic costimulatory signaling domain is 4-1BB and/or said cytoplasmic T cell receptor complex associated signaling domain is CD3, preferably CD3zeta, and preferably wherein said cytoplasmic signaling domain comprises a polypeptide of SEQ No.12 and /or a polypeptide of SEQ No.15.

11. The recombinant T cell according to any one of claims 2-10, wherein said chimeric antigen receptor comprises a CD4 transmembrane domain, preferably a transmembrane domain comprising a polypeptide of SEQ No.19.

12. The recombinant T cell according to any one of the preceding claims, wherein said recombinant switch receptor comprise a polypeptide of amino acid sequence of SEQ No.27, and wherein said 13. A pharmaceutical composition comprising a recombinant T cell according to any one of claims 1-12, and optionally a pharmaceutically acceptable carrier. 14. A recombinant T cell according to any one of claims 1-12 or a pharmaceutical composition according to claim 13 for use in medicine, wherein said use in medicine is the treatment of a disease or disorder, preferably the treatment of cancer.