Switchable universal chimeric antigen receptors and their use

Abstract

The present invention relates to a switchable chimeric antigen receptor (CAR) comprising a tag or tag-binding domain, which is capable of binding a tag-binding domain or a tag of a targeting module, wherein the targeting module comprises a target cell-binding domain. The invention also relates to a nucleic acid, vector or cell comprising a nucleotide sequence encoding the switchable CAR, a pharmaceutical composition comprising a cell comprising a nucleotide sequence encoding the switchable CAR, a kit and the use as a medicament, in particular for use in the treatment of cancer, infectious disease or autoimmune disease.

Description

[0001]Switchable universal chimeric antigen receptors and their useThe present invention relates to a switchable chimeric antigen receptor (CAR) comprising a tagor tag-binding domain, which is capable of binding a tag-binding domain or a tag of a targeting module, wherein the targeting module comprises a target cell-binding domain. The invention also relates to a nucleic acid, vector or cell comprising a nucleotide sequence encoding the switchable CAR, a pharmaceutical composition comprising a cell comprising a nucleotide sequence encoding the switchable CAR, a kit and the use as a medicament, in particular for use in the treatment of cancer, infectious disease or autoimmune disease. Chimeric antigen receptors (CARs) are artificial receptors consisting of a binding moiety, which provides the antigen-specificity, e.g., a single chain variable fragment (scFv) recognizing asurface antigen of a tumor cell, a transmembrane domain, and one or several signaling chainsderived from immune receptors, e.g., CD3ζ, that activates an immune cell (Cartellieri et al.2010).The first-generation CAR comprising one signaling chain was modified by adding an intracellularsignaling domain of e.g. CD28 or CD137 (4-1BB), which are co-stimulatory molecules of a T cell,to increase the activation of immune cells (second generation CAR). A third generation CAR wasdeveloped by tandemly linking an additional complementary intracellular signaling domain derivedfrom e.g. CD28, CD137 (4-1BB) or CD134 (OX40), both which are tumor necrosis factor (TNF)receptor superfamily members, to a second-generation CAR. However, not all intracellularsignaling domains derived from every T cell signal transducing protein sufficiently stimulate a T cell to damage and / or kill a target tumor cell. Therefore, finding intracellular signaling domains of signal transducing proteins that are effective when linked to a CAR is desirable. Immune cells, genetically modified to express CARs, can be used to bind cells or tissue structuresexpressing the appropriate target of the CAR binding moiety. Cross-linking leads to an inductionof signal pathways via the CAR signaling chains, which will change the biologic properties of the CAR-engrafted immune cell. In contrast, CAR activation in gene-modified regulatory T cells (Tregs) leads to an activation of Treg-specific immunomodulatory and suppressive mechanisms like interleukin (IL)-10 or tumor growth factor-beta (TGF-β) secretion. The adoptive transfer of immune cells engineered with chimeric antigen receptors (CARs) is currently considered a highly promising therapeutic option for the treatment of otherwise incurable malignant, infectious or autoimmune diseases. Zarychta et al. describe CAR-T cells immunotherapies for the treatment of acute myeloidleukemia, in particular the results of an anti-CD33, -CD123, -FLT3 and -CLL-1 CAR-T cell therapy(Zarychta et al.2023).Fujiwara et al. describe the influence of hinge and transmembrane domains of chimeric antigenreceptors specific for VEGFR2 on the receptor expression and signaling threshold, in particular aCAR with hinge, transmembrane, and signal transduction domains derived from CD3ζ wascompared with six CAR variants whose hinge or hinge / transmembrane domains originated fromCD4, CD8α, and CD28 (Fujiwara et al. 2020). CAR expression level and stability on the T cellwas found to be affected by transmembrane rather than hinge domain. Furthermore, CARs witha CD8 α- or CD28-derived hinge domain showed significant differences in CAR-T cell function,despite equal expression levels. However, the conventional CAR technology comes along with a number of critical issues, which need to be solved before this treatment modality can be widely applied for clinical treatments. First of all, several safety issues have to be addressed. So far, immune responses of T cells engineered with conventional CARs are difficult to control after infusion into the patient. Seriousadverse event rates are high (Titov et al. 2018). Especially unexpected target gene expressionon normal tissue may provoke a rapid and rigorous immune reaction of engineered T cells againstnormal cells, which can cause severe side effects (Morgan et al.2010). Moreover, as CAR T cellsare a new class of self-amplifying cell drugs, infused T cells can undergo a vigorous expansion in the presence of heavy tumor burden leading to tumor lysis syndrome, cytokine release syndrome and macrophage activation syndrome (Brudno and Kochenderfer 2016). Another drawback of conventional CAR technology is the restriction of engineered T cell retargeting to a single antigen. Such a monotherapeutic approach implies the risk for the development of tumor escape variants, which have lost the target antigen during treatment. The emergence of tumor escape variants under conventional CAR T cell therapy after several months was already observed in clinical trials(Sotillo et al.2015). Taken together, these obstacles restrict the application of CAR T cells to veryfew indications. In fact, examples of clinical effectiveness have mostly been seen with CD19- andBCMA-targeting CAR T cells until now. Modular switchable “universal” CAR T (UniCAR) approaches can overcome these limitations by separating antigen recognition and activating domain of a CAR into two separate operational units. T cells are engineered to express a CAR with a universal binding domain recognizing a tag(Cartellieri et al.2016). Antigen-specificity is provided by soluble adapter molecules, which consistof an antigen-binding domain fused to the tag recognized by the UniCAR. Cartellieri et al. describethe treatment of CD33- and / or CD123-positive acute myeloid leukemia cells in vitro and in vivo.Next to the UniCAR approach for recognizing various antigens (EP 2 990 416 A1), a reverseduniversal CAR (RevCAR) approach is known that promotes binding of an immune cell engineered to express a RevCAR comprising a tag to a target cell through an adaptor molecule comprising atag-binding domain and a target cell binding domain (EP 3581200 A1).Moreover, switchable CAR T approaches like UniCAR or RevCAR provide the possibility to rest CAR T cells in-between cycles of activation and stimulation by pausing administration of thesoluble targeting module molecule. This is expected to prevent the exhaustion observed uponcontinuous stimulation of conventional CAR T cells thereby improving persistence (Weber et al. 2021).  WO 2019 / 238722 A1 describes reversed universal chimeric antigen receptors (RevCAR) with anextracellular LA / SSB derived tag and an adapter molecule comprising a CD123 scFv and a scFv binding to the tag (5B9 or 7B6), which is added to bridge the RevCAR and the tumor cells resulting in antigen specific cytotoxicity. Feldmann et al. disclose RevCAR T cells efficiently kill tumor cells, flexibly redirected againstmultiple targets by exchanging the targeting modules, in particular targeting modules againstPSMA and PSCA (Feldmann et al. 2020).Kittel-Boselli et al. describe targeting acute myeloid leukemia, in particular patient-derived AMLcells expressing CD33 and CD123, using the RevCAR platform, wherein the RevCARs consist of the extracellular peptide epitope E5B9 or E7B6 and CD28 (28) hinge domain (HiD), CD28 transmembrane domain (TMD), the intracellular CD28 costimulatory (CSD) and CDS zeta (3z)activating signaling domain (ASD) (Kittel-Boselli et al. 2021). The targeting modules areconstructed with the variable heavy (VH) and light chain (VL) domains derived from the monoclonal antibodies (mAbs) CD33, CD123, 5B9, or 7B6 connected via glycine (G)-serine (S) linkers.Saleh et al. describe targeting of glioblastoma using switchable RevCAR T cells, in particulartargeting the epidermal growth factor receptor (EGFR) and the disialoganglioside GD2 using EGFR / GD2-specific target module. Therefore, a full activation of Dual-RevCAR T cells is achievedwhen both receptors recognize EGFR and GD2 simultaneously via RevTMs, leading to asignificant killing of GBM cells both in vitro and in vivo (Saleh et al.2023).Viaud et al. disclose switchable CAR (sCAR) T cells, wherein an intermediary antibody-basedanti-CD19 switch with a peptide neoepitope (PNE) controls the function of the anti-PNE scFvcomprising CAR-T cell (Viaud et al. 2022). Viaud et al. describe efficacy, persistence, andexpansion of different murine sCAR constructs in a competent immune system, wherein the use of 4-1BB and CD28 costimulatory domains in controlling tumor burden and sCAR T cell persistence are emphasized. Furthermore, the dosage regime for administering the switch is advantageous, wherein a shorter dosing period with longer rest is applied.Patel et al. discloses a comparison of different chimeric immune receptors comprising the sameanti-HIV scFv but different extracellular spacer domains of varying size that these spacer domainssignificantly impact binding and function of the chimeric immune receptors (Patel et al. 1999).Guest et al. discloses that spacer size and target epitope location play a crucial role for efficiencyof chimeric immune receptors directed against TAAs CD19 and CEA (Guest et al.2005). Similarly,Jame et al. describes that the distance between receptor and target epitope must approximatethe length of a TCR-pMHC complex for maximum lysis and sensitivity (Jame et al.2008).The object of the present invention is to provide a switchable chimeric antigen receptor sufficientlystimulating a T cell to damage and / or kill target cells in vivo.According to the invention, the object is solved by the switchable chimeric antigen receptor (CAR),the nucleic acid, vector or cell comprising a nucleotide sequence encoding the switchable CAR, the pharmaceutical composition, and the kit according to the independent claims. Advantageous embodiments of the invention are indicated in the dependent claims. A first aspect of the invention is a switchable chimeric antigen receptor comprisinga. a tag or tag-binding domain,b. an extracellular hinge and transmembrane domain comprising an extracellular hinge and atransmembrane domain of CD4, CD8α, CD28, ICOS (CD278), IgG1, IgG2, IgG4 or mutants and combinations thereof, wherein the extracellular hinge and transmembrane domain is in the range of 32 to 159 aminoacids, andc. an intracellular signaling domain that comprises at least two signal transduction domainsindependently selected from the group comprising a cytoplasmic region of CD3, CD27, CD28, OX40 (CD134), 4-1BB (CD137), ICOS (CD278), DAP10, DAP12, PD-1, CTLA-4, IL-2 receptor, IL-7 receptor, IL-15 receptor or IL-21 receptor and mutants thereof.As used herein, the term “switchable chimeric antigen receptor” refers to an artificial chimericfusion protein, in particular a receptor comprising a tag or a tag-binding domain, an extracellular hinge and a transmembrane domain and an intracellular signaling domain. The domains can be derived from different sources and therefore, the receptor is called chimeric. Advantageously, the receptor can bind with the tag or tag-binding domain, respectively, to the tag-binding domain ortag of different targeting modules, which in turn bind to an antigen on a target cell. Thus, the tagor tag-binding domain serves as target cell binding domain. Advantageously, the switchable CAR according to the invention used in combination with a targeting module actively targets target cells, e.g. tumor cells, and is capable of inducing a significant anti-tumor response, wherein the anti-tumor response of the switchable CAR is only induced in the presence of the targeting module. The effect can be reversibly interrupted by withholding the administration of the targeting module. The switchable chimeric antigen receptor according to the invention used in combination with a targeting module is safer and more versatile than a classical CAR construct directed against a target. The versatility of the switchable CAR platform embodies a significant advantage for treating tumors with a highly heterogeneous antigenic profile. This therapy can be quickly adapted to the evolving antigenic profile to avoid a treatment-induced selection of tumor cells lacking thetargeted antigen and the consequent tumor relapse. Moreover, only one switchable CAR-T cellproduct is required for different indications and targets. Advantageously, the length of the switchable CAR according to the invention, in particular thelength of the hinge and transmembrane domain, was adapted resulting in an increased efficiencyof the target cell binding and / or lysis. As used herein, the term “domain” refers to a part of a protein sequence, which can exist and function independently from the rest of the protein. As used herein, the term “targeting module” refers to a molecule, preferably a polypeptide or protein, with at least two different domains, wherein each domain is specific for a target or a uniform group of targets, respectively, wherein at least one domain is specific for a target cell, e.g., a CD123-binding domain; and one domain is specific for a switchable CAR, in particular the tag or tag-binding domain of the switchable CAR.As used herein, the term “target cell-binding domain” refers to a protein, peptide, or low molecularweight organic ligand, which specifically binds a protein or protein complex (antigen) on the surface of a target cell, preferably a cancer cell, B cell, T cell, plasma cell, infected cell, pathogen or parasite. As used herein, the term “specific” refers to the ability of an antibody, antibody fragment or a protein, peptide or low molecular weight organic ligand to recognize and bind with a binding partner (e.g., a tumor antigen) protein present in a sample, but not substantially recognize or bind other molecules in the sample. As used herein, the term “binds” or “binding” refers to a non-covalent binding, in particular ionic bonds, hydrogen bonds, Van der Waals forces and / or hydrophobic interactions. As used herein, the terms “peptide”, “polypeptide” and “protein” are used interchangeably and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a proteins or peptides sequence. As used herein, the term “low molecular weight organic ligand” refers to an organic molecule with a molecular weight of maximal 10 kilodaltons, preferably of maximal 3 kilodaltons, which specifically binds a protein or protein complex (antigen) on the surface of a target cell, preferably a cancer cell, B cell, T cell, plasma cell, infected cell or pathogen or parasite.As used herein, the term “mutants” refers to peptides or proteins having at least 90 % sequenceidentity to the named antibodies, antibody fragments, proteins or peptides, preferably at least95 %, more preferably at least 99%, sequence identity. Advantageously, the mutants are capableof having one or more activities of the named domains, antibodies, antibody fragments, peptides or proteins.In embodiments, the mutant comprises a point mutation. As used herein, a „point mutation” is amutation, wherein a single nucleotide base is changed, inserted or deleted from nucleotidesequence. In embodiments, mutants are truncated variants of peptides or proteins. As usedherein, the term “truncated versions” refers to shortened peptides or proteins having at least 90 %sequence identity to the named peptides or proteins, preferably at least 95 %, more preferably atleast 99%, sequence identity, more preferably having a chain length of at least 90 % and asequence identity of 100 %, most preferably a chain length of at least 95 % and a sequence identity of 100 %, resulting from a mutation in the nucleotide sequence coding for the peptide orprotein. Advantageously, the truncated version has at least 80 %, preferably of at least 90 %,more preferably of at least 95 %; of the activity of the named peptide or protein.In embodiments, the switchable CAR comprises a tag. As used herein, the term “tag” refers to amarker, in particular a peptide sequence or an organic molecule, attached to peptides or proteinsto enable them to bind to specific atoms, ions or molecules, in particular the tag-binding domain. In embodiments, the tag-binding domain or tag is present at the amino-terminal end of the polypeptide that comprises the switchable CAR. Advantageously, locating the tag-binding domain or the tag at the amino terminus permits unhampered access to the targeting module that is bound to the target cell.In embodiments, the tag is selected from organic molecules including fluorescence labels, e.g.,FITC (Fluorescein isothiocyanate), and biotin. In embodiments, the tag is a peptide epitope tag. In further embodiments, the tag comprises 10 to 20 amino acids. In embodiments, the peptide epitope tag is a myc-tag, a His-tag, a peptide sequence from yeasttranscription factor GCN4, preferably according to SEQ ID No.1, SEQ ID No.2 or mutants thereof;a leucine zipper sequence, preferably SYNZIP 1 to SYNZIP 48, BATF, FOS, ATF4, ATF3,BACH1, JUND, NFE2L3, HEPTAD (Reinke et al. 2010), a sequence according to SEQ ID No. 3or SEQ ID No.4 or mutants thereof; or a peptide sequence from a human protein, preferably froma human nuclear protein, more preferably from the human La protein, even more preferablyaccording to SEQ ID No. 5, SEQ ID No.6, SEQ ID No.7 or mutants thereof.As used herein, the term “nuclear protein” refers to a protein found in the cell nucleus. Advantageously, tags, which are peptide sequences from nuclear antigens, cannot be accessed and bound by the corresponding tag-binding domain in the context of the native protein under physiological conditions. This leads to minimization of the risk of uncontrolled on-target off-site toxicities by CAR-expressing immune cells like the release of toxic levels of cytokines, referred tovariously as cytokine storms or cytokine release syndrome (CRS). Further advantageously, thetag is not immunogenic.In embodiments, the human protein is a human Alpha-fetoprotein or a human nuclear protein,more preferably from the human La protein. In embodiments, the His-tag is an amino acid sequence consisting of histidine residues, preferably in the range of six to fourteen histidine residues. In preferred embodiments, the peptide epitope tag is a myc-tag, a His-tag, a peptide sequencefrom yeast transcription factor GCN4, preferably according to SEQ ID No. 1 or SEQ ID No. 2; aleucine zipper sequence, preferably SYNZIP 1 to SYNZIP 48, BATF, FOS, ATF4, ATF3, BACH1,JUND, NFE2L3, HEPTAD, a sequence according to SEQ ID No.3 or SEQ ID No. 4; or a peptidesequence from a human nuclear protein, preferably from the human La protein according to SEQID No.5, SEQ ID No.6 or SEQ ID No. 7.Preferably, the peptide epitope tag from the human La protein is the human La epitope E5B9according to SEQ ID No.5 or E7B6 according to SEQ ID No. 6 or SEQ ID No. 7, most preferablythe human La epitope E5B9 according to SEQ ID No. 5 or E7B6 according to SEQ ID No. 7.In embodiments, the switchable CAR comprises a tag-binding domain.In embodiments, the tag-binding domain is an antibody or antigen-binding fragment.In embodiments, the tag-binding domain is an antibody or an antigen-binding fragment binding toa myc-tag, a His-tag, a peptide sequence from yeast transcription factor GCN4, preferablyaccording to SEQ ID No. 1, SEQ ID No. 2 or mutants thereof; a leucine zipper sequence,preferably SYNZIP 1 to SYNZIP 48, BATF, FOS, ATF4, ATF3, BACH1, JUND, NFE2L3, HEPTAD(Reinke et al.2010), a sequence according to SEQ ID No.3 or SEQ ID No.4 or mutants thereof;or a peptide sequence from a human protein. In embodiments, the tag-binding domain is anantibody or an antigen-binding fragment binding to a myc-tag, a His-tag, a peptide sequence fromyeast transcription factor GCN4 according to SEQ ID No. 1, SEQ ID No. 2, a leucine zippersequence selected from SYNZIP 1 to SYNZIP 48, BATF, FOS, ATF4, ATF3, BACH1, JUND,NFE2L3, HEPTAD (Reinke et al.2010), a sequence according to SEQ ID No.3 or SEQ ID No.4or a peptide sequence from a human nuclear protein. As used herein, the term “antibody” refers to a protein, which binds antigens via the antigen- binding fragment variable region (Fab). This is composed of one constant and one variable domain of each of the heavy (VH) and the light chain (VL). As used herein, the term “antibody fragment” or “antigen-binding fragment” refers to a protein comprising at least the VLor VHof an antibody. In embodiments, antibody fragments are selected from single-chain variable fragments (scFv), single-chain antibodies, Fc fragment, F(ab')2 fragments, Fab fragments, and fragments produced by a Fab expression library or single-domain antibodies (nanobodies). As used herein, the term “Fab fragments” refers to an antibody fragment comprising one constant and one variable domain of each of the heavy and the light chain. As used herein, the term “single-chain variable fragment (scFv)” refers to an artificial antibody fragment comprising a variable domain of a light chain and a variable domain of a heavy chain of an antibody covalently linked. In embodiments, the VLand VHof an antibody are covalently linked by a short peptide of 10 to 25 amino acids. In further embodiments, the short peptide links the N- terminus of the VH with the C-terminus of the VL, or vice versa. As used herein, the term “single-domain antibody (sdAb)” or “nanobody” is an antibody fragment consisting of a single monomeric variable antibody domain, in particular a VHH fragment. In embodiments, the antibody is obtained from an animal species, preferably from a mammal such as human, simian, mouse, rat, rabbit, lama, alpaca, camel, guinea pig, horse, cow, sheep, goat, pig, dog or cat. In embodiments, the antibody is derived from a shark. Preferably, the antibody or antibody fragment is a human, humanized or deimmunized antibody. Humanized antibodies can be prepared in various ways, for example, by resurfacing and CDR grafting. In case of resurfacing, a combination of molecular modeling, statistical analyses, and mutagenesis is used to modify all non-CDR regions on the surface of the antibody to become similar to the surface of antibodies of the target organism. In CDR grafting, the CDR regions according to theinvention are introduced into known human framework regions, which are similar in sequence tothe original ones. Deimmunized antibodies can be obtained by specifically mutating residues that confer immunogenicity hotspots as predicted based on in silico peptide-MHC affinity prediction. In embodiments, the antibody or antibody fragment is a polyclonal, a monoclonal or a chimeric antibody, wherein an antigen-binding region of a non-human antibody is transferred into the framework of a human antibody by recombinant DNA techniques including in silico design. In embodiments, antibodies to a selected tag or antigen may be produced by immunization of various hosts including, but not limited to, goats, rabbits, rats, mice, humans, through injection with cells expressing a particular protein, DNA or RNA encoding for the protein, the protein itself or any portion, fragment or oligopeptide that retain immunogenic properties of the protein. In embodiments, the antibody, antigen-binding fragment, protein or peptide comprises modifications selected from the group comprising D amino acids, pseudo peptide bonds,aminoalcohols, non-proteinogenic amino acids, unnatural amino acids, amino acids with modifiedside chains and / or circular proteins. Advantageously, these analogues reveal increased stability.In embodiments, the variable region(s) of the at least one tag-binding domain comprise(s) ahumanized amino acid sequence. In embodiments, the tag-binding domain is an antigen-binding fragment. In embodiments, the tag- binding domain is an scFv or a Fab fragment. In embodiments, the tag-binding domain is an scFv binding a La epitope. In embodiments, the tag-binding domain is an scFv binding La epitope 5B9 or 7B6 according to SEQ ID No.5, SEQ ID No.6 or SEQ ID No.7. In embodiments, VL and VH are connected via a glycine-serine linker with the structure (GxSy) with x and y selected from 1 to 10, preferably 3 to 5. Mostly preferred are 1 to 10 repeats of the sequence G4S1 (SEQ ID No. 20). In embodiments, linkers are used that are constituted of a peptide sequence that can increase the protease resistance of the antibody derivatives. As usedherein, the term “linker” (also spacer) refers to a molecule or molecule part separating at leasttwo elements under consideration, in particular selected from functional groups, tags, binding domains or binding domain subunits, such as a VL and a VH domain. In embodiments, the linker comprises 20 to 30 amino acids, preferably 25 amino acids.In embodiments, the linker is an amino acid sequence according SEQ ID No. 21 or SEQ ID No.22. As used herein, the term “CDR (Complementarity-determining regions)” refers to parts of the variable chains in antibodies or antibody fragments, where the antibodies or antibody fragments bind to their specific antigen. An antibody comprises three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, on the amino acid sequence of each variable domain and thus, six CDRs on the two variable domains (VHand VL), which can come into contact with the antigen. In embodiments, the tag-binding domain binding a human La epitope E5B9 comprises CDR sequences according to SEQ ID No.8, SEQ ID No.9, SEQ ID No.10, SEQ ID No.11, amino acid sequence WAS (Trp-Ala-Ser) and SEQ ID No.12. In embodiments, the tag-binding domain is an antibody or an antigen-binding fragment comprising a VLaccording to the following sequence: DIVMTQSPDSLAVSLGERATINCX24SSQSLLNSRTX35KNYLAWYQQKPGQPPKLLIYWASTR X61SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCKQSYNLX101TFGGGTKVElK (SEQ ID No. 13), wherein X24, X35, X61and X101are independently from each other selected from a proteinogenic alpha-amino acid residue; or an amino acid sequence having at least 90 %sequence identity, preferably at least 95 % sequence identity; to sequence SEQ ID No. 14 orSEQ ID No.16.In some embodiments, X24 to X101 are selected as follows:X24 is selected from polar and / or positive charged residues, such as Serine, Threonine, Asparagine, Glutamine, Histidine, Lysine and Arginine; preferably Lysine or Arginine; X35 is preferably selected from Lysine and Proline; X61 is selected from polar and charged residues, such as Asparagine, Aspartic Acid, Glutamine, Glutamic acid, Histidine, Lysine and Arginine, preferably Glutamic acid and Lysine; X101 is selected from hydrophobic residues, such as Isoleucine, Leucine, Valine, Alanine, Methionine, Phenylalanine, Proline and Tryptophan; preferably Leucine or Proline. In embodiments, the tag-binding domain is an antibody or an antigen-binding fragment comprising a VH with an amino acid sequence having at least 90 % sequence identity, preferably at least95 % sequence identity; to sequence SEQ ID No.15 or SEQ ID No. 17.In embodiments, the tag-binding domain comprises a sequence having each at least 90 % sequence identity, preferably at least 95 % sequence identity; to the sequences according to SEQ ID No.14 (VL) and SEQ ID No.15 (VH).In embodiments, the tag-binding domain is an anti-La 5B9 scFv comprising SEQ ID No. 14 (VL)and SEQ ID No.15 (VH). In embodiments, the tag-binding domain comprises a sequence having each at least 90 % sequence identity, preferably at least 95 % sequence identity; to the sequences according to SEQ ID No.16 (VL) and SEQ ID No.17 (VH).In embodiments, the tag-binding domain is an anti-La 7B6 scFv comprising SEQ ID No. 16 (VL)and SEQ ID No.17 (VH). In embodiments, the tag-binding domain comprises a VL-linker-VHstructure, wherein the VLregion of the tag-binding domain comprises a sequence with at least 95 % identity, preferably 99 % identity, with the sequence according to SEQ ID No.14 and / or the VHregion of the tag-binding domain comprises a sequence with at least 95 % identity, preferably 99 % identity, with the sequence according to SEQ ID No.15. As used herein, the term “VL-linker-VHstructure” refers to a structure, wherein the C-terminus of the VLregion is connected with a linker, which is connectedto the N-terminus of the VH region.In embodiments, the tag-binding domain is a Fab fragment binding a La epitope. In embodiments,the tag-binding domain is a Fab fragment binding La epitope 5B9 comprising an amino acidsequence according to SEQ ID No.18 and SEQ ID No.19.As used herein, the term “extracellular hinge and transmembrane domain” refers to a flexiblepeptide sequence connected to the tag or tag-binding domain, which anchors the switchable CARinto the cell membrane of the cell and protrudes from the surface of the cell for optimal binding to its particular targeting module.According to the invention, the extracellular hinge and transmembrane domain comprises anextracellular hinge and a transmembrane domain of CD4, CD8α, CD28, ICOS (CD278), IgG1, IgG2, IgG4 or mutants and combinations thereof, wherein the extracellular hinge andtransmembrane domain is in the range of 32 to 159 amino acids, preferably in the range of 32 to88 amino acids, more preferably in the range of 32 to 64 amino acids.As used herein, the term “extracellular hinge domain” refers to a peptide sequence between thetransmembrane domain and the tag or tag-binding domain and which protrudes from the surfaceof the cell for optimal binding to its particular targeting module. Advantageously, the extracellularhinge domain enables different alignments of the CAR and thus the positioning of the CAR(effector cell) to the targeting module, affecting the binding of the targeting module by the CAR(effector cell). Despite the shortening of the extracellular domain, an increase in efficiency wasobserved. Further advantageously, the extracellular hinge domain enables binding of varioustargeting module formats directed against various target epitopes and efficient immune synapseformation. Switchable CARs with shortened extracellular domain showed an increase in efficiencyin combination with various targeting module formats and against various target epitopes.In embodiments, the extracellular hinge and transmembrane domain comprises an extracellularhinge and a transmembrane domain of CD4, CD8α, CD28, ICOS (CD278), IgG1, IgG2, IgG4 andcombinations thereof, wherein the extracellular hinge and transmembrane domain is in the rangeof 32 to 159 amino acids, preferably in the range of 32 to 88 amino acids, more preferably in the range of 32 to 64 amino acids.In embodiments, the switchable CAR comprises an extracellular hinge domain of human CD4,CD8α, CD28, ICOS (CD278), IgG1, IgG2 or IgG4 or mutants thereof, wherein the extracellularhinge domain is in the range of 12 to 133 amino acids, preferably in the range of 12 to 62 aminoacids, more preferably in the range of 12 to 38 amino acids.In embodiments, the switchable CAR comprises an extracellular hinge domain of human CD4,CD8α, CD28, ICOS (CD278), IgG1, IgG2 or IgG4, wherein the extracellular hinge domain is inthe range of 12 to 133 amino acids, preferably in the range of 12 to 62 amino acids, morepreferably in the range of 12 to 38 amino acids.In embodiments, the switchable CAR comprises an extracellular hinge domain of human CD8αaccording SEQ ID No. 23 or SEQ ID No.24, CD28 according SEQ ID No. 25 or SEQ ID No. 26,IgG1 according to SEQ ID No.198, IgG2 according to SEQ ID No.199 or IgG4 according to SEQID No. 27 or mutants thereof, wherein the extracellular hinge domain is in the range of 12 to 133amino acids, preferably in the range of 12 to 62 amino acids, more preferably in the range of 12to 38 amino acids. In embodiments, the switchable CAR comprises an extracellular hinge domainof human CD8α according SEQ ID No. 23 or SEQ ID No. 24, CD28 according SEQ ID No.25 orSEQ ID No. 26, IgG1 according to SEQ ID No. 198, IgG2 according to SEQ ID No. 199 or IgG4according to SEQ ID No. 27, wherein the extracellular hinge domain is in the range of 12 to 133amino acids, preferably in the range of 12 to 62 amino acids, more preferably in the range of 12to 38 amino acids.In embodiments, the switchable CAR comprises an extracellular hinge domain of human CD8α,CD28, IgG4 or mutants thereof. In embodiments, the switchable CAR comprises an extracellularhinge domain of human CD8α, CD28 or IgG4. In embodiments, the switchable chimeric antigenreceptor comprises an extracellular hinge domain of human CD8α according SEQ ID No. 23 orSEQ ID No.24, CD28 according SEQ ID No.25 or SEQ ID No.26 or IgG4 according SEQ ID No.27.In embodiments, the switchable chimeric antigen receptor comprises an extracellular hingedomain of human CD8α according SEQ ID No. 23 or SEQ ID No. 24, CD28 according SEQ IDNo. 25 or IgG4 according SEQ ID No. 27. In embodiments, the switchable chimeric antigenreceptor comprises an extracellular hinge domain of human IgG4 according SEQ ID No.27.As used herein, the term “transmembrane domain” refers to a membrane-spanning proteindomain or the part of the extracellular hinge and transmembrane domain, which anchors theswitchable CAR into the cell membrane of the cell. In embodiments, a transmembrane domainconsists of at least one alpha-helix or a transmembrane beta barrel.In embodiments, the switchable CAR comprises a transmembrane domain of human CD8α,CD28, ICOS (CD278) or mutants thereof, wherein the transmembrane domain is in the range of20 to 26 amino acids. In embodiments, the switchable CAR comprises a transmembrane domainof human CD8α, CD28 or ICOS (CD278), wherein the transmembrane domain is in the range of20 to 26 amino acids.In embodiments, the switchable CAR comprises a transmembrane domain of human CD8αaccording to SEQ ID No.28, CD28 according to SEQ ID No.29, ICOS (CD278) according to SEQID No. 200 or mutants thereof, wherein the transmembrane domain is in the range of 20 to 26amino acids. In embodiments, the switchable CAR comprises a transmembrane domain of humanCD8α according to SEQ ID No. 28, CD28 according to SEQ ID No. 29, ICOS (CD278) accordingto SEQ ID No.200, wherein the transmembrane domain is in the range of 20 to 26 amino acids.In embodiments, the switchable CAR comprises a transmembrane domain of human CD8αaccording to SEQ ID No.28 or CD28 according to SEQ ID No.29.In embodiments, combinations of the extracellular hinge and transmembrane domain are CD8α extracellular hinge and transmembrane domain, CD28 extracellular hinge and transmembranedomain, a CD28 extracellular hinge domain combined with a CD8α transmembrane domain, anIgG4 extracellular hinge domain combined with a CD8α transmembrane domain or an IgG4extracellular hinge domain combined with a CD28 transmembrane domain. In embodiments, theswitchable CAR comprises an extracellular hinge and transmembrane domain according to oneof the amino acid sequences SEQ ID No. 30 to SEQ ID No. 35. In preferred embodiments, theswitchable CAR comprises an extracellular hinge and transmembrane domain according to oneof the amino acid sequences SEQ ID No.33 to SEQ ID No. 35.In embodiments, the extracellular hinge domain and / or the transmembrane domain comprisesadditional 1 to 25 flanking amino acids derived from the source protein.In embodiments, the extracellular hinge domain and / or the transmembrane domain comprises alinker sequence of preferably 1 to 25 amino acid residues.Preferred linkers are glycine-serine linkers with the structure (GxSy) with x and y selected from 1 to 10, preferably 1 to 5. Mostly preferred are 1 to 10 repeats of the sequence G4S1(SEQ ID No. 20). Moreover, linkers are preferred that are constituted of a peptide sequence that can increase the protease resistance of the antibody derivatives.In embodiments, the linker is SEQ ID No. 21 or SEQ ID No.22.In embodiments the linkers comprise 3-24 alanine residues, preferably multiples of 3. In embodiments, the mutant of the extracellular hinge domain and / or the transmembrane domaincomprises one- or two-point mutations. In embodiments, the mutants are truncated variants ofthe extracellular hinge domain and / or the transmembrane domain, domains having a chain lengthof at least 90 % and a sequence identity of 100 %, most preferably a chain length of at least 95% and a sequence identity of 100 %, resulting from a mutation in the nucleotide sequence coding for the domain. According to the invention, the intracellular signaling domain comprises at least two signal transduction domains independently selected from a cytoplasmic region of a CD3, CD27, CD28, CD134 (OX40), CD137 (4-1BB), CD278 (ICOS), DAP10, DAP12, programmed cell death-1 (PD- 1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), IL-2 receptor, preferably CD122 (interleukin-2receptor β) or CD132 (interleukin-2 receptor γ); IL-7 receptor, preferably CD127 (interleukin-7receptor α); IL-15 receptor or CD360 (interleukin-21 receptor), and mutants thereof.As used herein, the term “intracellular signaling domain” refers to a peptide sequence whichtransmits a signal into the cell by cross-linkage of the cell expressing the switchable CAR (effector cell) to a human cell surface protein or protein complex (target cell). Cross-linkage between effector and target cell is mediated by the targeting module.As used herein, the term “mutants” refers to proteins having at least 90 % sequence identity tothe signal transduction domains, preferably at least 95 % sequence identity. Advantageously, the mutant transmits a signal into the cell by cross-linkage of the cell expressing the switchable CAR (effector cell) to a human cell surface protein or protein complex (target cell) in the same way as the named signal transduction domains. In embodiments, mutants are truncated versions. As used herein, the term “truncated versions” refers to shortened proteins having at least 90 % sequence identity to the signal transduction domains, preferably at least 95 % sequence identity, more preferably having a chain length of at least 90 % and a sequence identity of 100 %, most preferably a chain length of at least 95 % and a sequence identity of 100 %. Advantageously, the truncated version has an activity of at least80 %, preferably of at least 90 %, more preferably of at least 95 %; of the named signaltransduction domains.Hombach et al. describes the use of cytoplasmic regions of CD28 as signal transduction domainin CARs (Hombach et al. 2001). Guedan et al. describes the use of a mutant of cytoplasmicregions of CD28 as signal transduction domain (Guedan et al.2020).Finney et al. describes the use of cytoplasmic regions of CD137 (4-1BB) and of CD134 (OX40)as signal transduction domain (Finney et al.2004).Guedan et al. describes the use of cytoplasmic regions of CD278 (ICOS) as signal transductiondomain (Guedan et al. 2018).Zhang et al. describes the use of DAP10 as signal transduction domain (Zhang et al. 2005).Fedorov et al. describes the use of programmed cell death 1 (PD-1) and of cytotoxic T-lymphocyteantigen 4 (CTLA-4) as signal transduction domain in CARs (Fedorov et al.2013).Gong et al. describes the use of cytoplasmic regions of CD3 chains, in particular the CD3ζ chain,as signal transduction domain in CARs (Gong et al. 1999).Töpfer et al. describes the use of DAP12 as signal transduction domain in CARs (Töpfer et al.2015).Kagoya et al. describes the use of signaling chains or motifs derived from interleukin receptorsas signal transduction domain in CARs (Kagoya et al.2018).In embodiments, the intracellular signaling domain comprises at least two signal transductiondomains independently selected from a cytoplasmic region of a CD3 according to SEQ ID No.41,CD27 according to SEQ ID No.201, CD28 according to SEQ ID No.37 or SEQ ID No.38, CD134(OX40) according to SEQ ID No.202, CD137 (4-1BB) according to SEQ ID No.39 or SEQ ID No.40, CD278 (ICOS) according to SEQ ID No. 203, DAP10 according to SEQ ID No. 204, DAP12according to SEQ ID No. 205, programmed cell death-1 (PD-1) according to SEQ ID No. 206,cytotoxic T-lymphocyte antigen 4 (CTLA-4) according to SEQ ID No. 207 or mutants thereof. Inembodiments, the intracellular signaling domain comprises at least two signal transductiondomains independently selected from a cytoplasmic region of a CD3 according to SEQ ID No.41,CD27 according to SEQ ID No.201, CD28 according to SEQ ID No.37 or SEQ ID No.38, CD134(OX40) according to SEQ ID No.202, CD137 (4-1BB) according to SEQ ID No.39 or SEQ ID No.40, CD278 (ICOS) according to SEQ ID No. 203, DAP10 according to SEQ ID No. 204, DAP12according to SEQ ID No. 205, programmed cell death-1 (PD-1) according to SEQ ID No. 206,cytotoxic T-lymphocyte antigen 4 (CTLA-4) according to SEQ ID No.207.In embodiments, the intracellular signaling domain comprises at least two signal transductiondomains independently selected from a cytoplasmic region of a CD3, CD27, CD28, CD134 (OX40), CD137 (4-1BB), CD278 (ICOS), DAP10, DAP12, programmed cell death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), IL-2 receptor, preferably CD122 (interleukin-2receptor β) or CD132 (interleukin-2 receptor γ); IL-7 receptor, preferably CD127 (interleukin-7receptor α); IL-15 receptor or CD360 (interleukin-21 receptor).In embodiments, the intracellular signaling domain comprises at least a cytoplasmic region ofCD3ζ, 4-1BB, CD28 or mutants thereof.In embodiments, the intracellular signaling domain comprises two or three signal transduction domains selected from the group comprising CD28, 4-1BB, ICOS, CD3ζ, IL-7Rα and mutantsthereof. In embodiments, the intracellular signaling domain comprises two or three signaltransduction domains selected from the group comprising CD28, 4-1BB, ICOS, CD3ζ and IL-7Rα. In embodiments, the intracellular signaling domain comprises at least a cytoplasmic region ofCD28 or mutants thereof, preferably an amino acid sequence according to SEQ ID No.37 or SEQID No.38. In embodiments, the intracellular signaling domain comprises at least a cytoplasmic region of 4-1BB or mutants thereof, preferably an amino acid sequence according to SEQ ID No.39 or SEQID No.40. In further embodiments, the intracellular signaling domain comprises at least a cytoplasmic regionof CD3ζ or mutants thereof, preferably according to SEQ ID No. 41.In further embodiments, the switchable CAR comprises a further domain, wherein the furtherdomain is a short peptide linker in the extracellular portion of the receptor that may serve to detect the chimeric antigen receptor on the cell surface or stimulate the chimeric antigen receptor T cell.Advantageously, the switchable CAR engrafted cells with the further domain can be specificallystimulated to proliferate preferentially and persist longer compared to non-engrafted cells eitherin vitro or in vivo. Further advantageously, the further domain may also be used to purifyswitchable CAR engrafted cells from mixed cell populations or to dampen switchable CAR engrafted cell-mediated immune response and to eliminate switchable CAR engrafted cells in vivo.In embodiments, the further domain forms a linear epitope for a monoclonal antibody (mab)specifically binding to the further domain. In some embodiments, the further domain comprises atleast one linear epitope, preferably E7B6 according to SEQ ID No. 6 or SEQ ID No. 7.In embodiments, the further domain is located in between the tag or tag-binding domain and theextracellular hinge domain or is an integral part of the extracellular hinge domain.In embodiments, the switchable CAR is a reversible chimeric antigen receptor (RevCAR)comprising a tag. As used herein, the term “reversible chimeric antigen receptor (RevCAR)” refersto an artificial chimeric fusion protein, in particular a receptor comprising a tag, an extracellularhinge and a transmembrane domain and an intracellular signaling domain. The term “reversible”results from the effect that the induction of a significant anti-tumor response can be reversiblyinterrupted by withholding the administration of the targeting module. The domains can be derived from different sources and therefore, the receptor is called chimeric. Advantageously, the receptorcan bind with the tag to the tag-binding domain of different targeting modules, which in turn bindto an antigen on a target cell. Thus, the tag serves as target cell binding domain.In embodiments, the RevCAR comprises a tag present at the amino-terminal end.In embodiments, the switchable CAR comprises a signal peptide selected from a human CD8α,CSF2Rα, CD3ζ, IL-2, lysozyme C, a heavy chain of an antibody, a light chain of an antibody or apart of a light chain of an antibody or mutants thereof. In embodiments, the signal peptide is anamino acid sequence selected from the group comprising SEQ ID No. 42 to SEQ ID No. 46.Suitably, the signal peptide is located at the N-terminus of the switchable CAR sequence ahead of the tag, the extracellular hinge and transmembrane domain and the intracellular signaling domain. As used herein, the term “signal peptide” (also leader peptide) refers to a short amino acid sequence at the N-terminus of proteins meant for secretion or membrane localization.Advantageously, the signal peptide effects the transport of the switchable CAR on the cell surfaceof an effector cell. In embodiments, the switchable universal chimeric antigen receptor comprises a signal peptide of a human immunoglobulin with an amino acid sequence in the range of 16 to 30 amino acids. The term “immunoglobulin” refers to Y-shaped protein consisting of two identical heavy chains and two identical light chains connected by disulfide bonds used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses, called antigens. Advantageously, using signal peptides influences the switchable CAR expression levels on the surface of an effector cell and thus, the efficiency.In embodiments, the switchable CAR comprises a sequence according to SEQ ID No.53 to SEQID No. 112. In embodiments, the switchable CAR comprises a sequence according to SEQ IDNo. 53 to SEQ ID No.82.Another aspect of the invention is a nucleic acid, vector or cell comprising a nucleotide sequenceencoding the switchable CAR according to the invention. The nucleic acid, vector and / or cell areisolated.In embodiments, the nucleic acid, vector or cell comprises a nucleotide sequence encoding asignal peptide according to SEQ ID No. 47 to SEQ ID No. 51.In embodiments, the nucleotide sequence encoding a switchable chimeric antigen receptorcomprises a nucleotide sequence according to SEQ ID No. 113 to SEQ ID No. 142. The nucleicacid, vector and / or cell are isolated. In embodiments, the vector is a plasmid, an artificial chromosome, linearized DNA or RNA, a virus particle or another vector that contains an expression cassette that is incorporated stably into the genome of a host cell or host organism.In embodiments, the vector further comprises a promoter, wherein the promoter is selected fromthe group comprising an EF-1 promoter, a CMV IE gene promoter, an EF-1α promoter, a ubiquitin C promoter, or a phosphoglycerate kinase (PGK) promoter.In embodiments, the cell comprises an exogenous nucleotide sequence encoding the switchableCAR that is expressed on the surface of the cell. In embodiments, the cell is selected from immune cells, preferably with cytolytic, phagocytic or immunosuppressive activity, such as T cells, Natural Killer (NK) cells and macrophages. Inembodiments, the cell is selected from T cells, including alpha / beta and gamma / delta T cells orsubpopulations of T cells like stem-cell memory T cells or central memory T cells, cytotoxic T cells or NK cells. In embodiments, the vector or cell further comprises an inducible expression system. In some embodiments, the inducible expression system is based on a prokaryotic operon, including, but not limited to, the lac operon, transposon Tn10 or tetracycline operon. In other embodiments, the inducible expression system is based on components of a eukaryotic signaling pathway, including, but not limited to, expression systems based on a steroid receptor, an estrogen receptor, progesterone or metallothionein. In embodiments, the inducible expression system induces the transcription of the nucleotidesequence encoding a switchable CAR and optionally a nucleotide sequence encoding a targetingmodule.In embodiments, the cell is an engineered human cell comprising at least one geneticmodification.In embodiments, the cell is an engineered allogeneic immune cell. In embodiments, theengineered allogeneic immune cell is obtained by at least one genetic modification of a donorcell.In embodiments, the cell comprises a reduced or eliminated surface expression of endogenous Tcell receptor alpha chain (TRAC) by a genetic modification in the T cell receptor alpha chain gene,a reduced or eliminated surface expression of HLA-A relative to an unmodified T cell by a geneticmodification in the HLA-A gene, and / or a reduced or eliminated surface expression of HLA classII by a genetic modification in the CIITA gene. Advantageously, the three knock outs (TRAC, HLA-A gene, CIITA) result in a reduction of the rejection by the recipient subject’s immune cells, inparticular decrease the chance of GvHD for allogeneic T cells. In embodiments, the genetic modification in the TRAC gene comprises at least one nucleotide within the genomic coordinates chr14:22547524-chr14:22547544. In embodiments, the genetic modification in the TRAC gene comprises at least 10 or at least 15 contiguous nucleotides within the genomic coordinates. In embodiments, the genetic modification in the TRAC gene comprises at least one nucleotide of an exon of the TRAC gene. In embodiments, the genetic modification in the TRAC gene comprises at least one insertion, deletion, substitution, or deamination of at least one nucleotide within the genomic coordinates.In embodiments, the genetic modification in the TRAC gene comprises an indel.In embodiments, the genetic modification in the HLA-A gene comprises at least one nucleotidewithin the genomic coordinates chosen from: chr6:29942854-chr6:29942913 and chr6:29943518- chr6:29943619.In embodiments, the T cell is homozygous for HLA-B and / or homozygous for HLA-C genotypes.Preferably, the T cell is homozygous for HLA-B and HLA-C genotypes. In embodiments, the T cell has reduced or eliminated expression of at least one HLA-A allele selected from: HLA-A1, HLA-A2, HLA-A3, HLA-A11, and HLA-A24.In embodiments, the genetic modification in the HLA-A gene comprises at least 5, 6, 7, 8, 9, or10 contiguous nucleotides within the genomic coordinates, preferably at least 10, at least 15, atleast 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleotides within the genomic coordinates.In embodiments, the genetic modification in the HLA-A gene comprises at least one C to Tsubstitution or at least one A to G substitution within the genomic coordinates.In embodiments, the genetic modification in the HLA-A gene comprises an indel.In embodiments, the T-cell further comprises a reduced or eliminated surface expression of HLA- B relative to an unmodified T cell by a genetic modification in the HLA-B gene and / or a reduced or eliminated surface expression of HLA-C relative to an unmodified T cell by a genetic modification in the HLA-C gene. In further embodiments, the T-cell further comprises a reduced or eliminated surface expression of HLA-B relative to an unmodified T cell by a genetic modification in the HLA-B gene and the Tcell is homozygous for HLA-C genotype.In alternative embodiments, the T-cell further comprises a reduced or eliminated surface expression of HLA-C relative to an unmodified T cell by a genetic modification in the HLA-C geneand the T cell is homozygous for HLA-B genotype.In further alternative embodiments, the T-cell further comprises a reduced or eliminated surface expression of HLA-B relative to an unmodified T cell by a genetic modification in the HLA-B gene and a reduced or eliminated surface expression of HLA-C relative to an unmodified T cell by a genetic modification in the HLA-C gene. In embodiments, the genetic modification in the CIITA gene comprises at least one nucleotide of at least one nucleotide of a splice site within the genomic coordinates chr16:10902171- chr16:10923242. In embodiments, the genetic modification in the CIITA gene comprises a modification of at leastone nucleotide of a splice acceptor site, preferably wherein the one nucleotide is A or G or T.In embodiments, the genetic modification in the CIITA gene comprises a modification of a splicesite boundary nucleotide.In embodiments, the genetic modification in the CIITA gene comprises at least 5, 6, 7, 8, 9, or 10contiguous nucleotides within the genomic coordinates chr16:10902171- chr16:10923242.In embodiments, the genetic modification in the CIITA gene comprises at least 10 or at least 15 contiguous nucleotides within the genomic coordinates. In embodiments, the genetic modification in the CIITA gene comprises an indel.A further aspect of the invention is a pharmaceutical composition comprising a cell comprising anucleotide sequence encoding the switchable CAR according to the invention and apharmaceutically acceptable thinner or carrier. In embodiments, the pharmaceutical composition is administered parenterally, particularly preferred intravenously. In embodiments, the pharmaceutical composition is present in a form suitable for intravenous administration. Preferably, the pharmaceutical composition is a solution, emulsion or suspension. In embodiments, the pharmaceutical composition is an injectable buffered solution comprising a concentration in the range of 1·105to 1·108per mL of the cell comprising a nucleotide sequence encoding the switchable CAR according to the invention. The pharmaceutical composition comprises a pharmaceutically acceptable thinner (dilution agent) or carrier. In embodiments, the carrier is selected from water, an aqueous buffer solution, 0.9 % saline solution, 5 % glucose, 5 % xylitol, 0.3 % glycine solution, ringer solutions or amino acid solutions. In further embodiments, the aqueous buffer solution is selected from an aqueous histidine, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate-buffered solution with a pH value in the range of pH 5.0 to pH 7.0. In embodiments, the aqueous buffersolution has a buffer concentration in the range of 1 mmol / l (mM) to 500 mM, preferably in therange of 5 mM to 20 mM, more preferably in the range of 5 mM to 10 mM. In embodiments, the carrier comprises sodium chloride. In embodiments, the carrier comprises sodium chloride with a concentration in the range of 1 mM to 300 mM. In embodiments, the carrier comprises sodium chloride with a concentration of about 150 mM. In embodiments, the pharmaceutical composition comprises a stabilizer. In embodiments, the pharmaceutical composition comprises a stabilizer with a concentration in the range of 1 mM to 900 mM. In embodiments, the pharmaceutical composition comprises a stabilizer with a concentration in the range of 50 mM and 600 mM. In embodiments, the stabilizer is sucrose, trehalose or L-methionine. In embodiments, the pharmaceutical composition further comprises pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipients” refers to compounds, which provide approximately physiological conditions and / or increase the stability, such as agents for adjusting the pH value and buffering agents, agents for adjusting the toxicity and the like. In embodiments, pharmaceutically acceptable excipients are selected from sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and polysorbate-80, preferablypolysorbate-80 in the range of 0.0001 % (w / v) to 1 % (w / v). In embodiments, the concentration ofthe pharmaceutically acceptable excipient is in the range of 0.001 % (w / v) to 0.1 % (w / v).In embodiments, the pharmaceutical composition further comprises a targeting module.In embodiments, the pharmaceutical composition comprises at least one targeting module, wherein the at least one targeting module comprises at least one target cell-binding domain and a tag or a tag-binding domain, wherein the at least one target cell-binding domain is an antibody, antibody fragment, a protein, a peptide or a low molecular weight organic ligand that binds tosurface antigens selected from the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10,CD15, CD19, CD20, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD79a, CD79b, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, a cytokine receptor, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, an epithelial cell adhesion molecule, an alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a disialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and a tumor-specific glycan. In embodiments, the at least one target cell-binding domain is an antibody, antibody fragment, aprotein, a peptide or a low molecular weight organic ligand that binds to surface antigens selectedfrom the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD19, CD20, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD79a, CD79b, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182,CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, acytokine receptor, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, an epithelial cell adhesion molecule, an alpha- fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a disialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and a tumor-specific glycan. In embodiments, the pharmaceutical composition is an injectable buffered solution comprising a concentration in the range of 1·105to 1·108per mL of the cell comprising a nucleotide sequence encoding the switchable CAR according to the invention and a concentration in the range of1 ng / ml to 500 mg / ml of the targeting module. In embodiments, the pharmaceutical compositioncomprises a concentration in the range of 50 µg / ml to 5 mg / ml of the targeting module.In embodiments, the pharmaceutical composition comprises the targeting module in a dosagequantity in the range of 25 µg / day to 100 mg / day. In embodiments, the pharmaceuticalcomposition comprises the targeting module in a dosage quantity in the range of 0.1 mg / day to 20 mg / day. In embodiments, the pharmaceutical composition is sterile. In embodiments, the pharmaceutical composition is sterilized by conventional well-known techniques including, but not limited to, sterile filtration. In embodiments, the pharmaceutical composition is used for administration to a subject. In embodiments, the pharmaceutical composition is lyophilized prior to storage or stored as solution at ambient temperature or below, including, but not limited to, frozen storage. In embodiments, the pharmaceutical composition is reconstituted and / or diluted in an infusion and stabilizer solution prior to administration to a subject. The solutions used for reconstitution or infusion / stabilization may contain any of the components mentioned for the pharmaceutical composition or similar components.Another aspect of the invention is a kit comprisinga) a nucleic acid, vector and / or cell comprising a nucleotide sequence encoding the switchableCAR according to the invention, andb) a targeting module comprising at least one target cell-binding domain capable of binding atarget antigen and a tag or tag-binding domain or at least one nucleic acid, vector or cellencoding a targeting module, wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimeric antigen receptor or the tag of the targeting module binds to the tag-binding domain of the switchable chimeric antigen receptor. In embodiments, the targeting module is isolated. As used herein, the term “isolated” meansaltered or removed from the natural state. In embodiments, the targeting module is expressed asa recombinant protein. In further embodiments, the targeting module is chemically synthesized. In embodiments, the targeting module is in monomeric, dimeric or polymeric form, preferably in monomeric form. As used herein, the term “target cell-binding domain” refers to a peptide, protein, or low molecular weight organic ligand, which specifically binds a protein or protein complex (antigen) on thesurface of a target cell, in particular a cancer cell, T cell, infected cell, pathogens or parasites.In embodiments, the at least one target cell-binding domain of the targeting module is an antibody,antigen-binding fragment, a protein, a peptide or a low molecular weight organic ligand that bindsto a surface antigen selected from the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10,CD15, CD19, CD20, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD79a, CD79b, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, a cytokine receptor, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family,epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesionmolecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle- stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folatebinding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, amember of the epithelia glycoprotein family, a disialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan.In embodiments, the at least one target cell-binding domain of the targeting module is an antibody,antigen-binding fragment, a protein, a peptide or a low molecular weight organic ligand that bindsto a surface antigen selected from the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10,CD15, CD19, CD20, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD79a, CD79b, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, a cytokine receptor, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle- stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folatebinding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, amember of the epithelia glycoprotein family, a disialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan. The term “target cell-binding domain” also comprises soluble T cell receptors, which are composed of the alpha and beta or the gamma and delta chains of a T cell receptor (TCR), fragments or mutants thereof. Such TCR-derived binding moieties recognize and bind to peptides presented by human leukocyte antigen class (HLA) I and II protein complexes. Examples are, but are not limited to, TCRs specific for peptides derived from proteins like EGFR family, survivin, sry- like high motility group box (SOX) protein family, melanoma-associated antigens (e.g., autoimmunogenic cancer / testis antigen NY-ESO-1, members of the melanoma antigen family A MAGEA, the preferentially expressed antigen in melanoma PRAME), and leukemia-associated antigens (e.g. Wilms tumor gene 1 WT1). In further embodiments, the target cell-binding domain is a soluble T cell receptor consisting of the alpha and beta or the gamma and delta chain of a TCR. In embodiments, the at least one target cell-binding domain is an antibody, antibody fragment, a protein, a peptide or a low molecular weight organic ligand that binds to CD19, CD20, CD123, IL13Rα2, HER-2, PD-L1 and / or PD-L2.In embodiments, the target cell-binding domain of the targeting module is an antibody or antigen-binding fragment. In embodiments, the target cell-binding domain of the targeting module is an antigen-bindingfragment. In embodiments, the target cell-binding domain is selected from single-chain variablefragments (scFv), single-chain antibodies, Fc fragment, F(ab')2 fragments, Fab fragments, and fragments produced by a Fab expression library or single-domain antibodies (nanobodies).In embodiments, the at least one target cell-binding domain is an antibody fragment that binds toCD19, CD20, CD123, IL13Rα2, HER-2, PD-L1 and / or PD-L2.In embodiments, the variable region(s) of the at least one target cell-binding domain comprises ahumanized amino acid sequence. In embodiments, the different domains of the targeting module are linked with each other by a linker. The linker comprises a short sequence of preferably 10 to 20 amino acid residues. In embodiments, the targeting module comprises a flexible peptide sequence that is selected such that the domains have a three-dimensional folding that allows them to exhibit the specificity for effector cell and target cell binding. Preferred linkers are glycine-serine linkers with the structure (GxSy) with x and y selected from 1 to 10, preferably 1 to 5. Mostly preferred are 1 to 10 repeats of the sequence G4S1(SEQ ID No. 20). Moreover, linkers are preferred that are constituted of a peptide sequence that can increasethe protease resistance of the antibody derivatives. As used herein, the term “derivative” refersto a molecule (linker) having a high degree of structural identity to the molecule, preferably the same scaffold, wherein at least one atom, group of atoms, functional group or substructure is replaced with another atom, group of atoms functional group or substructure, e.g., a hydroxygroup. Advantageously, the derivative is capable of performing one or more activities of thenamed molecule.In embodiments, the linker is SEQ ID No. 21 or SEQ ID No.22.In embodiments, the targeting module comprises a further domain selected from the group comprising co-stimulatory ligands, radionuclides, cell death-inducing chemical compounds and half-life increasing domains, preferably IgG1 Fc, IgG2 Fc, IgG3 Fc, IgG4 Fc, HSA, FcRn-binding peptides or mutants thereof. As used herein, the term “mutants” refers to proteins having at least 90 % sequence identity to the half-life increasing domain, preferably at least 95 % sequence identity. Advantageously, the mutant is capable of having one or more activities of the named peptides or proteins; in particular, the mutant increases the half-life like the half-life increasing domain. In preferred embodiments, the targeting module comprises a further domain selected from the group comprising co-stimulatory ligands, radionuclides, cell death-inducing chemical compoundsand half-life increasing domains, preferably IgG1 Fc, IgG2 Fc, IgG3 Fc, IgG4 Fc, HSA or FcRn-binding peptides.In embodiments, the tag-binding domain of the targeting module comprises at least one half-lifeincreasing domain. In embodiments, the tag-binding domain comprises at least one half-lifeincreasing domain selected from an amino acid sequence according to SEQ ID No. 143 or SEQID No.144.In embodiments, the tag-binding domain of the targeting module comprises at least one leaderpeptide. In embodiments, the tag-binding domain comprises at least one leader peptide selectedfrom an amino acid sequence according to SEQ ID No.145 or SEQ ID No.146.In embodiments, the length of the targeting module is in the range of 20 to 1600 amino acids,preferably 600 to 1600 amino acids. In embodiments, the targeting module comprises two or three chains, wherein the length of the chains is independently from each other in the range of 200 to 550 amino acids. In embodiments, the at least one target cell-binding domain is an antibody, antibody fragment, a protein, a peptide or a low molecular weight organic ligand that binds to CD19 and / or CD20. In embodiments, the targeting module comprisesi) at least one CD19-binding domain comprising one of the sequences selected from SEQ IDNo.180 to SEQ ID No.182 or a sequence identity of at least 95 % with one of the sequencesselected from SEQ ID No.180 to SEQ ID No. 182,ii) at least one CD20-binding domain comprising SEQ ID No. 183 or one of the sequencesselected from SEQ ID No.184 to SEQ ID No.186 or with a sequence identity of at least 95 %with one of the sequences selected from SEQ ID No. 184 to SEQ ID No. 186, andiii) a tag-binding domain or a tag.Advantageously, the trispecific targeting module targets both CD19 and CD20 simultaneously. In embodiments, the targeting module comprises at least three chains comprising sequencesfrom the group comprising SEQ ID No. 147 to SEQ ID No.179.In embodiments, the targeting module comprises at least three chains comprising -one amino acid sequence selected from the group comprising SEQ ID No. 142, SEQID No.149, SEQ ID No.150, SEQ ID No.175, SEQ ID No.176, SEQ ID No.177, SEQ ID No.178, and SEQ ID No.179, and -one amino acid sequence selected from the group comprising SEQ ID No. 147 andSEQ ID No. 148, and- one amino acid sequence selected from the group comprising SEQ ID No. 151, SEQID No.152, SEQ ID No.153, SEQ ID No.154, SEQ ID No.155, SEQ ID No.156, SEQID No.157, SEQ ID No.158, SEQ ID No.159, SEQ ID No.160, SEQ ID No.161, SEQID No.162, SEQ ID No.163, SEQ ID No.164, SEQ ID No.165, SEQ ID No.166, SEQID No.167, SEQ ID No.168, SEQ ID No.169, SEQ ID No.170, SEQ ID No.171, SEQID No.172, SEQ ID No.173, and SEQ ID No.174.In embodiments, the targeting module comprises -SEQ ID No. 149, SEQ ID No.147 and SEQ ID No. 151, or- SEQ ID No. 150, SEQ ID No. 148 and SEQ ID No. 152, or- SEQ ID No. 149, SEQ ID No. 147 and SEQ ID No. 153, or- SEQ ID No. 150, SEQ ID No. 148 and SEQ ID No. 154, or- SEQ ID No. 149, SEQ ID No. 147 and SEQ ID No. 155, or- SEQ ID No. 150, SEQ ID No. 148 and SEQ ID No. 156, or- SEQ ID No. 149, SEQ ID No. 147 and SEQ ID No. 157, or- SEQ ID No. 150, SEQ ID No. 148 and SEQ ID No. 158, or- SEQ ID No. 149, SEQ ID No. 147 and SEQ ID No. 159, or- SEQ ID No. 150, SEQ ID No. 148 and SEQ ID No. 160, or- SEQ ID No. 149, SEQ ID No. 147 and SEQ ID No. 161, or- SEQ ID No. 150, SEQ ID No. 148 and SEQ ID No. 162, or- SEQ ID No. 142, SEQ ID No. 147 and SEQ ID No. 163, or- SEQ ID No. 179, SEQ ID No. 148 and SEQ ID No. 164, or- SEQ ID No. 142, SEQ ID No. 147 and SEQ ID No. 165, or- SEQ ID No. 179, SEQ ID No. 148 and SEQ ID No. 166, or- SEQ ID No. 142, SEQ ID No. 147 and SEQ ID No. 167, or- SEQ ID No. 179, SEQ ID No. 148 and SEQ ID No. 168, or- SEQ ID No. 142, SEQ ID No. 147 and SEQ ID No. 169, or- SEQ ID No. 179, SEQ ID No. 148 and SEQ ID No. 170, or- SEQ ID No. 142, SEQ ID No. 147 and SEQ ID No. 171, or- SEQ ID No. 179, SEQ ID No. 148 and SEQ ID No. 172, or- SEQ ID No. 142, SEQ ID No. 147 and SEQ ID No. 173, or- SEQ ID No. 179, SEQ ID No. 148 and SEQ ID No. 174, or- SEQ ID No. 175, SEQ ID No. 147 and SEQ ID No. 157, or- SEQ ID No. 176, SEQ ID No. 148 and SEQ ID No. 158, or- SEQ ID No. 177, SEQ ID No. 147 and SEQ ID No. 157, or- SEQ ID No. 178, SEQ ID No. 148 and SEQ ID No. 158, or- SEQ ID No. 175, SEQ ID No. 147 and SEQ ID No. 159, or- SEQ ID No. 176, SEQ ID No. 148 and SEQ ID No. 160, or- SEQ ID No. 177, SEQ ID No. 147 and SEQ ID No. 159, or- SEQ ID No. 178, SEQ ID No. 148 and SEQ ID No. 160, or- SEQ ID No. 175, SEQ ID No. 147 and SEQ ID No. 161, or- SEQ ID No. 176, SEQ ID No. 148 and SEQ ID No. 162, or- SEQ ID No. 177, SEQ ID No. 147 and SEQ ID No. 161, or- SEQ ID No. 178, SEQ ID No. 148 and SEQ ID No. 162, or- SEQ ID No. 175, SEQ ID No. 147 and SEQ ID No. 151, or- SEQ ID No. 176, SEQ ID No. 148 and SEQ ID No. 152, or- SEQ ID No. 177, SEQ ID No. 147 and SEQ ID No. 151, or- SEQ ID No. 178, SEQ ID No. 148 and SEQ ID No. 152, or- SEQ ID No. 175, SEQ ID No. 147 and SEQ ID No. 153, or- SEQ ID No. 176, SEQ ID No. 148 and SEQ ID No. 154, or- SEQ ID No. 177, SEQ ID No. 147 and SEQ ID No. 153, or- SEQ ID No. 178, SEQ ID No. 148 and SEQ ID No. 154, or- SEQ ID No. 175, SEQ ID No. 147 and SEQ ID No. 155, or- SEQ ID No. 176, SEQ ID No. 148 and SEQ ID No. 156, or- SEQ ID No. 177, SEQ ID No. 147 and SEQ ID No. 155, or- SEQ ID No. 178, SEQ ID No. 148 and SEQ ID No. 156.In embodiments, the at least one target cell-binding domain is an antibody, antibody fragment, a protein, a peptide or a low molecular weight organic ligand that binds to CD123.In embodiments, the targeting module according to the invention comprisesi) at least one CD123-binding domain comprising a sequence with at least 95 % identity,preferably 99 % identity, with the sequence according to SEQ ID No.187 and SEQ ID No.188, andii) a tag-binding domain or a tag.In embodiments, the targeting module according to the invention comprisesi) at least one CD123-binding domain comprising a sequence with at least 95 % identity,preferably 99 % identity, with the sequence according to SEQ ID No. 187 and SEQ ID No. 188,andii) a tag-binding domain binding a human La epitope E5B9 comprising a VL-linker-VHstructure, wherein the VL region of the tag-binding domain comprises a sequence with at least 95% identity, preferably 99 % identity, with the sequence according to SEQ ID No.14 and / or the VHregion of the tag-binding domain comprises a sequence with at least 95 % identity, preferably 99 % identity, with the sequence according to SEQ ID No.15.In embodiments, the CD123-binding domain comprises the sequences SEQ ID No.187 and SEQID No.188. In preferred embodiments, the CD123-binding domain comprises a sequence according to SEQ ID No.189.In embodiments, the targeting module comprises one of the sequences according to SEQ ID No.190 to SEQ ID No. 197.In alternative embodiments, the kit comprises a nucleic acid, vector or cell encoding the targeting module. The nucleic acid, vector and / or cell are isolated.According to the invention, the nucleic acid, vector and / or cell comprising a nucleotide sequenceencoding the switchable CAR according to the invention are isolated.In embodiments, the nucleic acid is a cDNA. As used herein, the term “cDNA” (complementary DNA) refers to double-stranded DNA synthesized from a single-stranded RNA, e.g. mRNA, in a reaction catalyzed by the enzyme reverse transcriptase. In embodiments, cDNA is of synthetic origin. In further embodiments, cDNA is derived from mRNA, therefore containing only exons but no introns, as opposed to genomic DNA. The vector is preferably a plasmid, an artificial chromosome, linearized DNA or RNA, a virus particle or another vector that contains an expression cassette that is incorporated stably into the genome of a host cell or host organism. In embodiments, the cell is selected from immune cells, preferably with cytolytic, phagocytic or immunosuppressive activity, such as T cells, Natural Killer (NK) cells and macrophages. In preferred embodiments, the cell is selected from T cells, including alpha / beta and gamma / delta T cells or subpopulations of T cells like stem-cell memory T cells or central memory T cells, cytotoxic T cells or NK cells. In embodiments, the cell comprising a nucleotide sequence encoding a reversible chimeric antigen receptor and / or the targeting module are in the form of a pharmaceutical composition.In embodiments, the kit further comprises at least one further targeting module or at least onefurther nucleic acid, vector or cell encoding a further targeting module,wherein the at least one further targeting module comprises at least one target cell-binding domain and a tag-binding domain or a tag, wherein the at least one target cell-binding domain of the further targeting module is an antibody, antigen-binding fragment, a protein, a peptide or a low molecular weight organic ligand that bindsto a surface antigen selected from the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10,CD15, CD19, CD20, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD79a, CD79b, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle- stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a disialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan, wherein the targeting module and the at least one further targeting module comprise different target cell-binding domains, and identical tag-binding domains or tags.In embodiments, the at least one target cell-binding domain of the further targeting module is anantibody, antigen-binding fragment, a protein, a peptide or a low molecular weight organic ligandthat binds to a surface antigen selected from the group comprising CD2, CD3, CD4, CD5, CD7,CD8, CD10, CD15, CD19, CD20, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD79a, CD79b, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle- stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a disialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan.In embodiments, the kit comprises one to three targeting modules.In embodiments, the kit comprises one to three targeting modules targeting CD33, CD123 andCD371, or CD19, CD20 and CD22, or CD19, CD38 and CD269.In embodiments, the kit comprises one to five targeting modules targeting CD38, CD269,GPRC5D, CD79a and CD79b.In embodiments, the switchable CAR, the cell, the pharmaceutical composition or the kit is usedas a medicament.In embodiments, the switchable CAR according to the invention, the nucleic acid, vector or cellaccording to the invention, the pharmaceutical composition according to the invention or the kitaccording to the invention is used for preparing a medication for therapeutic and / or diagnosticuse in case of cancer, an infection or an autoimmune disease. The term “autoimmune disorder” refers to an abnormal immune response of the body against substances and tissues normally present in the body (autoimmunity).In embodiments, the switchable CAR, the cell, the pharmaceutical composition or the kit is usedin the treatment of cancer, infectious disease or autoimmune disease.In embodiments, the switchable CAR according to the invention, the cell, the pharmaceuticalcomposition or the kit is used in the treatment of cancer. In embodiments, the switchable CARaccording to the invention is used in the treatment of tumors of the hematopoietic and lymphoidtissues. In embodiments, the switchable CAR according to the invention is used in the treatmentof blood cancer. In embodiments, the switchable CAR according to the invention is used in thetreatment of b cell lymphomas.In embodiments, the cell according to the invention is administered in combination with a targetingmodule, wherein the tag of the switchable CAR binds to the tag-binding domain of the targeting module or the tag-binding domain of the switchable CAR binds to the tag of the targeting module. As used herein, the term “administered in combination” refers to a treatment, wherein the targeting module is administered prior to, simultaneously with and / or after the administration of the cellcomprising a nucleotide sequence encoding the switchable CAR.In embodiments, the switchable CAR according to the invention and a targeting module are usedin a method for treating cancer, infectious disease or autoimmune disease in a subject in needthereof. For therapeutic applications, a sterile pharmaceutical composition according to the invention or a sterile kit according to the invention, comprising a pharmacologically effective quantity of the cellcomprising a nucleotide sequence encoding a switchable CAR according to the invention and atargeting module, is administered to a subject in order to treat the aforementioned illnesses. In embodiments, the method for stimulating a CAR-mediated immune response in a mammal; preferably, the method for treatment of cancer, infectious or autoimmune disease, comprises the following steps: a) administering to a mammal an effective amount of a targeting module andb) administering to the mammal an effective amount of a cell comprising a nucleotidesequence encoding a switchable CAR according to the invention, wherein the tag of the switchable CAR binds to the tag-binding domain of the targeting module or the tag-binding domain of the switchable CAR binds to the tag of the targeting module, wherein the targeting module is administered to a mammal prior to, concurrent with or after the administration of the cell. In embodiments, the targeting module is administered one hour to 2 days, preferably 4 to24 hours, prior to the administration of the cell comprising a nucleotide sequence encoding theswitchable CAR. Advantageously, the administration of the targeting module prior to theadministration of the cell comprising the nucleotide sequence encoding the switchable CAR stimulates the switchable CAR and increases the expansion of the switchable CAR carrying effector cells and their accumulation at the target site. In embodiments, the targeting module is administered simultaneously with the cell comprising the nucleotide sequence encoding a switchable CAR.In embodiments, the targeting module is administered until, preferably in the range of 3 days to30 days, after the administration of the cell comprising the nucleotide sequence encoding theswitchable CAR. In embodiments, additional such doses of the targeting module may be administered following resting periods to reactivate the switchable CAR-carrying effector cells. In embodiments, a dosage of the targeting module is continuously administered to a subjecthaving cancer, in particular hematological cancer, with a dosage quantity in the range of0.01 mg / day to 100 mg / day from day 0 of the treatment (beginning of the treatment) for a periodbetween 10 days and 180 days, preferably, between 10 days and 25 days, and at least one dosage of a clinically effective amount of the T cell comprising a nucleotide sequence encoding a switchable CAR is administered to the subject with a dosage quantity in the range of 1·108to 1·109cells once within day 0 to day 5 of the treatment. In embodiments, a first dosage of the targeting module is continuously administered to a subjecthaving cancer, in particular hematological cancer, with a dosage quantity in the range of0.01 mg / day to 100 mg / day from day 0 of the treatment (beginning of the treatment) for a periodbetween 10 days and 25 days, and at least one dosage of a clinically effective amount of the T cell comprising a nucleotide sequence encoding a switchable CAR is administered to the subject with a dosage quantity in the range of 1·108to 1·109cells once within day 0 to day 5 of the treatment, and wherein 7 days to 21 days after the administering of the first dosage of the targeting module at least one further dosage of the targeting module is continuously administered to the subject with a dosage quantity in the range of 0.01 mg / day to 100 mg / day for a period between 4 days and 25 days. In embodiments, targeting module is administered to a subject having cancer, in particularhematological cancer, from day 0 of the treatment (beginning of the treatment) for a periodbetween 7 days and 180 days, preferably between 7 days and 28 days.In embodiments, targeting module is administered by 1 to 7 injections or infusions per week oreach once a week to a subject having cancer, in particular hematological cancer. In embodiments, targeting module is administered with a dosage quantity in the range of0.01 mg / day to 100 mg / day.In embodiments, at least one dosage of a clinically effective amount of the T cell comprising anucleotide sequence encoding a switchable CAR is administered to the subject with a dosage quantity in the range of 1·108to 1·109cells once within day 0 to day 5 of the treatment.In embodiments, targeting module is administered by 1 to 7 bolus injections or short infusions perweek or each once a week to a subject having cancer.As used herein, the term “bolus” refers to the administration of a discrete amount of targetingmodule within a specific time, in particular 1 to 30 minutes.The invention is not limited to the specifically described combinations of features but may also bedefined by any other combination of specific features of all the individual features disclosed as a whole, provided that the individual features are not mutually exclusive, or a specific combination of individual features is not explicitly excluded. In the following, the invention will be explained in more detail by means of an embodiment example. The embodiment example is intended to describe the invention without limiting it.Implementations of the invention will be described, by way of example only, with reference toaccompanying drawings in which:Fig. 1A, 1B and 1C show switchable CAR (RevCAR) surface detection on transduced primaryhuman T cells by flow cytometry. Transduced primary human T cells were characterized after manufacturing by staining with mouse anti-human La / SSB mab (clone 5B9) conjugated to AF647. For each CAR construct one representative product is depicted. Isolated T cells were transduced with lentivirus encoding for the respective switchable CAR construct and TRAC was knocked out using CRISPR / Cas9. Isotype control is shown in light grey. Fluorescence for mab 5B9 AF647 is shown in dark grey.Fig. 2 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20 in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 valuesrepresent the sensitivity of switchable CAR T products to the targeting module used.Fig. 3 shows in vitro potency assay results for switchable CAR (allo-RevCAR) T cells againstNalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20) or anti-CD123 targeting module (R-TM123), respectively. Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry,dead cells are discriminated with propidium iodide and specific lysis is calculated (relative tocontrol without targeting module). Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell productsto the targeting module used.Fig. 4 shows results of a serial killing assay results of allogeneic switchable CAR (allo-RevCAR)T cells against Nalm6-CD20 cells. Co-culture assay of allo-RevCAR T cell products with targetcell line Nalm6-CD20 in presence of 1 nM anti-CD19 / CD20 targeting module (R-TM19 / 20). Targetcells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidium iodide andspecific lysis is calculated (relative to control without targeting module). Mean of three replicatesis plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the capacity of RevCAR T products to kill multiple target cells.Fig. 5 shows results of a long-term restimulation assay results of allogeneic switchable CAR(allo-RevCAR) T cells against Nalm6 cells. Co-culture assay of allo-RevCAR T cell products withtarget cell line Nalm6 (mcherry positive) in presence of 0.2 nM anti-CD19 / CD20 targeting module(R-TM19 / 20). Every 3 to 4 days 2·104 fresh target cells are added. Mcherry positive target cellcounts are determined by fluorescence microscopy (Incucyte S3) twice a day over three weeks.Mean and standard deviation of four replicates is plotted.Fig. 6 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20 in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without R-TM). Mean of three replicatesis plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent thesensitivity of RevCAR T cell products to the targeting module used.Fig. 7 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6- CD20 in presence of varying concentrations of anti-CD123 targeting module (R-TM123). Targetcells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cellcount is determined by flow cytometry, dead cells are discriminated with propidium iodide andspecific lysis is calculated (relative to control without targeting module). Mean of three replicatesis plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent thesensitivity of RevCAR T cell products to the targeting module used.Fig. 8 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20 in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20).Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viabletarget cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 valuesrepresent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 9 shows serial killing assay results of allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20 cells. Co-culture assay of allo-RevCAR T cell products with target cell lineNalm6-CD20 in presence of 1 nM anti-CD19 / CD20 targeting module (R-TM19 / 20). Target cellswere stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidium iodide and specificlysis is calculated (relative to control without targeting module). Mean of three replicates is plottedand fitted with a 4-parameter logistic regression. Calculated EC50 values represent the capacity of RevCAR T cells products to kill multiple target cells.Fig. 10 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) Tagainst MV4-11. Co-culture assay of allo-RevCAR T cell products with target cell line MV4-11 inpresence of varying concentrations of anti-CD123 targeting module (R-TM123). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidium iodide and specificlysis is calculated (relative to control without targeting module). Mean of three replicates is plottedand fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 11 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Oci-AML-CD19 and Oci-AML-CD20. Co-culture assay of allo-RevCAR T cell productswith target cell line Oci-AML-CD19 and Oci-AML-CD20 in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry,dead cells are discriminated with propidium iodide and specific lysis is calculated (relative to control without targeting module). Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 12 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Raji lymphoma cells. Co-culture assay of allo-RevCAR T cell products with target cell lineRaji in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20).Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viabletarget cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 13 shows in Long-term restimulation assay results of allogeneic switchable CAR (allo-RevCAR) T cells against Nalm6 and Nalm6-CD20 cells. Co-culture assay of allo-RevCAR T cellproducts with target cell line Nalm6 (mcherry positive) and Nalm6-CD20 (mcherry positive) inpresence of 0.2 nM anti-CD19 / CD20 targeting module (R-TM19 / 20). Every 3 to 4 days 2·104 freshtarget cells are added. Mcherry positive target cell counts are determined by fluorescencemicroscopy (Incucyte S3) twice a day over three weeks. Mean and standard deviation of threereplicates is plotted.Fig. 14 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20 in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20).Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viabletarget cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 15 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Raji lymphoma cells. Co-culture assay of allo-RevCAR T cell products with target cell lineRaji in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 16 shows in vitro potency assay for allogeneic switchable CAR (allo-RevCAR) T cells againstMV4-11. Co-culture assay of allo-RevCAR T cell products with target cell line MV4-11 in presence of varying concentrations of anti-CD123 targeting module (R-TM123). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidium iodide and specific lysis iscalculated (relative to control without targeting module). Mean of three replicates is plotted andfitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity ofRevCAR T cell products to the targeting module used.Fig. 17 shows serial killing assay of allogeneic switchable CAR (allo-RevCAR) T cells againstRaji lymphoma cells. Co-culture assay of allo-RevCAR T cell products with target cell line Raji inpresence of 0.1 nM anti-CD19 / CD20 targeting module (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidium iodide and specific lysis iscalculated (relative to control without targeting module). Mean of three replicates is plotted andfitted with a 4-parameter logistic regression. Calculated EC50 values represent the capacity of RevCAR T cell products to kill multiple target cells.Fig.18 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst MV4-11. Co-culture assay of allo-RevCAR T cell products with target cell line MV4-11 inpresence of varying concentrations of anti-CD123 targeting module (R-TM123). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidium iodide and specificlysis is calculated (relative to control without targeting module). Mean of three replicates is plottedand fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivityof RevCAR T cell products to the targeting module used.Fig.19 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20 in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 valuesrepresent the sensitivity of RevCAR T cell products to the targeting module used.Fig.20 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Raji lymphoma cells. Co-culture assay of allo-RevCAR T cell products with target cell lineRaji in presence of varying concentrations of anti-CD19 / CD20 targeting module (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 valuesrepresent the sensitivity of RevCAR T cell products to the targeting module used.Fig.21 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Raji CD19Ko lymphoma cells. Co-culture assay of allo-RevCAR T cell products with targetcell line Raji CD19Ko (negative for CD19) in presence of varying concentrations of anti- CD19 / CD20 targeting module (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry,dead cells are discriminated with propidium iodide and specific lysis is calculated (relative tocontrol without targeting module). Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 22A and 22B show in vivo efficacy results of allogeneic switchable CAR (allo-RevCAR) Tcells against a B-ALL Nalm6-CD20 tumor. Evaluation of tumor control and tumor regressioncapacity of allo-RevCAR T cells in Nalm6-CD20-Fluc xenograft mice. Mice received 5·105Nalm6- CD20-Fluc cells 7 days prior to transplantation of 15·106allo-RevCART cells (total). Therapy wasinitiated one day before mice received T cells with a bolus injection of 0.2 µg / g or 0.02 µg / g anti-CD19 / CD20 targeting module (R-TM19 / 20) intravenously, respectively. Mice which received allo-RevCAR T cells and targeting module were rechallenged with tumor cells at day 17 (1·106 cells),day 28 (2·106cells) and day 37 (5·106cells). Normalized radiance for bioluminescent imaging(BLI) is ranging from 5·104 to 1·107 [p / sec / cm²sr].Fig.23 shows in vivo efficacy results of allogeneic switchable CAR (allo-RevCAR) T cells againsthigh burden B-ALL Nalm6-CD20 tumor in late-stage mice. Evaluation of tumor control and tumorregression capacity of allogeneic RC62T cells and RC63T cells in late-stage high tumor burdenNalm6-CD20-Fluc xenograft model. Mice received 5·105Nalm6-CD20-Fluc cells 7 days prior totransplantation of 15·106 allo-RevCAR T cells (total). Therapy was initiated at day 21 after tumorapplication with intravenous bolus injections of anti-CD19 / CD20 targeting module (R-TM19 / 20) indoses of 1.0 µg / g (day 21, day 28 and day 35) and 0.2 µg / g (day 44). Normalized radiance forBLI is ranging from 5·104to 1·107[p / sec / cm²sr].Fig. 24 shows cytokine release of human allogeneic switchable CAR (allo-RevCAR) T cells inmice. Quantification of human cytokines (GM-CSF, IFN-γ, IL-2, TNF-α and Perforin) fromperipheral blood of Nalm6-CD20 xenograft mice three days after allo-RevCAR T transplantation and initiation of therapy with anti-CD19 / CD20 targeting module (R-TM19 / 20). (MACSPlexCytotoxic T / NK Cell kit from Miltenyi, Germany).Fig.25 shows tumor and T cell chimerism determined at individual end points via flow cytometry.Mice received 5·105Nalm6-CD20-Fluc cells 7 days prior to transplantation of 15·106allogeneic switchable CAR (allo-RevCAR) T cells (total). Therapy was initiated one day before mice receivedallo-RevCAR T cells with a bolus injection of 0.2 µg / g or 0.02 µg / g anti-CD19 / CD20 targetingmodule (R-TM19 / 20) intravenously, respectively. Mice which received allo-RevCAR T andtargeting module were rechallenged with tumor cells at day 17 (1·106 cells), day 28 (2·106 cells)and day 37 (5·106cells).Fig. 26 shows tumor and T cell chimerism determined at individual end points via flow cytometryin high tumor burden mice. Mice received 5·105 Nalm6-CD20-Fluc cells 7 days prior totransplantation of 15·106allogeneic switchable CAR (allo-RevCAR) T cells (total). Therapy wasinitiated at day 21 after tumor application with intravenous bolus injections of anti-CD19 / CD20targeting module (R-TM19 / 20) in doses of 1.0 µg / g (day 21, day 28 and day 35) and 0.2 µg / g (day44).Fig.27 shows in vivo efficacy of allogeneic switchable CAR (allo-RevCAR) T cells against an AMLMV4-11 tumor. Evaluation of tumor control and tumor regression capacity of allo-RevCAR T cellsagainst MV4-11 Fluc in NSG mice. NSG mice received 5·105 MV4-11-Fluc cells intravenously 7days prior to transplantation of 15·106 allo-RevCAR T cells (total). Therapy was initiated parallelto allo-RevCAR T cell transplantation with 1 µg / g anti-CD123 targeting module (R-TM123)intraperitoneal twice a day, in cycle of five consecutive days and two days break in between. Micewhich received allo-RevCAR T cells and targeting module were rechallenged once with tumorcells at day 28 (1·106cells). Normalized radiance for BLI is ranging from 5·104to 1·107[p / sec / cm²sr].Fig. 28 shows in vivo efficacy of allogeneic switchable CAR (allo-RevCAR) T cells against anAML MV4-11 tumor in high tumor burden mice. Evaluation of tumor control and tumor regressioncapacity of allo-RevCAR T against MV4-11 Fluc high tumor burden in NSG mice. NSG micereceived 5·105 MV4-11-Fluc cells intravenous 7 days prior to transplantation of 15·106 allo-RevCAR T cells (total). Therapy was initiated at day 21 (for groups treated with allo-RevCAR Tcells according to the invention: RC62T and RC63T) and day 28 (from the group treated withRC30T cells as reference) with 1 µg / g anti-CD123 targeting module (R-TM123) intraperitonealtwice a day for 12 consecutive days. For groups treated with RC62T and RC63T cells two moretherapy cycles (five days each) with 1 µg / g targeting module intraperitoneal bolus twice a daywere applied, first started from day 35 and the second started at day 42. Normalized radiance for BLI is ranging from 5·104to 1·107[p / sec / cm²sr].Fig. 29 shows cytokine release of human allogeneic switchable CAR (allo-RevCAR) T cells inmice. Quantification of human cytokines (GM-CSF, IFN-γ, IL-2, IL-10, TNF-α and Perforin) fromperipheral blood of MV4-11 Fluc engrafted NSG mice two days after allo-RevCAR T celltransplantation and initiation of therapy with anti-CD123 targeting module (R-TM123). Cytokines IL-4, IL-6, IL-17A, IL-21, MCP-1 und Granzyme B were below the detection limit (MACSPlexCytotoxic T / NK Cell kit from Miltenyi, Germany).Fig.30A to 30F show in vivo efficacy of allogeneic switchable CAR (allo-RevCAR) T cells againstRaji lymphoma. Evaluation of tumor control and tumor regression capacity of allo-RevCAR T cellsagainst Raji-Fluc in NSG mice. NSG mice received 5·105 Raji-Fluc cells intravenously 7 days priorto transplantation of 15·106 or 5·106 allo-RevCAR T cells (total). Therapy was initiated 3 daysprior to T cell transplantation with 0.2 µg / g or 0.02 µg / g anti-CD19 / CD20 targeting module (R-TM19 / 20) intravenously and biweekly repeated. Mice which received allo-RevCAR T cells andtargeting module were rechallenged once with 2·106 Raji-Fluc tumor cells at day 15 and 2·106Raji CD19KO tumor cells at days 22. For groups of allo-RevCAR T cells according to theinvention: allo-RC62T and allo-RC63T, which initially received no targeting module, therapystarted at day 17 with 0.02 µg / g targeting module intravenously and was repeated weekly, hereno tumor rechallenge was applied.Fig. 31 shows in vivo efficacy of allogeneic switchable CAR (allo-RevCAR) T cells against B-celllymphoma. Evaluation of tumor control and tumor regression capacity of allo-RevCAR T cellsagainst Raji-Fluc in NSG mice. NSG mice were engrafted with 5·105Raji-Fluc cells intravenously11 days prior to receiving 3·106 CAR T cells intravenously. One day before allo-RevCAR T cellsgot transplanted, therapy with 0.05 µg / g anti-CD19 / CD20 targeting module (R-TM19 / 20)intravenously started and was repeated weekly. All targeting module treated animals gotrechallenged with 2·106CD19neg Raji cells at day 39. Normalized radiance for BLI is ranging from 5·104to 1·107[p / sec / cm² / sr]. Switchable CAR T cells according to the invention The immune cells can be genetically engineered to express switchable CARs. For the genetical engineering to express switchable CARs, a polynucleotide vector encoding the switchable CAR and all elements to ensure its expression in the genetically engineered immune cell is transferredinto the immune cell. In particular, the switchable CAR comprises a human signal peptide, tag,ECD (extracellular domain), TMD (transmembrane domain), ICD (intracellular domain).The transfer of the vector can be performed by electroporation or transfection of nucleic acids orthe help of viral vector systems like adeno-, adeno-associated, retro-, foamy- or lentiviral viralgene transfer. The lentiviral gene transfer is applied for stable expression of switchable CARs in immune cells by first constructing a lentiviral vector encoding for a selected switchable CAR. The lentiviral vector is pLVX-EF1alpha UniCAR 28 / ζ (Clontech, Takara Bio Group), in which the lentiviral parts of the vector are derived from the human immunodeficiency virus (HIV) and the MSC / IRES / ZxGreenI portion was replaced by the switchable CAR construct. The lentiviral particles are produced by transient transfection of human embryonal kidney (HEK) 293T (ACC 635) cells with the switchable CAR encoding lentiviral vector plasmid and co- transfection with a group specific antigen (gag) and Polymerase (pol) encoding plasmid (psPAX2) plus a plasmid encoding for an envelope (pMD2.G). After transfection, the packaging plasmid expresses Gag and Pol protein of HIV-1. The plasmid MD2.G encodes the glycoprotein of the vesicular stomatitis virus (VSV-G). VSV-G protein is used to lentiviral vectors to transduce a broad range of mammalian cells. Various envelopes from different virus species can be utilized for this purpose. Lentiviral vectors can successfully pseudotype with the envelope glycoproteins (Env) ofamphotropic murine leukemia virus (MLV) or the G protein of vesicular stomatitis virus (VSV-G),a modified envelope of the prototypic foamy virus (PFV) or chimeric envelope glycoprotein variants derived from gibbon ape leukemia virus (GaLV) and MLV.Supernatants from transfected HEK293T cells are harvested 24 h to 96 h after transfection andvirus particles are concentrated from the supernatant by ultracentrifugation or other methods. Forlentiviral transduction of immune cells, peripheral blood mononuclear cells (PBMC) or isolated Tcells are activated with mab specific for the CD3 complex, e.g., clone OKT3 or UCHT1, eithergiven in solution or coated to plastic cell culture dishes or magnetic beads or a biodegradable polymer matrix. Activation of PBMC or isolated T cells is further enhanced by stimulating costimulatory pathways with mabs or ligands specific for CD27, CD28, CD134 or CD137 either alone or in combinations coated to plastic cell culture dishes or magnetic beads or a biodegradable polymer matrix and the supply with exogenous recombinant cytokines like interleukin (IL)-2, IL-7, IL-12, IL-15 and IL-21. Concentrated or non-concentrated virus particlesare added to PBMC or T cell cultures 24 h to 96 h after initial administration of activating CD3specific antibodies and / or antibodies specific for costimulatory receptors CD27, CD28, CD134 or CD137 and / or recombinant cytokines as single or multiple doses. T cell electroporation, transduction and expansion may be performed in open cell culture systems by manual handling or in closed partially or fully automated systems. Stable transduction of T cells may be determined by flow cytometry after staining with tag- containing molecules for surface expression of switchable CARs or mabs directed against the tag or a fourth domain of switchable CARs from day 3 onwards after the final administration of virussupernatant. Switchable CAR transduced T cells can be propagated in vitro by culturing themunder the supply of recombinant cytokines and activating anti-CD3 mabs.In case the switchable CAR harbors a tag or the optional fourth domain, a peptide sequenceforming a linear epitope for a mab, immune cells genetically modified to express switchable CARscan be specifically propagated in vitro by coating a mab or antibody fragments thereof binding tothe fourth domain to the surface of culture dishes or to beads of any kind or a biodegradable polymer matrix, which are added to the cell culture at a defined ratio. The binding of surface-coated mabs to the switchable CAR peptide domain induces cross-linkage of cell-surfaceexpressed switchable CARs and formation of an immune synapse, which leads to the activation of signal pathways specifically triggered by the signal domain of the switchable CAR. Depending on the signal pathways induced, this may lead to enhance proliferation and sustained resistance against activation-induced cell death of the switchable CAR-carrying immune cells and thereforeenrichment of switchable CAR genetically modified immune cells in a mixed population.The tag or the optional fourth domain, a peptide sequence forming a linear epitope for a mab, can be further utilized to enrich and purify switchable CAR-expressing immune cells from mixed populations. Enrichment and purification are performed with the help of a mab or antibody fragment thereof binding to the fourth domain to either mark switchable CAR-expressing cells forcell sorting or to transiently link the switchable CAR expressing immune cell to small particles,which can be utilized for cell isolation. In one aspect, switchable CAR-engrafted immune cells are incubated with the mab recognizing the fourth domain. Next, magnetic beads are added, whichare conjugated with antibodies or fragments thereof directed against the species- and isotype-specific heavy and light chains of the mab binding to the optional fourth domain. Thus, switchableCAR-expressing immune cells and magnetic beads are linked and are trapped and separated from other immune cells in a magnetic field.Tab.1 Switchable CARs as used in examplesSwitchable CAR code SEQ ID No. of switchable CAR SEQ ID No. of switchable CARincluding a leader peptide RC30 (reference) - 52RC48 53 83RC49 54 84RC50 55 85RC51 56 86RC52 57 87RC53 58 88RC54 59 89RC55 60 90RC56 61 91RC57 62 92RC58 63 93RC59 64 94RC60 65 95RC61 66 96RC62 67 97RC63 68 98RC64 69 99RC65 70 100RC66 71 101RC67 72 102RC68 73 103RC69 74 104RC70 75 105RC71 76 106RC72 77 107RC73 78 108RC74 79 109RC75 80 110RC76 81 111RC77 82 112Design of targeting modulesThe targeting module R-TM123 is a soluble, recombinant fusion protein comprising two antibody-derived binding domains. One selectively binds to the target antigen CD123, the other recognizesa tag presented on the switchable CAR expressing cells (epitope E5B9 from the human Laprotein). Thus, R-TM123 functions as a bridging module between switchable CAR-T cell and aCD123-expressing target cancer cell. The targeting module further comprises an 8x-histidine tag for detection and purification purposes at the C-terminus.The targeting module R-TM19 / 20 is a soluble, recombinant fusion protein comprising threeantibody-derived binding domains. One selectively binds to the target antigen CD19, the secondselectively binds to the target antigen CD20, the third recognizes a tag presented on theswitchable CAR expressing cells (epitope E5B9 from the human La protein). Thus, R-TM19 / 20functions as a bridging module between switchable CAR-T cell and a target cancer cell expressingCD19 and / or CD20. The targeting module further comprises an Fc tag for half-life extension,detection, and purification purposes at the C-terminus of its two heavy chains. R-TM19 / 20comprises two antibody derived heavy chains and one light chain.Characterization of the switchable CART cells transduced to express various switchable CARs, in particular RevCARs, were analyzedfor CAR expression with a fluorochrome-labeled anti-tag antibody or GFP as a surrogate marker(Fig.1). The switchable CAR-T cells were functionally characterized in vitro (Fig.2 to 9, 11 to 15and 19 to 21) and in vivo in immunodeficient mice in conjunction with R-TM19 / 20 against CD19-and / or CD20-expressing cell lines (i.e. Nalm6, Nalm6-CD20, Raji, CD19 knockout Raji, OCI-AML3-CD19 or OCI-AML3-CD20) (Fig. 22 to26, 30 and 31. The switchable CAR-T cells werefurther functionally characterized in conjunction with anti-CD123 targeting module (R-TM123)against CD123-expressing acute myeloid leukemia cell line MV4-11 in vitro (Fig. 10, 16 and 18)and in vivo in immunodeficient mice (Fig.27-29).Target cells used in short-term in vitro assay were stained with efluor prior setup and used atindicated effector to target cell (e:t) ratios. Target cells were quantified by flow cytometry and lysiswas calculated normalizing the cell count of each sample to a control sample where only tumor cells were plated. Data were fitted with a four-parameter model with a variable slope for sigmoidalcurves. In in vitro cytotoxicity assays, efluor stained target cells and switchable CAR T cells wereco-cultured at various targeting module concentrations at fixed e:t ratio. The calculated EC50 valuecan be interpreted as a representative value for the targeting module potency against these tumorcells. In serial killing assays, efluor stained target cells and switchable CAR T cells were co-cultured at various e:t ratios and EC50 value is the e:t ratio at which half-maximal lysis occurs andrepresents the capacity of switchable CAR T cell products to kill multiple target cells.Long-term in vitro restimulation co-culture assays were carried out with mcherry positive targetcells which were re-added at indicated time points. Mcherry positive target cell counts weredetermined by fluorescence microscopy (Incucyte S3, Sartorius). In vivo studies were carried out in immunodeficient mice, which were transplanted with luciferase positive tumor cells and allogeneic switchable CAR T cells at indicated cell numbers at indicatedtimepoints. Tumor growth was followed by bioluminescence imaging.Switchable CAR T cell chimerism was monitored by flow cytometry. Cytokine secretion byswitchable CAR T cells was quantified using the MACSPlex Cytotoxic T / NK Cell kit (Miltenyi,Germany). 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Claims

Claims 1. A switchable chimeric antigen receptor comprisinga. a tag or tag-binding domain,b. an extracellular hinge and transmembrane domain comprising an extracellularhinge and a transmembrane domain of CD4, CD8α, CD28, ICOS (CD278), IgG1, IgG2, IgG4 or mutants and combinations thereof, wherein the extracellular hinge and transmembrane domain is in the range of 32to 159 amino acids, and c. an intracellular signaling domain that comprises at least two signal transductiondomains independently selected from the group comprising a cytoplasmic region of CD3, CD27, CD28, OX40 (CD134), 4-1BB (CD137), ICOS (CD278), DAP10, DAP12, PD-1, CTLA-4, IL-2 receptor, IL-7 receptor, IL-15 receptor or IL-21 receptor and mutants thereof.

2. The switchable chimeric antigen receptor according to claim 1, wherein the tag is a peptideepitope tag.

3. The switchable chimeric antigen receptor according to claim 2, wherein the peptide epitopetag is a myc-tag, a His-tag, a peptide sequence from yeast transcription factor GCN4, a leucine zipper sequence or a peptide sequence from a human protein.

4. The switchable chimeric antigen receptor according to claim 1, wherein the tag-bindingdomain is an antibody or antigen-binding fragment, a protein or a peptide binding to a myc- tag, a His-tag, a peptide sequence from yeast transcription factor GCN4, a leucine zippersequence or a peptide sequence from a human protein.

5. The switchable chimeric antigen receptor according to one of the claims 1 to 4, wherein theextracellular hinge and transmembrane domain comprises an extracellular hinge and atransmembrane domain of CD8α, CD28 or IgG4 and mutants thereof.

6. The switchable chimeric antigen receptor according to one of the claims 1 to 5, wherein theintracellular signaling domain comprises at least a cytoplasmic region of CD3ζ, 4-1BB, CD28 or mutants thereof.

7. The switchable chimeric antigen receptor according to one of the claims 1 to 6, wherein theswitchable chimeric antigen receptor is a reversible chimeric antigen receptor comprising a tag.

8. The switchable chimeric antigen receptor according to one of the claims 1 to 7 comprising asignal peptide selected from human CD8α, CSF2Rα, CD3ζ, IL-2, lysozyme C, a heavy chainof an antibody, a light chain of an antibody or a part of a light chain of an antibody.

9. The switchable chimeric antigen receptor according to one of the claims 1 to 8 comprising asequence according to SEQ ID No.53 to SEQ ID No. 82.

10. A nucleic acid, vector or cell comprising a nucleotide sequence encoding the switchable CARaccording to one of the claims 1 to 9.

11. The vector according to claim 10, wherein the vector is selected from the group comprisinga DNA vector, an RNA vector, a plasmid, a lentiviral vector, retroviral vector, adenoviral vector and an adeno-associated viral vector.

12. The vector of claim 11, further comprising a promoter, wherein the promoter is selected fromthe group comprising an EF-1 promoter, a CMV IE gene promoter, an EF-1α promoter, a ubiquitin C promoter, or a phosphoglycerate kinase (PGK) promoter.

13. The cell according to claim 10, wherein the cell is an immune effector cell selected from thegroup comprising a cytotoxic T lymphocyte, regulatory T cell, Natural Killer cell, and macrophage.

14. A pharmaceutical composition comprising a cell comprising a nucleotide sequence encodingthe switchable CAR according to one of the claims 1 to 9 and a pharmaceutically acceptablethinner or carrier.

15. A kit comprisinga) a nucleic acid, vector and / or cell comprising a nucleotide sequence encoding theswitchable CAR according to one of the claims 1 to 9, and b) a targeting module comprising at least one target cell-binding domain capable ofbinding a target antigen and a tag or tag-binding domain and / or at least onenucleic acid, vector and / or cell encoding a targeting module,wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimeric antigen receptor or the tag of the targeting module binds to the tag- binding domain of the switchable chimeric antigen receptor.

16. The kit according to claim 15, wherein the target cell-binding domain of the targetingmodule is an antibody, antigen-binding fragment, a protein, a peptide or a low molecular weight organic ligand that binds to a surface antigen selected from the group comprisingCD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD19, CD20, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD79a, CD79b, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellularadhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, aligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a disialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan.

17. The kit according to claim 15 or 16, wherein the length of the targeting module is in therange of 20 to 1600 amino acids, preferably 200 to 1450 amino acids.

18. The kit according to one of the claims 15 to 17, wherein the cell comprising a nucleotidesequence encoding a reversible chimeric antigen receptor and / or the targeting module are in the form of a pharmaceutical composition.

19. The kit according to one of the claims 15 to 18, wherein the kit further comprises at leastone further targeting module or at least one further nucleic acid, vector or cell encoding afurther targeting module,wherein the at least one further targeting module comprises at least one target cell-binding domain and a tag-binding domain or a tag, wherein the at least one target cell-binding domain of the further targeting module is an antibody, antigen-binding fragment, a protein, a peptide or a low molecular weight organic ligand that binds to a surface antigen selected from the group comprising CD2, CD3, CD4,CD5, CD7, CD8, CD10, CD15, CD19, CD20, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD79a, CD79b, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C- type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a disialoganglioside, a glypican, a G protein- coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan, wherein the targeting module and the at least one further targeting module comprise different target cell-binding domains, and identical tag-binding domains or tags.

20. The switchable chimeric antigen receptor according to one of the claims 1 to 9, the cellaccording to claims 10 or 13, the pharmaceutical composition according to claim 14 or thekit according to one of the claims 15 to 19 for use as a medicament.

21. The switchable chimeric antigen receptor according to one of the claims 1 to 9, the cellaccording to claims 10 or 13, the pharmaceutical composition according to claim 14 or thekit according to one of the claims 15 to 19 for use in the treatment of cancer, infectiousdisease or autoimmune disease.