Chimeric antigen receptor

Abstract

The present invention provides a chimeric antigen receptor (CAR) comprising an antigen binding domain comprising a chromogranin A (CgA) peptide or a fragment or derivative thereof.

Description

[0001]CHIMERIC ANTIGEN RECEPTOR FIELD OF THE INVENTIONThe present invention relates to CARs that are specific for integrins αvβ6 and αvβ8 and theiruse in the treatment of disease, for example cancer. BACKGROUND TO THE INVENTIONThe αvβ6 and αvβ8 integrins are members of the human integrin superfamily. αvβ6 and αvβ8are heterodimers formed from the αv chain and either the β6 or β8 chain (Takada, Y., Ye, X. & Simon, S. Genome Biol. 2007;8:215). Integrins αvβ6 and αvβ8 are highly expressed in processes such as tissue modelling and wound healing. They are also highly expressed in multiple cancer types and expression level of αvβ6 and αvβ8 is correlated with poor prognosisin cancer patients (Hazelbag S, et al. J Pathol. 2007;212:316-24; Zhou M et al. J Cancer.2020;11:3803-15.). Integrin αvβ6 is upregulated in a wide-range of epithelial-derived cancer, including liver, cervical, pancreatic, ovarian, colon and oral cancers (Bandyopadhyay A,Raghavan S. Curr Drug Targets.2009; 7:645-52). Integrin αvβ8 expression is seen in ovarianand squamous cell carcinoma (Takasaka N, et al., JCI Insight.2018;3(20):e122591) and is associated with poor prognosis in colon cancer (Zhou M, et al. J Cancer.2020;11(13):3803-3815). In addition, αvβ8 is expressed by tumor-infiltrating immunosuppressive regulatory Tcells (Treg) (Dodagatta-Marri E, et al. Cell Rep. 2021;36:109309). Both αvβ6 and αvβ8 canadopt different conformations involving conformational changes and regulating the transitionfrom low- to high-affinity ligand-binding states (Hynes, R. O. Cell. 2002;110:673–687).Therefore, integrins αvβ6 and αvβ8 function as tumor associated antigens (TAAs) which may be used to direct therapeutic agents to tumors. In particular, αvβ6 and αvβ8 are overexpressed in both primary and metastatic pancreatic ductal adenocarcinoma (PDAC), effective treatment of which is an urgent, unmet clinical need. PDAC represents the fourth leading cause of cancer-related death with a 5-year survival rateof about 10% (Siegel et al., A Cancer Journal for Clinicians. 2023;73(1):17–48). Novelchemotherapy regimens, such as FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) and gemcitabine with nab-paclitaxel (nanoparticle albumin-bound paclitaxel) have reported only incremental increases in overall survival compared with standard gemcitabine chemotherapy (T. Conroy et al., New England Journal of Medicine.2011;364(19):1817–25; TConroy et al., Current Oncology Reports. 2013;15(2):182–89), thus underlying the need formore efficacious therapeutic strategies. The present invention describes the design and validation of novel Chimeric Antigen Receptors (CARs) specific for αvβ6 and αvβ8, to be exploited in adoptive T cell therapy of cancer and in particular in PDAC. SUMMARY OF THE INVENTION In one aspect, the present invention provides a chimeric antigen receptor (CAR) comprising an antigen binding domain comprising a Chromogranin A (CgA) peptide or a fragment orderivative thereof. In one aspect, the invention provides a CAR wherein the antigen bindingdomain comprises a chromogranin A peptide or a fragment or derivative thereof. In one aspect, the chromogranin A peptide or fragment or derivative thereof comprises a RGDL or RGDE motif. In a further aspect, the chromogranin A peptide or fragment or derivative thereof additionally comprises a peptide sequence capable of forming an amphiphilic alpha helix, preferably wherein said peptide sequence is adjacent and to the immediate C-terminal side of the RGDL or RGDE motif. In one aspect, the CAR comprises a modified chromogranin A peptide or a fragment or derivative thereof. In one aspect, the modified chromogranin A peptide or fragment or derivative thereof comprises a RDGL motif. In a further aspect, the modified chromogranin Apeptide or fragment or derivative thereof additionally comprises a peptide sequence capableof forming an amphiphilic alpha helix, preferably wherein said peptide sequence is adjacent and to the immediate C-terminal side of the RGDL motif. In one aspect, the chromogranin A is human chromogranin A. In one aspect, the CAR comprises an antigen binding domain which comprises a polypeptide comprising SEQ ID NO: 1; or a polypeptide with at least 80% sequence identity to SEQ ID NO: 1. In one aspect, the CAR comprises an antigen binding domain which comprises a polypeptide comprising SEQ ID NO: 35; or a polypeptide with at least 80% sequence identity to SEQ ID NO: 35. In one aspect, the present invention provides a CAR comprising an antigen binding domain comprising an RGDE or RGDL motif as described herein, and is capable of binding αvβ6 integrin. In one aspect, the present invention provides a CAR comprising an antigen binding domaincomprising an RGDL motif as described herein, and is capable of binding αvβ8 integrin.In one aspect, the present invention provides a CAR comprising an antigen binding domaincomprising an RGDL motif as described herein, and is capable of binding both αvβ6 and αvβ8 integrin. Integrin αvβ6 and αvβ8 are potential therapeutic agents for the treatment of cancersexpressing these integrins. The CARs of the present invention provide efficient and specifickilling of tumors expressing the respective integrin targets.In one aspect, the CAR comprises: a) a spacer; b) a transmembrane domain; and / or c) one or more intracellular signaling domains. In a further aspect, the spacer (a) of the CAR comprises a IgG1 domain, a IgG1 hinge, atruncated nerve growth receptor domain (NWL), or a CH2CH3 spacer.In one aspect, the CAR comprises a LNGFR spacer. In one aspect, the LNGFR spacer is a LNGFR wild type long spacer (NWL). In one aspect, the LNGFR spacer comprises the sequence of SEQ ID NO: 4. In one aspect, the LNGFR spacer consists of the sequence of SEQ ID NO: 4. In one aspect, the LNGFR spacer comprises a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 4. In one aspect, the LNGFR spacer comprises or consists of a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 4, such as at least 80%, at least 85%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%,at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 4.In one aspect, the CAR comprises a CH2CH3 spacer.In one aspect, the CH2CH3 spacer comprises the sequence of SEQ ID NO: 5.In one aspect, the CH2CH3 spacer consists of the sequence of SEQ ID NO: 5.In one aspect, the CH2CH3 spacer comprises a sequence having at least 90% sequenceidentity to the sequence of SEQ ID NO: 5.In one aspect, the CH2CH3 spacer comprises or consists of a sequence having at least 75%sequence identity to the sequence of SEQ ID NO: 5, such as at least 80%, at least 85%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%,at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQ ID NO: 5. In one aspect, the CAR comprises an IgG1 hinge. In one aspect, the IgG1 hinge comprises the sequence of SEQ ID NO: 3. In one aspect, the IgG1 hinge consists of the sequence of SEQ ID NO: 3. In one aspect, the IgG1 hinge comprises a sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 3. In one aspect, the IgG1 hinge comprises or consists of a sequence having at least 75% sequence identity to the sequence of SEQ ID NO: 3, such as at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%,at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence of SEQID NO: 10.In a further aspect, the spacer of the CAR comprises:i) a NWL domain which comprises SEQ ID NO: 4, or a sequence with at least 80%identity to SEQ ID NO: 4, ii) a CH2CH3 domain which comprises SEQ ID NO: 5, or a sequence with at least 80%identity to SEQ ID NO: 5, iii) an IgG1 hinge which comprises SEQ ID NO: 3, or a sequence with at least 80%identity to SEQ ID NO: 3, or iv) an IgG1 which comprises SEQ ID NO: 2, or a sequence with at least 80% identityto SEQ ID NO: 2.In a further aspect, the transmembrane domain (b) of the CAR comprises a CD4 or a CD28 transmembrane domain. In a further aspect, the transmembrane domain (b) of the CAR comprises a human CD28 transmembrane domain or a murine CD4 transmembrane domain. In a further aspect, the transmembrane domain of the CAR comprises: i) a human CD28 transmembrane domain which comprises SEQ ID NO: 7, or a sequence with at least 80% identity to SEQ ID NO: 7, or ii) a murine CD4 transmembrane domain which comprises SEQ ID NO: 6, or a sequence with at least 80% identity to SEQ ID NO: 6. In a further aspect, the one or more intracellular signaling domains (c) of the CAR comprise a CD28 intracellular signaling domain and / or a CD3ζ intracellular signalling domain. In a further aspect, the one or more intracellular signalling domains (c) of the CAR comprise a human CD28 intracellular signaling domain, a murine CD28 intracellular signaling domain,a human CD3ζ and / or a murine CD3ζ intracellular signaling domain.In a further aspect, the one or more intracellular signaling domains of the CAR comprise: i) a human CD28 intracellular signaling domain which comprises SEQ ID NO: 10, or a sequence with at least 80% identity to SEQ ID NO: 10, andii) a human CD3ζ intracellular signaling domain which comprises SEQ ID NO: 11, or asequence with at least 80% identity to SEQ ID NO: 11. In a further aspect, the one or more intracellular signaling domains of the CAR comprise: iii) a murine CD28 intracellular signaling domain which comprises SEQ ID NO: 8, or asequence with at least 80% identity to SEQ ID NO: 8, andiv) a murine CD3ζ intracellular signaling domain which comprises SEQ ID NO: 9, or asequence with at least 80% identity to SEQ ID NO: 9. In one aspect, the CAR comprises: i) a NWL domain, a human CD28 transmembrane domain, a human CD28 intracellular signaling domain and a human CD3ζ intracellular signaling domain,ii) a CH2CH3 domain, a human CD28 transmembrane domain, a human CD28intracellular signaling domain and a human CD3ζ intracellular signaling domain,iii) an IgG1 hinge, a human CD28 transmembrane domain, a human CD28 intracellularsignaling domain and a human CD3ζ intracellular signaling domain, oriv) an IgG1 domain, a murine CD4 transmembrane domain, a murine CD28 intracellular signaling domain, and a murine CD3ζ intracellular signalling domain. In a further aspect, the CAR comprises: i) an amino acid sequence which comprises SEQ ID NO: 14, or a sequence with at least 80% sequence identity to SEQ ID NO: 14, ii) an amino acid sequence which comprises SEQ ID NO: 15, or a sequence with at least 80% sequence identity to SEQ ID NO: 15, iii) an amino acid sequence which comprises SEQ ID NO: 13, or a sequence with atleast 80% sequence identity to SEQ ID NO: 13, oriv) an amino acid sequence which comprises SEQ ID NO: 12, or a sequence with at least 80% sequence identity to SEQ ID NO: 12. In one aspect, the CAR comprises an amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or a sequence with at least 80% sequence identity to SEQ ID NO: 14 or SEQ ID NO: 15. In one aspect, the CAR comprises an amino acid sequence of any one of SEQ ID NOs: 12- 15, or a variant thereof having at least 80% sequence identity thereto, such as at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto.In one aspect, wherein the CAR is able to bind both αvβ6 and αvβ8 integrin, the CAR is ableto induce T cell signalling when bound to αvβ6 and / or αvβ8. In one aspect, the CAR comprises: i) an amino acid sequence which comprises SEQ ID NO: 44, or a sequence with at least 80% sequence identity to SEQ ID NO: 44, ii) an amino acid sequence which comprises SEQ ID NO: 45, or a sequence with atleast 80% sequence identity to SEQ ID NO: 45, iii) an amino acid sequence which comprises SEQ ID NO: 43, or a sequence with at least 80% sequence identity to SEQ ID NO: 43, oriv) an amino acid sequence which comprises SEQ ID NO: 42, or a sequence with atleast 80% sequence identity to SEQ ID NO: 42. In one aspect, the CAR comprises an amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 45, or a sequence with at least 80% sequence identity to SEQ ID NO: 44 or SEQ ID NO: 45. In one aspect, the CAR comprises an amino acid sequence of any one of SEQ ID NOs: 42- 45, or a variant thereof having at least 80% sequence identity thereto, such as at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto.In one aspect, the CAR is able to induce T cell signalling when bound to αvβ6.In one aspect, the CAR is able to induce T cell signalling when bound to αvβ8.In one aspect, a nucleic acid is provided which encodes a CAR of the invention.In a further aspect, the nucleic acid which encodes a CAR of the invention comprises a polynucleotide sequence with at least 70% sequence identity to SEQ ID NO: 18, SEQ ID NO:19, SEQ ID NO: 17 or SEQ ID NO: 16.In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence of SEQ ID NO: 18 or SEQ ID NO: 19. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence which encodes the CAR of the invention, that comprises a polynucleotide sequence of any one of SEQ ID NOs: 16-19, or a variant thereof having at least 70% sequence identity thereto, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence which encodes the CAR of the invention, that comprises a polynucleotide sequence of any one of SEQ ID NOs: 16-19, or a variant having at least 70% sequence identity thereto, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%,at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity thereto, wherein the CAR is able to bind both αvβ6 and αvβ8 integrin. In a further aspect, the nucleic acid which encodes a CAR of the invention comprises a polynucleotide sequence with at least 70% sequence identity to SEQ ID NO: 49, SEQ ID NO: 50, or SEQ ID NO: 48. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence of SEQ ID NO: 49 or SEQ ID NO: 50. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence which encodes the CAR of the invention, that comprises a polynucleotide sequence of any one of SEQ ID NOs: 48-50, or a variant thereof having at least 70% sequence identity thereto, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence which encodes the CAR of the invention, that comprises a polynucleotide sequence of any one of SEQ ID NOs: 48-50, or a variant having at least 70% sequence identity thereto, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto, wherein the CAR is able to bind both αvβ6 and αvβ8 integrin. In one aspect, the nucleic acid which encodes a CAR of the invention comprises a polynucleotide sequence with at least 70% sequence identity to SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 39, or SEQ ID NO: 38. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence of SEQID NO: 40 or SEQ ID NO: 41.In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence which encodes the CAR of the invention, that comprises a polynucleotide sequence of any one of SEQ ID NOs: 38-41, or a variant thereof having at least 70% sequence identity thereto, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% sequence identity thereto.In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence which encodes the CAR of the invention, that comprises a polynucleotide sequence of any one of SEQ ID NOs: 38-41, or a variant having at least 70% sequence identity thereto, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto, wherein the CAR is able to bind αvβ6 integrin. In one aspect, the nucleic acid which encodes a CAR of the invention comprises a polynucleotide sequence with at least 70% sequence identity to SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 51. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence of SEQ ID NO: 52 or SEQ ID NO: 53. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence which encodes the CAR of the invention, that comprises a polynucleotide sequence of any one of SEQ ID NOs: 51-53, or a variant thereof having at least 70% sequence identity thereto, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto. In one aspect, there is provided a nucleic acid comprising a polynucleotide sequence which encodes the CAR of the invention, that comprises a polynucleotide sequence of any one of SEQ ID NOs: 51-53, or a variant having at least 70% sequence identity thereto, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto, wherein the CAR is able to bind αvβ6 integrin. In one aspect, the polynucleotide comprises a sequence encoding the IgG1 hinge that comprises or consists of the sequence of SEQ ID NO: 3 or a variant thereof having at least 75% sequence identity thereto, such as at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto. In one aspect, the polynucleotide comprises a sequence encoding the LNGFR spacer that comprises or consists of the sequence of SEQ ID NO: 4, or a variant thereof having at least 75% sequence identity thereto, such as at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto.In one aspect, the polynucleotide comprises a sequence encoding the CH2CH3 spacer thatcomprises or consists of the sequence of SEQ ID NO: 5, or a variant thereof having at least 75% sequence identity thereto, such as at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity thereto.In one aspect, a vector is provided which comprises a nucleic acid which encodes a CAR ofthe invention. In one aspect, the vector is a viral vector.In one aspect, the vector is a lentiviral vector.In one aspect, the vector is a bidirectional vector, such as a bidirectional lentiviral vector. In one aspect, the vector is an adeno-associated viral (AAV) vector. In one aspect, the vector is in the form of a nanoparticle. In one aspect, the polynucleotide or vector comprises one or more promoter(s), operably linked to the nucleotide sequence encoding the CAR. In one aspect, a cell is provided which comprises; a vector which comprises a nucleic acid of the invention, a nucleic acid of the invention, and / or a CAR of the present invention. In one aspect, the cell is a eukaryotic cell, such as a mammalian cell. In one aspect, the cell is selected from the group consisting of a rodent cell, such as a mouse or rat cell, a feline cell, a canine cell, and a human cell. In a preferred aspect, the cell is a human cell. In one aspect the cell is an immune cell. In a further aspect, the cell is an effector immune cell. In one aspect, the cell is selected from the group consisting of a T cell, an NK cell, an invariant NK cell, a cytokine-induced killer (CIK) cell, and a macrophage. In one aspect, the cell is a T cell or an NK cell. In one aspect, the cell is a T cell. In one aspect, the cell is an autologous or allogenic cell. In one aspect, there is provided a composition comprising a plurality of cells which comprises; a vector of the invention, a nucleic acid of the invention, and / or a CAR of the present invention. In one aspect there is provided a method for making a cell of the invention, which comprisesthe step of transducing or transfecting a sample of cells from a subject ex vivo with a nucleicor a vector of the invention. In one aspect there is provided a pharmaceutical composition comprising; i) a nucleic acid of the invention, ii) a vector of the invention, iii) a cell which comprises; a vector of the invention, a nucleic acid which encodes a CAR of the invention, and / or a CAR of the present invention, and / or iv) a composition which comprises a plurality of cells which comprise; a vector of the invention, a nucleic acid of the invention, and / or a CAR of the present invention. In one aspect, there is provided a CAR, a nucleic acid, a vector, a cell, a composition which comprises a plurality of cells, or a pharmaceutical composition according to the invention for use as a medicament. In one aspect, there is provided a CAR, a nucleic acid, a vector, a cell, a composition which comprises a plurality of cells, or a pharmaceutical composition according to the invention foruse in treating or preventing cancer. In one aspect, the CAR, nucleic acid, vector, cell,composition which comprises a plurality of cells, or pharmaceutical composition according to the invention is for use in treating or preventing cancer in a subject in need thereof.In one aspect, there is provided a use of a CAR, a nucleic acid, a vector, a cell, a compositionwhich comprises a plurality of cells, and / or a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prevention of cancer. In one aspect, there is provided a method for treating or preventing cancer, wherein the method comprises administering a CAR, a nucleic acid, a vector, a cell, a composition which comprises a plurality of cells, and / or a pharmaceutical composition according to the invention to a subject in need thereof. In one aspect, the subject is a human subject. In another aspect, the subject is a non-human animal. In one aspect, the subject has, or is at risk of developing, a cancer. In one aspect, the cancer is a primary cancer. In another aspect, the cancer is a secondary cancer. In one aspect, thecancer is a solid tumour. In another aspect, the cancer is a blood cancer.In one aspect, the subject has a solid or blood-derived cancer expressing αvβ6, αvβ8 or bothαvβ6 and αvβ8. In one aspect, the cancer is a solid tumour cancer selected from the group consisting of pancreatic cancer, stomach cancer, melanoma, lung cancer, ovarian cancer and prostate cancer. In one aspect, the cancer is pancreatic ductal adenocarcinoma (PDAC). In one aspect, the cancer is a blood cancer selected from the group consisting of multiple myeloma, Burkitt lymphoma, mature T malignancy, T-acute lymphoblastic leukemia, Anaplastic large cell lymphoma, Acute myeloid leukemia, Chronic myeloid leukemia (lymphoid blast crisis), Hodgkin lymphoma, Primary mediastinal B-cell lymphoma and Chronic lymphocytic leukemia. In one aspect, the cancer is a blood cancer selected from the group consisting of chronic myeloid leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, multiple myeloma, mature t-malignancy, pre-b-acute lymphoblastic leukemia, hairy cell leukemia, diffuse large b- cell lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, myeloproliferative neoplasm, primary effusion lymphoma, anaplastic large cell lymphoma, T- acute lymphoblastic leukemia, natural killer malignancy, and Burkitt lymphoma. In one aspect, the cancer is metastatic disease. In one aspect, the cancer is a metastatic cancer expressing αvβ6, αvβ8 or both αvβ6 and αvβ8. In one aspect, the cancer is liver metastasis of pancreatic ductal adenocarcinoma. In one aspect, the cancer is metastatic melanoma.In one aspect, wherein the cell comprising the CAR expresses the CAR on the surface of the cell, binding of the CAR to the binding target of the CAR activates intracellular signaling of the cell. In a further aspect, binding of the CAR and the resulting intracellular signaling activates effector function in the cell of the invention. In one aspect, the cell is a cytotoxic immune cell, and the effector function is a form of cell-mediated cytotoxicity. In one aspect, binding of the CAR to a binding target when the CAR is expressed by a cell of the invention results in cytotoxic activity of the cell towards the cell expressing the binding target.In one aspect, the CAR of the invention is capable of binding to tumour cells that expressavβ6, or both avβ6 and avβ8.In one aspect, the CAR of the invention is capable of binding to tumour cells that expressavβ8. In one aspect, the CAR of the invention is capable of binding to tumour cells that express avβ6.In one aspect, the CAR of the invention is capable of recognizing Tregs. In one aspect, theCAR of the invention is capable of binding to Tregs that express avβ8.In one aspect, a cell, a composition comprising a plurality of cells or a pharmaceuticalcomposition according to the invention is administered to the subject systemically. In one aspect, a cell, a composition comprising a plurality of cells, or a pharmaceutical composition according to the invention is administered to the subject locally. In one aspect, the cell, composition or pharmaceutical composition is administered intravenously. In one aspect, the cell, composition and / or pharmaceutical composition is administered within the site of primaryoccurrence (i.e intrapancreatically for PDAC). In one aspect, the cell, composition orpharmaceutical composition is administered within the site of metastasis dissemination (i.eintrahepatic for PDAC).DESCRIPITON OF THE FIGURESFigure 1 – avβ6 / avβ8 expression is indicative of poor prognosis and of relevance for CAR-Tcell therapy A) Data from RNA dataset across different tumors and relative normal counterpart (TCGA / GTEx). PDAC n=179 and normal pancreas n=171; OV (ovarian serous cystadenocarcinoma n=426; normal ovary n=88; STAD (stomach adenocarcinoma) n=408 and normal stomach n=211; LUSC Lung squamous cell carcinoma n=486, normal lung n=338; CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma n=306, normal Cervix Uteri n=13; UCEC Uterine Corpus Endometrial Carcinoma n=174, normal uterus n= 91; UCS Uterine Carcinosarcoma n=57, normal uterus n= 78; LGG Brain Lower Grade Glioma n= 518, normal brain n=207; ESCA Esophageal carcinoma n=182, normal esophagus n=286; GBM Glioblastoma multiforme n=163, normal brain n=207; KIRP Kidney renal clear cell carcinoma n=523, normal Kidney n=100; LUAD Lung adenocarcinoma n=483, normal lung n=347; BRCA Breast invasive carcinoma n=1085, normal breast n=291; HNSC Head and Neck squamous cell carcinoma n=519; SKCM Skin Cutaneous Melanoma n=461, normal skin n=558. B-C) Comparison of avβ6 and avβ8 mRNA expression between PDAC and Normal pancreas in TCGA / GTEx (B) and in the OSR-LIMET patient cohort (C). D) Disease-free survival (top) and overall survival (bottom) in the TCGA / GTEx data set stratified according to integrin expression level (high and low as indicated in the panels). E) protein expression of β6, β8 and CEA in primary PDAC (protein ATLAS). F) Immunohistochemistry analysis of β6 expression in normal pancreas (a), PanIN (b), IPMN (c), primary PDAC (d) and PDAC liver metastasis (e). The arrow identify normal islets, while asterisks identify transformed PDAC.Figure 2 – Generation of species-agnostic avβ6-specific RGDE-mCAR-TsA) Schematic representation of the modules comprising the RGDE-mCAR. B) Representativedot plots of control (Mock T) and RGDE-mCAR transduced mouse T cells. C-D) RGDE-mCAR-Ts or control CEA-CAR Ts were cultured on immobilized avβ5 (as a control), avβ6 or avβ8recombinant human integrins. Representative images taken after 48h of culture (C) andquantification of IFN-gamma in culture supernatants (D).Figure 3 – Generation of species-agnostic avβ6 / avβ8-specific RGDL-mCAR-TsA) Schematic representation of the modules comprising the RGDL-mCAR. B) Representative dot plots of control (Mock T) and RGDL-mCAR transduced mouse T cells. C-D) Mock Ts andRGDL-mCAR-Ts were cultured on immobilized avβ6 or avβ8 recombinant integrins of mouseand human origin or on the anti-C8A antibody (5A8 mAb). Representative images after 48h ofculture (C) and quantification of IFN-gamma in culture supernatants (D). Where indicated the 5a-RGDL peptide was adopted as competitor.Figure 4 – RGDL-mCAR-Ts react and kill avβ6 / avβ8 expressing tumors in co-culturesA) FACS analysis of avβ6 surface expression on human (BXPC3) and mouse (5M7101 andM4436) PDAC cell lines. B-C) RGDL-mCAR or mock transduced T cells were cultured for 4hwith human BXPC3 or mouse 5M7101 and M4436 PDAC cells for 4h. Thereafter cells wererecovered, and intracellular IFN-gamma release was quantified. Representative dot plots (B), and frequencies of CD8+ IFN-gamma+ cells (C). D-E) RGDL-mCAR or mock transduced T cells were co-cultured with mouse 5M7101 PDAC cells. Culture supernatants were recoveredafter 48h and IFN-gamma levels analyzed by ELISA (D). Cytotoxicity was analyzed by MTTassays (E). In panel F, representative images of GFP+ 5M7101 tumor cells in cocultures taken at 3h and 40h (endpoint).Figure 5 – RGDL-IRDye800 conjugate identifies mouse subcutaneous and liver PDACmetastases in vivo C57BL / 6 mice received a subcutaneous injection of 1065M7101 PDAC cells. At day 17 and upon the development of a palpable tumors (>200mm3) mice received an i.v. injection of the5a-RGDL-IRDye800 peptide conjugate. Mice (A) and explanted tumors (B) were imaged byIVIS. In C overall fluorescence emission is shown. D) 5M7101 were injected in the portal vein (105cells in 200µl). At day 21 mice were imaged by MRI (top panel). At day 33 mice wereinjected with the 5a-RGDL-IRDye800 conjugate. After 24h mice were sacrificed, and the liverwere explanted and imaged by IVIS (bottom panels). GFP and 5a-RGDL-IRDye800-derivedsignals are shown and quantified.Figure 6 – RGDL-mCAR-Ts control the growth of avβ6 / avβ8 expressing tumors in vivoA-B) Mice with measurable 5M7101 tumors were randomized and either left untreated ortreated with an intravenous injection of 107 RGDL-mCAR-Ts or with an equivalent totalnumbers of Mock-transduced T cells as control. Five mice per group were used. Tumor volume(A) and the area under the curve (B) are shown. C-D) In C, representative IVIS images of control and treated mice are shown. In D, the s.c. lesions were segmented, and the GFP signal quantified. E-H) Tumors were explanted and analyzed by H&E (E-F) or stained with anti-^^ Ab (G-H). Representative images (E,G) and relative quantification (F, H).Figure 7 – RGDL-mCAR-Ts do not evoke detectable off-tumor effectsMice with 5M7101 PDAC were treated as described in Figure 6. A) Mouse weight wasmeasured over time. B) To monitor off-tumor effects, lung, kidney and liver were explantedand analyzed by H&E analyses.Figure 8 – Engineering RGDL-hCAR-Ts with dual avβ6 / avβ8-specificityA) RGDL-bearing second generation human CAR structures including a CH2CH3 (234 aa) ora NWL (222 aa) spacers or a 15aa hinge domain. B) Representative FACS analysis of anti-CD19 or RGDL hCAR-transduced T cells stained with anti-NGFR and anti-CD20 Ab. Events are depicted after gating on viable CD4+CD8+ cells. C) CAR-T cells were stained with anti-CD62L and anti-CD45RA mAbs. The frequency of Stem Cell Memory (CD62L+; CD45RA+),Central Memory (CD62L+; CD45RA-), Effector Memory (CD62L-; CD45RA-) and TerminalEffector (CD62L-; CD45RA+) is depicted. D-E) RGDL CAR-Ts (in the CH2CH3, NWL or hingeconfiguration) or Mock Ts stimulated with plastic-bound recombinant human or mouserecombinant av^^ or av^^ in the absence or the presence of free 5a-RGDL-peptide. Humanavb5 was used as control. In D, representative cultures images are shown. In E, IFN-gamma in 48h culture supernatant was measured.Figure 9 – RGDL-hCAR-Ts specifically target avβ6 / avβ8 expressing tumorsA-B) PDAC (BxPC-3, T3M4), non small cell lung cancer (H1975), metastatic melanoma(MeWo), ovarian cancer (IGROV-1) or normal endothelial (Huvec) cells were stained with anti-av^^, av^^ Ab or isotype controls. Representative FACS plots (A) and relative quantification (B). C-D) Mock or RGDL-hCAR Ts were cocultured with the indicated tumor cells. Cytotoxicity(C) and IFN^ release (D) were measured after 48 hours. E-F) Control anti-CD19 CAR-T orav^^ / av^^-specific RGDL-hCAR Ts (Hinge; NWL; CH2CH3) were cocultured with T3M4 PDAC cells transduced with a nuclear-restricted red fluorescence protein (Incucyte) for 48h.In E, kinetics and overall cytotoxicity are depicted. In F, IFN-gamma in culture supernatantswas measured.Figure 10 – RGDL-hCAR-T cells delay the growth of PDAC Xenografts(A-C) BxPC-3 were subcutaneously injected in NSG mice (n=5 per group). Adoptive cell transfer (ACT) of Mock, RGDL-NWL-hCAR or RGDL-CH2CH3-hCAR Ts were performed at the indicated time. Schematic representation of the experiment (A). Tumor volume and mice body weight were monitored over the course of the experiments (B-C). D-F) T3M4 metastaticPDAC cells were subcutaneously injected in NSG mice. ACT of CD19- or RGDL-NWL-hCAR-Ts were performed at the indicated time. Schematic representation of the experiment (D). Tumor volume and mice body weight were monitored over the course of the experiment (E- F).Figure 11 – RGDL-hCAR Ts react to PDAC patient derived organoids.A-B) PDAC patient derived organoids (PDOs) were stained with anti-av^^, av^^ Ab or withisotype control or with the Cys-IRDye680 or 5a-RGDL-IRDye680 conjugate. RepresentativeFACS plots (A), and relative quantifications (B). C) PDAC PDOs (#211 and #250) werecocultured for 72h with RGDL-NWL-hCAR or CD19-hCAR Ts. IFN-gamma was measured in culture supernatants (C). D) PDO#250 was cocultured with RGDL-NWL-hCAR or CD19-hCARTs and apoptosis was measured over time exploiting activation of caspase 3 / 7. E-F) PDACPDOs were orthotopically injected in the pancreas of NSG mice. At day 28 a fraction of mice(indicated in the figure) received an intravenous injection of D-Luciferin or 5a-RGDL-IRDye800conjugate. 24h later mice were sacrificed, pancreas were explanted and imaged.Representative images and relative signal quantification are depicted. G-H) PDAC PDOswere orthotopically injected in the pancreas of NSG mice. Two days later, mice were imaged and treated with RGDL-NWL-hCAR or CD19 hCAR Ts. Luciferase emission was measuredas indicative of tumor growth. Longitudinal luciferase emission (mean+ / - SEM) (G) and theAUC are shown (H).Figure 12 – RGDL peptide identify human Tregs and retargets human CAR-Ts against T-regulatory cells. A-C) Human Tconvs and Tregs were stained with anti-CD4, anti-CD25 and anti-FoxP3 mAbs and with the 5a-RGDL-IRDye680 or Cys-IRDye680 conjugate. In A, representative FACS plot of Tconvs (CD4+CD25-FoxP3-) and Tregs (CD4+CD25+FoxP3+) T cells. In B, the 5a-RGDL- IRDye680 / Cys-IRDye680 relative mean fluorescent intensity is depicted. Panel C refers to the frequency of 5a-RGDL-IRDye680 or Cys-IRDye680 positive cells. Unfractionated PBMC, T3M4 and IGROV-1 cells are also shown. D) Tconvs or Tregs cells were loaded with the CMTMR fluorescent dye and cocultured with control CD19 CAR Ts or with RGDL-NWL or RGDL-CH2CH3 hCAR Ts and imaged over time (Incucyte). Tregs or Tconvs viability (longitudinal analyses and area under the curve) is depicted. The experiment is representative of three independent determinations with different donors.Figure 13 – ITGB6 and ITGB8 expression on blood cancer.A-C) In-silico analysis of ITGB6 and ITGB8 expression obtained from RNA-Seq data of the LL-100 panel covering 22 entities of human leukemia and lymphoma including T-cell, B-celland myeloid malignancies (https: / / celldive.dsmz.de / rna / ll-100). A-B) Relative normalized RNAexpression. C) List of abbreviation.Figure 14 - Generation of avβ6-specific RGDE-hCAR-TsA) RGDE-bearing second generation human CAR structures including the NWL spacers. B) Representative FACS analysis of Mock T and RGDL, RGDE or RGEE-hCAR-T cells stained with anti-CD20 Ab. Events are depicted after gating on viable CD4+CD8+ cells. C) RGDL,RGDE or RGEE-hCAR-Ts or Mock Ts were stimulated with plastic-bound human avβ6 or avβ8recombinant. Human avβ5 was used as control. IFN-gamma was measured in 48h culture supernatants.Figure 15 - RGDL-hCAR-T cells efficiently control patient-derived PDAC tumors at differentdevelopment stages A) PDAC PDOs were orthotopically injected in the pancreas of NSG mice. At day 28 mice received an intravenous injection of 5a-RGDL IRDye800 conjugate. 24h later mice were imaged in-vivo (left panel) or the pancreas and spleen were explanted and imaged ex-vivo (right panel). B) Orthotopic PDAC PDO derived tumor sections were stained with anti-αvβ6 or anti-αvβ8 Ab. Representative immunocytochemistry images are depicted. C) PDAC PDOs were orthotopically injected in the pancreas of NSG mice. Mice were adoptively transferred with CD19 hCAR Ts or with RGDL-NWL-hCAR as indicated (n>5 mice). D) Representative bioluminescent luciferase imaging is depicted and used as measure of tumor growth. E-F)Relative longitudinal luciferase emission (mean + / - SEM) (E) and the AUC are shown (F). G) Kaplan-Meier survival curves indicative of the overall mice survival of mice with orthotopic PDAC PDO tumors not treated (NT) or treated with CD19 or RGDL-NWL hCAR-Ts is depicted. H) PDAC PDOs were orthotopically injected in the pancreas of NSG mice. Tumors were allowed to grow for 15 days and then mice were adoptively transferred with CD19 hCAR Ts or with RGDL-NWL-hCAR as indicated (n=6 mice). I) Representative bioluminescentluciferase imaging is depicted and relative longitudinal luciferase emission (mean + / - SEM)were calculated, AUC are shown (right panel). L) Frequency of CAR+ cells in the circulatingblood of mice depicted in I, 10 days after the intravenous administration (mean + / - SD).Figure 16 - RGDL-mCAR-T cell therapy efficiently controls PDAC liver metastasesA) K8484 cells (105cells in 200µl) were injected into the portal vein of mice. Following diagnosis, mice were treated with a sublethal dose of irradiation (6Gy, day 14) and intravenously administered with either Mock-transduced (Mock) T cells or RGDL-mCAR-Ts(day 15). Follow-up MRI imaging was performed at day 22 (representative mouse isrepresented on the left panel) and the total volume of liver metastases was quantified (rightpanel). Data represent mean + / - SEM, with individual mice shown. B) Kaplan-Meier survivalcurves show the overall survival of the mice described in panel A. C) After follow-up MRIimaging, some mice treated either with Mock T cells or RGDL-mCAR-T cells were sacrified.Leukocytes were isolated from PDAC liver metastases or the spleen. Flow cytometry analysis was performed and the frequency of donor CD45.1+ T cells positive for GranzymeB isindicated (mean + / - SEM).Figure 17 - RGDL-CAR T Cell specificity is genetically dependent on β6 and β8 integrinsA) CD19-, RGDL-, RGDE- or RGEE-hCAR T cells were cocultured with T3M4 metPDAC cellsor with IGROV-1 ovarian cancer cells trasduced with a nuclear-restricted red fluorescence protein (Incucyte) for 48h. Area under the curve of total normalized tumor cell area over thecourse of the co-culture is depicted (mean+ / - SD). B) Expression of αvβ6 and αvβ8 by T3M4WT (WT) and T3M4 β6 / β8 KO (KO) cells is depicted. T3M4 WT or T3M4 β6 / β8 KO were stained with anti-αvβ6 or anti-αvβ8 Ab or with isotype control. Normalized frequency is depicted. C) T3M4 WT or T3M4 β6 / β8 KO were stained with the Cys-IRDye680, 2a-RGEE- RDye680 or 5a-RGDL-IRDye680 conjugate. Normalized frequency is depicted. D) ControlCD19- or RGDL-hCAR Ts were cocultured with T3M4 WT or β6 / β8 KO cells transduced witha nuclear-restricted red fluorescence protein (Incucyte) for 48h. Kinetics of relative tumor cellarea over the course of the co-culture are depicted (means + / - SD).Figure 18 - Tumor-infiltrating human regulatory T cells are an addition target of RGDL-CAR Tcells A) 0,75x106T3M4 cells were subcutaneously injected in NSG mice and on the same day 106unfractionated PBMCs were intravenously injected (n=5 per group).4 days after, mice were left untreated or adoptively transferred (ACT) with RGDL-NWL hCAR T cells (derived from the same PMBCs donor). Schematic representation of the experimental setup is provided. B) Leukocytes were isolated from subcutaneous PDAC tumors and spleens, then stained with5a-RGDL-IRDye680 conjugates, hCD4, hFoxP3, hCD25 and hTIGIT. Flow cytometry analysiswas performed. Overlay FACS plots (left panel) and the frequency of 5a-RGDL-IRDye680within CD4+, FoxP3+ population is quantified (right panel, mean + / - SEM).Figure 19 - Expression of HSV-TK suicide gene in RGDL-pepti CAR T cells renders themsensitive to ganciclovir while preserving their function A) Schematic representation of the modules comprising the RGDL-TK CAR lentiviral vector. The vector contains two promoters in opposite orientations: the minimal CMV promoter drives the expression of the HSC-TK coding sequence, while the PGK promoter drives theexpression of the RGDL-NWL CAR coding sequence. B) RGDL- or RGDL-TK hCAR T cellswere cocultured with T3M4 cells transduced with a nuclear-restricted red fluorescence protein (Incucyte) for 48h. The kinetics of relative tumor cell area during the coculture are shown asmean + / - SD. C-D) RGDL- or RGDL-TK hCAR T cells were stimulated with PHA (2ug / ml) andtreated or not with different concentrations of antiviral drug ganciclovir (GVC) for 7 days. T cells were harvested and stained with CD8 and anti-NWL Ab (to identify CAR+ T cells). Representative FACS plots are depicted in panel C, and the frequency of CAR+ T cells under the indicated conditions is quantified as mean in panel D. E) PDAC PDOs were orthotopically injected in the pancreas of NSG mice. Mice were adoptively transfer at days 3 and days 8 post-PDAC PDO injection with 5x106RGEE-, RGDL or RGDL-TK hCAR T cells or left untreated (NT) (n=6 mice / group). Relative tumor size measured by ultrasound ecography isshown in the left panel as mean + / - SEM. The area under the curve (AUC) for relative tumorsize is represented in the right panel as mean+ / -SEM.Figure 20 – Schematic Representation of Non-Viral Sleeping Beauty Gene Delivery SystemA) Illustration of the structural components of the RGDL-CAR Sleeping Beauty (SB) plasmid,including a polynucleotide encoding an RGDL-CAR sequence fused to a safety switch with T2A self-cleaving peptide sequence, a WPRE sequence, a promoter sequence and flanking inverted repeats (IR). DETAILED DESCRIPTION OF THE INVENTIONT cell recognition of target antigenT cells are able to recognise target antigen when presented by major histocompatibilitycomplex (MHC) molecules on the surface of other body cells through the T cell receptor (TCR)that is expressed on the surface of the T cell. TCR binding to a presented target antigenpeptide results in activation of the T cell via a series of signalling processes involving receptor-associated enzymes, co-receptors, adaptor molecules, and transcription factors.Chimeric Antigen Receptor (CAR)The term “chimeric antigen receptor” or “CAR” or “chimeric T cell receptor” or “artificial T cell receptors” or “chimeric immunoreceptors”, as used herein, refers to a synthetic chimeric trans- membrane protein which connects an extracellular antigen-binding domain (binder) to an intracellular section (endodomain). Chimeric antigen receptors can provide both antigen-binding and T cell activating functions when expressed in T cells. Chimeric antigen receptorscan be designed to be directed against a broader range of antigens compared to conventionalT cells, which activation requires antigen peptides to be presented by MHC molecules.Chimeric antigen receptors contain costimulatory signalling domains within the intracellularmoiety and as such provide improved activation of T cells than endogenous TCR.The antigen-binding domain may comprise any polypeptide that has binding activity to the target antigen. CARs may have an antigen-binding domain derived from single chain variable fragments (scFvs) or fragment antigen-binding regions (Fabs) derived from immunoglobulins such as antibodies, or natural or synthetic ligands that engage a receptor / binding partner. The antigen-binding domain (binder) is normally connected to endodomain via a spacer domain and a transmembrane domain. The spacer domain may function to separate the antigen- binding domain from the T cell membrane to facilitate its binding activity and allow the antigen- binding domain to adopt a suitable orientation. The transmembrane domain anchors the protein in the cell membrane and connects the spacer and antigen-binding domain to the endodomain. CARs are commonly classified into ‘generations’, by virtue of the composition of their intracellular signalling domain(s). All CARs typically comprise an extracellular antigen-binding domain, historically an scFv, joined to a membrane-anchoring transmembrane domain by a linker or spacer sequence. Whilst first generation CARs comprise a single intracellular signalling domain that is typically a single CD3 zeta chain, second and third generation CARs additionally comprise one or two further co-stimulatory domains (respectively), typically CD28, 4-1BB, and / or OX-40. Fourth generation CARs are structurally similar to second generation CARs, however, are typically provided alongside an expression cassette (e.g., in a CAR T cell) that encodes an additional transgene such as a cytokine. In one embodiment the CAR of the invention is a first generation CAR. In one embodiment the CAR of the invention is a second generation CAR. In one embodiment the CAR of the invention is a third generation CAR. In one embodiment the CAR of the invention is a fourth generation CAR. Preferably the CARs of the invention comprise an antigen-specific targeting region, which may comprise an antigen-specific peptide, an extracellular domain such as a linker or hinge, a transmembrane domain, optionally one or more co-stimulatory domains, and an intracellular signaling domain. Antigen binding domain The antigen-specific targeting domain provides the CAR with the ability to bind to the target antigen of interest. The antigen-specific targeting domain preferably targets an antigen of clinical interest against which it would be desirable to trigger an effector immune response thatresults in, for example, tumour killing. The antigen-specific targeting domain may be anyprotein or peptide that possesses the ability to specifically recognize and bind to a biological molecule (e.g., a cell surface receptor or tumour protein, or a component thereof). Illustrative antigen-specific targeting domains include antibodies or antibody fragments or derivatives,extracellular domains of receptors, ligands for cell surface molecules / receptors, or receptorbinding domains thereof, and tumor binding proteins. The antigen-specific targeting domain includes any naturally occurring, synthetic, semi-synthetic, or recombinantly produced binding partner for a biological molecule of interest. Suitably, the antigen-binding domain may be based on a peptide ligand. For example, the antigen-binding domain may comprise a peptide derived from a ligand for a target receptor protein.With respect to targeting domains that target cancer antigens, the selection of the targetingdomain will depend on the type of cancer to be treated, and may target tumor or tumor- associated antigens. A tumor sample from a subject may be characterized for the presence of certain biomarkers or cell surface markers. Preferred target antigens of the present invention are integrin αvβ6 and integrin αvβ8. Integrin-binding domainThe antigen-binding domain of the present CAR is capable of binding to an integrin.The present inventors have identified that targeting αvβ6 and / or αvβ8 integrins via a CAR- expressing cytotoxic cell described within the present invention may intrinsically and simoultaneously mediate direct anti-tumour effects via cytotoxicity, and also reshape the tumour microenvironment. αvβ6 is weakly expressed or absent in adult tissue, and only up- regulated during wound healing, tissue remodelling and carcinogenesis (Koivisto et al., Int. J.Biochem. Cell Biol. 2018;99:186–96; Liu et al., Am. J. Nucl. Med. Mol. Imaging.2014;4(4):333–45; Breuss et al., J. Cell Sci. 1995;108(6):2241–51). In addition, αvβ8 isoverexpressed by various carcinoma cells and by tumor-infiltrating regulatory T cells (Treg)(McCarty JH. J. Cell Sci.2020;133; Takasaka N. JCI Insight. 2018;3; Jin S. Mol Cancer Res.2019;17:2126-38; Van Aarsen LA, Cancer Res.2008;68:561-70; Dodagatta-Marri E, et al. Cell Rep.2021;36:109309). Thus, targeting these tumour-associated antigens is unlikely to result in off-target activity. Suitably, the antigen-binding domain may comprise or consist of a polypeptide sequence derived from an arginine-glycine-aspartate (RGD) containing protein capable of binding integrins. Suitably, the antigen-binding domain may be a polypeptide sequence containing a consensus motif for integrin binding. Integrins may be in multiple conformations, including a bent, inactive conformation, and extended higher affinity conformations where ligand binding is possible (Askari JA. Et al., JCell Sci. 2009;122(2):165-170). Such extended conformations may be termed active states.Without wishing to be bound by theory, the antigen-binding domain may be a polypeptide sequence that binds to integrins when in their active conformation. Suitably the antigen- binding domain may be a polypeptide sequence containing a consensus motif for integrin binding wherein the integrin is in an active conformation In one embodiment, the antigen-binding domain may comprise or consist of a polypeptide sequence derived from chromogranin A. Chromogranin A is a natural ligand of αvβ6 integrin, and peptides derived from chromogranin A can inhibit cell-mediated TGFβ-activation and have anti-tumour effects.In one embodiment, the antigen-binding domain may comprise or consist of a polypeptidesequence derived from human chromogranin A.In one embodiment, the antigen-binding domain may comprise or consist of a modifiedpolypeptide sequence derived from human chromogranin A.In one embodiment, the antigen-binding domain may comprise or consist of an unmodifiedpolypeptide sequence derived from human chromogranin A. Chromogranin A (CgA) is a neurosecretory protein precursor that is cleaved into various biologically active fragments that have roles in regulation of the cardiovascular system, metabolism, innate immunity, tissue repair and tumor physiology. CgA and fragments thereof, such as vasostatin-1 (CgA amino acids 1-76), are capable of selective binding of integrin αvβ6. A CgA-derived peptide comprising residues 39-63 is sufficient for this binding activity. This peptide comprises an arginine-glycine-aspartate (RGD) motif, which is an integrin-binding motif. Replacement of the glutamic acid present in the human CgA at position 46 with leucine generates a peptide with selective binding and strong affinity to both αvβ6 and αvβ8 integrins (FETLRGDLRILSILRHQNLLKELQD, SEQ ID NO: 1) (Nardelli F, et al. Chem Commun (Camb).2019 Dec 5;55(98):14777-14780). Of note, no binding of CgA39-63 was observed to other integrins (such as α1β1, α6β4, α3β1, α9β1 α6β7, α5β1, αvβ3, αvβ5, and αvβ8) at low-nanomolar concentrations (Curnis F. et al., Cell. Mol. Life Sci. 2012;69:2791–2803).Intriguingly, the replacement of E46 with L not only increased, as expected, the binding affinity for αvβ6, but, unexpectedly, also that for the integrin αvβ8 (Nardelli F, et al. Chem Commun (Camb). 2019 Dec 5;55(98):14777-14780). Of note, these RGD-Cga-derived peptides bind with high affinity only functionally active avb6 / avb8 (Nardelli F, et al. Chem Commun (Camb). 2019 Dec 5;55(98):14777-14780; Monieri et al. Int J Biol Sci.2023 Jan 1;19(1):156-166. doi: 10.7150 / ijbs.76148. Accordingly, the antigen-binding domain of the present invention may comprise or consist of an amino acid sequence derived from human chromogranin A. The antigen-binding domain may comprise an amino acid sequence derived from a sequence corresponding to amino acids 1-76 of human chromogranin A. The antigen-binding domain may comprise a modified amino acid sequence corresponding to amino acids 39-63 of human chromogranin A, wherein the glutamic acid at position 46 is replaced with a leucine, or a functional fragment, portion or derivative thereof that retains specific binding activity to αvβ6 and αvβ8 integrin. The antigen-binding domain of the present invention may comprise or consist of an amino acid sequence of SEQ ID NO: 1, or a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1. SEQ ID NO: 1 (RGDL integrin-binding peptide) FETLRGDLRILSILRHQNLLKELQD A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 1, provided that the peptide is able to specifically bind tointegrin αvβ6, or alternatively that the peptide is able to specifically bind to integrin αvβ6 andintegrin αvβ8.A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%sequence identity to SEQ ID NO: 1, provided that the sequence comprises an RGD motif,preferably an RGDL motif, more preferably wherein the RGD or RGDL motif is in the positionin the peptide where the RGDL motif is in SEQ ID NO: 1, which is amino acid position 5-8 ofthe peptide. A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 1, across amino acids 1-4, 9, 10 and 15-25. A variant sequence may have sequence of: X RGDLXX L / IXwherein the peptide is able to specifically bind integrins αvβ6 and αvβ8, wherein amino acid11 can be L or I, and wherein X can be any amino acid.Without wishing to be bound by theory, X9, X10 and X12-25 may individually be any amino acid, wherein the intervening amino acid sequence from X9 to X25 is capable of forming an alpha-helix, particularly an amphipathic helix. Suitably, amino acids X9, and X12 may be hydrophilic,and amino acids X10, X13, and X14 may be hydrophobic. In one embodiment, the antigen-binding domain of the present CAR is capable of binding to αvβ6 or αvβ8 integrin. In certain embodiments, the antigen-binding domain of the present CAR is capable of binding to both the αvβ6 and αvβ8 integrins. Suitably, the antigen-binding domain of the present CAR which is capable of binding to both the αvβ6 and αvβ8 integrins comprises SEQ ID NO: 1 or a variant sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99% sequence identity to SEQ ID NO: 1; as described herein, provided that the sequencecomprises an RGD motif, preferably an RGDL motif, more preferably wherein the RGD or RGDL motif is in the position in the peptide where the RGDL motif is in SEQ ID NO: 1, which is amino acid position 5-8 of the peptide. Suitably, the antigen-binding domain of the present invention may comprise or consist of an amino acid sequence of SEQ ID NO: 35, or a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 35.SEQ ID NO: 35 (RGDE integrin-binding peptide) FETLRGDERILSILRHQNLLKELQD A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, provided that the peptide is able to specifically bind to integrin αvβ6. A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, provided that the sequence comprises an RGD motif, preferably an RGDE motif, more preferably wherein the RGD or RGDE motif is in the position in the peptide where the RGDE motif is in SEQ ID NO: 35, which is amino acid position 5-8 of the peptide. A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35, across amino acids 1-4, 9, 10 and 15-25. A variant sequence may have sequence of: X RGDEXX L / IX wherein the peptide is able to specifically bind integrin αvβ6, wherein amino acid 14 can be Lor I, and wherein X can be any amino acid. Suitably, a sequence comprising RGDE has verylow affinity to αvβ8 integrin (Ki= 7663+ / -1704).Without wishing to be bound by theory, X9, X10 and X12-25 may individually be any amino acid, wherein the intervening amino acid sequence from X9to X25is capable of forming an alpha- helix, particularly an amphipathic helix. Suitably, amino acids X9, and X12may be hydrophilic, and amino acids X10, X13, and X14may be hydrophobic. The chromogranin A peptide, or fragment or derivative thereof may, in addition to providing binding activity to the CAR of the present invention, exert anti-tumour activity through its interaction with integrin αvβ6 or αvβ8. Without wishing to be bound by theory, integrins αvβ6 and αvβ8 can activate TGFβ which is a potent immunosuppressive cytokine via interaction with the RGD sequence of latency-associated peptide (LAP)-TGFβ, releasing active TGFβ. Chromogranin A peptide binding to the integrin(s) may block this activity, resulting in reducedimmunosuppression (Yang et al., Journal of Cell Biology. 2007;176(6):787–93; Aluwihare etal., Journal of Cell Science. 2009;122(Pt 2):227–32; Conroy, Kitto, and Henderson, Cell andTissue Research. 2016;365(3):511–19). The chromogranin A peptide, or fragment orderivative thereof may advantageously provide additional anti-tumour activity in addition to facilitating targeting of the CAR of the invention to tumour cells expressing integrin αvβ6 and / or αvβ8. Spacer domainThe CAR may comprise an extracellular spacer domain which connects the antigen-bindingdomain to the transmembrane domain. The spacer domain may also be referred to as a hingeor linker. The spacer domain may allow the antigen-binding domain to adopt orientations thatallow binding to the target. Spacer domains may be of a length and / or flexibility to help improveCAR binding and signalling efficiency. Spacer domains of appropriate length may optimise theimmune synapse distance, which can be important for efficiency of endodomain signalling andeffectiveness of T cell cytotoxic mechanisms such as lytic granule delivery. Spacer domainswith high flexibility may improve efficiency of recognition of sterically hindered targets (J.Jayaraman et al., eBiomedicine.2020;58:102931).In the CAR of the present invention, the spacer sequence may comprise or consist of a lowaffinity nerve growth factor receptor (LNGFR) spacer, in particular a LNGFR wild-type long(NWL) spacer sequence; an immunoglobulin-derived hinge and constant region; animmunoglobulin-derived hinge region, or fragments or derivatives thereof. The spacer sequence may, for example, comprise a human NWL spacer, a murine IgG1spacer, a human IgG1 hinge region, or a mutated human IgG-derived CH2CH3 spacer.The spacer may alternatively comprise a linker sequence with similar length, flexibility and / or domain spacing properties as a murine IgG1 spacer, a human hinge region, a human NWLspacer, or a mutated human IgG-derived CH2CH3 spacer.In some embodiments, the spacer comprises at least part of the extracellular domain of human low affinity nerve growth factor receptor (LNGFR) or a derivative thereof. LNGFR is not expressed on the majority of human hematopoietic cells, thus allowing quantitative analysis of transduced gene expression by immunofluorescence, with single cell resolution. Thus, fluorescence activated cell sorter analysis of expression of LNGFR may be performed in transduced cells to study gene expression. Further details on analysis usingLNGFR may be found in Mavilio, Blood.1994;83,1988-1997.In one embodiment, the CAR of the invention comprises a truncated LNGFR (also known as ∆LNGFR). Preferably the LNGFR used in the present invention is truncated in its intracytoplasmic domain. Such a truncation is described in Mavilio, Blood. 1994;83,1988- 1997. Thus, preferably the LNGFR spacer of the present invention comprises at least part of the extracellular domain or a derivative thereof but lacks the intracellular domain of LNGFR. Theextracellular domain may comprise amino acids 29 – 250 of LNGFR or a derivative thereof.Exemplary human LNGFR [UNIPROT accession P08138, TNR16_HUMAN] (SEQ ID NO: 25): MGAGATGRAMDGPRLLLLLLLGVSLGGAKEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCL DSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVF SCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEG SDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNLIPVYCSILAAVVVGLVAYIAF KRWNSCKQNKQGANSRPVNQTPPPEGEKLHSDSGISVDSQSLHDQQPHTQTASGQALKGDGGLYSSLP PAKREEVEKLLNGSAGDTWRHLAGELGYQPEHIDSFTHEACPVRALLASWATQDSATLDALLAALRRI QRADLVESLCSESTATSPV In one embodiment, the spacer comprises at least part of a protein having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to amino acids 29-250 of the LNGFR protein (e.g., SEQ ID NO: 25). In one embodiment, the spacer comprises a protein having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to amino acids 29-250 of SEQ ID NO: 25. An exemplary extracellular domain within the human LNGFR is given by SEQ ID NO: 4, which may also be referred to as the LNGFR wild type long spacer (NWL). SEQ ID NO: 4 (human NWL spacer): KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMS APCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPC LPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVV TTVMGSSQPVVTRGTTDN Further exemplary spacers are illustrated below.SEQ ID NO: 26 (LNGFR wild type short (NWS)):KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMS APCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPC LPCTVCEDTERQLRECTRWADAECEESEQ ID NO: 27 (LNGFR mutated long (NML)): KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMS APCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEAARAADA ECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDN LNGFR comprises 4 TNFR-Cys domains (TNFR-Cys 1, TNFR-Cys 2, TNFR-Cys 3 and TNFR- Cys 4). Sequences of the domains are exemplified below: TNFR-Cys 1 (SEQ ID NO: 28) ACPTGLYTHSGECCKACNLGEGVAQPCGANQTVC TNFR-Cys 2 (SEQ ID NO: 29) PCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVC TNFR-Cys 3 (SEQ ID NO: 30) RCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVC TNFR-Cys 4 (SEQ ID NO: 31) ECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAEC In one embodiment, the spacer comprises TNFR-Cys 1, 2 and 3 domains or fragments or derivatives thereof. In another embodiment, the spacer comprises the TNFR-Cys 1, 2, 3 and 4 domains or fragments or derivatives thereof. In one embodiment the spacer comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity or 100% identity to TNFR-Cys 1 (SEQ ID NO: 28), a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity or 100% identity to TNFR- Cys 2 (SEQ ID NO: 29), or a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity or 100% identity to TNFR-Cys 3 (SEQ ID NO: 30). The spacer may further comprise a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity or 100% identity to TNFR-Cys 4 (SEQ ID NO: 31). Rather than comprise the full TNFR-Cys 4 domain, the spacer may comprise a TNFR-Cys 4 domain with the following amino acids deleted from said domain: NHVDPCLPCTVCEDTERQLRECTRW (SEQ ID NO: 32) In one embodiment, the NHVDPCLPCTVCEDTERQLRECTRW (SEQ ID NO: 32) amino acids are replaced with the following amino acids: ARAIn one embodiment the spacer lacks the LNGFR serine / threonine-rich stalk. In anotherembodiment the spacer comprises the LNGFR serine / threonine-rich stalk.The spacer may comprise or consist of a sequence of SEQ ID NO: 28 or a sequence havingat least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28.The spacer may comprise or consist of a sequence of SEQ ID NO: 29 or a sequence havingat least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29.The spacer may comprise or consist of a sequence of SEQ ID NO: 30 or a sequence havingat least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30.The spacer may comprise or consist of a sequence of SEQ ID NO: 31 or a sequence havingat least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 31. In one embodiment the spacer comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to any one of SEQ ID NOs: 4, 26, or 27. In one embodiment the spacer consists of a sequence of about the same length as the NWL spacer. In one embodiment the spacer comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to any one of SEQ ID NOs: 4 or 27.In one embodiment, the spacer comprises at least part of a protein having at least 75%, 80%,85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to the extracellular domain of LNGFR (e.g., SEQ ID NO: 4). Preferably, the spacer comprises a protein having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 4. Preferably, the spacer may comprise a LNGFR wild-type long (NWL) spacer of SEQ ID NO: 4In some embodiments, the spacer may comprise an IgG-derived CH2CH3 spacer. The IgG-derived CH2CH3 spacer may comprise the hinge region, Ch2 and Ch3 domains of an IgG.The IgG-derived CH2CH3 spacer may be derived from a human IgG. The IgG-derivedCH2CH3 spacer may be a mutated version of the IgG1 CH2CH3 spacer that is unable torecognise FcγRI as described in Hombach et al. (Hombach, A.et al. 2010 Gene Ther 17,1206–1213). The present inventors have surprisingly found that CARs comprising an NWL spacer or a CH2CH3 spacer display unexpectedly improved cytotoxicity and anti-tumour properties when expressed in effector immune cells. In preferred embodiments of the invention, the CAR comprises a spacer sequence whichcomprises a human NWL spacer or a mutated human IgG-derived CH2CH3 spacer. Thespacer sequence may comprise a human NWL spacer, a mutated human IgG-derivedCH2CH3 spacer, or a linker sequence with similar length, flexibility and / or domain spacingproperties as said human NWL spacer or said human CH2CH3 spacer.A spacer with a similar length may be a sequence of around the same length as the NWLspacer and said human CH2CH3 spacer, and longer than the human IgG1 hinge region. Aspacer of similar length to the NWL and CH2CH3 spacers may be, for example, from about50 to about 500 amino acids, from about 100 to about 400 amino acids, from about 150 toabout 350 amino acids, from about 200 to about 300 amino acids, from about 210 to about250 amino acids, or from about 220 to about 240 amino acids in length. A spacer with similar flexibility may be a sequence that is capable of adopting as wide a rangeof conformational positions as the NWL and CH2CH3 spacers.A spacer with similar domain spacing properties may be a sequence that is capable ofproviding similar binding distance between the integrin binding domain and the cell membrane.The skilled person would understand that this distance depends on the overall amino acid length, the flexibility of the structure, and the secondary and tertiary domains formed by the sequence. The spacer may confer properties to the CAR such that it allows for immunoselection of cells, preferably T-cells, expressing said CAR. The CAR of the present invention (e.g. comprising the spacer referred to herein) preferably enables T-cells expressing the CAR to proliferate in the presence of cells expressing the antigen for which the CAR is designed. The CAR of the present invention (e.g. comprising the spacer referred to herein) preferably enables T-cells expressing the CAR to mediate therapeutically significant anti-cancer effects against a cancer that the CAR is designed to target. The CAR of the present invention (e.g. comprising the spacer referred to herein) is preferably suitable for facilitating immunoselection of cells transduced with said CAR. An exemplary CAR of the present invention comprising the LNGFR-based spacer may avoid activation of unwanted and potentially toxic immune responses as the LNGFR-based spacer is not expected to be immunogenic, and may allow CAR-expressing T cells to persist in vivo without being prematurely cleared by the host immune system. The CAR of the present invention may comprise a sequence selected from SEQ ID NOs: 2-5, or a sequence having at least 80% sequence identity to a sequence selected from SEQ ID NOs: 2-5.SEQ ID NO: 2 (mouse IgG1 domain):DPVPRDGGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHT AQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVCTIPPP KEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNT FTCSVLHEGLHNHHTEKSLSHSPGSEQ ID NO: 3 (human hinge):EPKSCDKTHTCPPCPPSEQ ID NO: 5 (mutated human CH2CH3 spacer):EPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK In some embodiments, the CAR comprises the spacer domain SEQ ID NO: 2, or a variant thereof having at least 80% sequence identity. In some embodiments, the CAR comprises the spacer domain SEQ ID NO: 3, or a variant thereof having at least 80% sequence identity. In some embodiments, the CAR comprises the spacer domain SEQ ID NO: 4, or a variant thereof having at least 80% sequence identity. In some embodiments, the CAR comprises the spacer domain SEQ ID NO: 5, or a variant thereof having at least 80% sequence identity. In some embodiments, the CAR comprises the spacer domain SEQ ID NO: 2. In some embodiments, the CAR comprises the spacer domain SEQ ID NO: 3. In some embodiments, the CAR comprises the spacer domain SEQ ID NO: 4. In some embodiments, the CAR comprises the spacer domain SEQ ID NO: 5. A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%sequence identity to any one of SEQ ID NOs: 2 to 5, provided that the spacer domain is ableto orient the antigen-binding domain to facilitate binding. Without wishing to be bound by theory, the CAR of the present invention may, for example, comprise a spacer which provides an optimal immune synapse distance when expressed in aT cell and when recognising its target, and has sufficient flexibility to allow efficient binding ofthe binder of the CAR to bind to the target. The inventors of the present application have surprisingly shown that the NWL and CH2CH3 spacers are able to provide superior T cell activation when used in a CAR of the invention. Without wishing to be bound by theory, this may be due to improved integrin engagement due to optimal spacer length and flexibility to allow αvβ6 or αvβ8 integrin engagement by the CAR integrin binding domain. Transmembrane domain The transmembrane domain is the region of the CAR that anchors the CAR to the cell membrane, and connects the extracellular antigen-binding domain, optionally via the spacer, to the endodomain. Transmembrane domains are protein sequences that are thermodynamically stable in the lipid bilayer of a cell membrane. They are most simply comprised of a protein sequence that crosses the cell membrane only once. Other modalities are possible, such as proteins thatcross the membrane multiple times. For use in CARs, a simple transmembrane domain thatcrosses the cell membrane a single time is most commonly used. The most typical form is an α helix comprising several hydrophobic residues. Transmembrane domains for use in CARs can be sourced from any transmembrane protein. Suitability of a protein sequence as a transmembrane domain can be determined by the person skilled in the art using the DeepTMHM algorithm (https: / / dtu.biolib.com / DeepTMHMM) to determine the membrane spanning section of a transmembrane domain. Alternatively, as prediction of a hydrophobic α helix’s ability to form a transmembrane domain is possible due to its relatively simple structure, artificially designed transmembrane domains may be used. Such synthetic transmembrane components are described in e.g. US 7052906 B1. Example transmembrane domains used in CARs in the art are, the CD28 TM region (Pule et al, Mol Ther, 2005, Nov;12(5):933-41; Brentjens et al, CCR, 2007, Sep 15;13(18 Pt 1):5426-35; Casucci et al, Blood, 2013, Nov 14;122(20):3461-72), the OX40 TM region (Pule et al, MolTher, 2005, Nov;12(5):933-41), the 41BB TM region (Brentjens et al, CCR, 2007, Sep 15;13(18 Pt 1):5426-35), the CD3ζ TM region (Pule et al, Mol Ther, 2005, Nov;12(5):933-41;Savoldo B, Blood, 2009, Jun 18;113(25):6392-402), and the CD8a TM region (Maher et al,Nat Biotechnol, 2002, Jan;20(1):70-5.; Imai C, Leukemia, 2004, Apr;18(4):676-84; Brentjens et al, CCR, 2007, Sep 15;13(18 Pt 1):5426-35; Milone et al, Mol Ther, 2009, Aug;17(8):1453- 64.). In the CAR of the present invention, the transmembrane domain may be derived from a CD28 transmembrane domain, a CD4 transmembrane domain, or any other transmembrane domain which provides good receptor stability. In the CAR of the present invention, the transmembrane domain may be derived from a humanCD28 transmembrane domain, a murine CD4 transmembrane domain, or any other human ormurine transmembrane domain which provides good receptor stability.The CAR of the present invention may comprise a sequence selected from SEQ ID NO: 7 or6, or a sequence having at least 80% sequence identity to a sequence selected from SEQ IDNO: 7 or 6.SEQ ID NO: 7 (human CD28 transmembrane domain):FWVLVVVGGVLACYSLLVTVAFIIFWV SEQ ID NO: 6 (murine CD4 transmembrane domain): IVFLACVLGGSFGFLGFLGLCILCCVIn some embodiments, the CAR comprises the transmembrane domain SEQ ID NO: 7, or avariant thereof having at least 80% sequence identity thereto. In some embodiments, the CAR comprises the transmembrane domain SEQ ID NO: 6, or avariant thereof having at least 80% sequence identity thereto.In some embodiments, the CAR comprises the transmembrane domain SEQ ID NO: 7. In some embodiments, the CAR comprises the transmembrane domain SEQ ID NO: 6. A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%sequence identity to SEQ ID NO: 7 or 6, provided that the transmembrane domain is stable inthe membrane and provides good receptor stability. Endodomain The endodomain or cytoplasmic domain refers to the intracellular portion of the CAR whichcomprises one or multiple intracellular signalling domains that induce T cell activatorysignalling upon CAR target binding. Upon CAR target binding, the intracellular domains activate downstream signalling processes. So-called first-generation CARs use, for example, the CD3ζ signalling domain in the absence of any co-stimulatory domains. Upon target binding, this domain transmits an activation signalto the T cell via its three ITAM domains. The CD3ζ signalling domain alone may not provide afully competent activation signal for sustained signalling and T cell persistence andproliferation. Second- and third-generation CARs add a single or multiple co-stimulatorydomain(s), respectively, to provide enhanced signalling and T cell activation.In the CAR of the present invention the endodomain may comprise a CD3ζ signalling domain.Further intracellular signalling domains are known in the art, for example, FcyRIII, FcsRI, the cytoplasmic tail of an Fc receptor and immunoreceptor tyrosine-based activation motif (ITAM) bearing cytoplasmic receptors. The endodomain of the CAR of the present invention may further comprise a costimulatory signalling domain. The costimulatory domain may comprise a CD28 co-stimulatory domain. The endodomain of the CAR of the present invention may comprise a CD3ζ signalling domain and a CD28 co-stimulatory domain. Other co-stimulatory endodomains are known in the art, for example, CD28, CD137 (4-1BB),CD134 (OX40), DaplO, CD27, CD2, CD5, ICAM-1, LFA-1, Lck, TNFR-I, TNFR-II, Fas, CD30and CD40. The endodomain of the CAR of the present invention may comprise a costimulatory domain selected from the group consisting of the endodomains of CD28, 4-1BB, OX40, CD27 andICOS. The endodomain of the CAR of the present invention may comprise a CD3ζ signallingdomain and one or more costimulatory domains selected from the group consisting of the endodomains of CD28, 4-1BB, OX40, CD27 and ICOS. The CAR of the present invention may comprise one or more intracellular signalling domains.The one or more intracellular signalling domains may comprise a human CD3ζ or a murineCD3ζ. The one or more intracellular signalling domains may comprise a human or a murineCD3ζ and a further co-stimulatory domain. The further co-stimulatory domain may be a humanCD28 co-stimulatory domain or a murine CD28 co-stimulatory domain.The CAR of the present invention may comprise a sequence selected from the groupconsisting of SEQ ID NOs: 8-11.SEQ ID NO: 8 (murine CD28 intracellular domain):NSRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPARDFAAYRPSEQ ID NO: 9 (human CD28 intracellular domain):RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSSEQ ID NO: 10 (murine CD3ζ intracellular domain):LRAKFSRSAETAANLQDPNQLYNELNLGRREEYDVLEKKRARDPEMGGKQQRRRNPQEGVYNALQKDK MAEAYSEIGTKGERRRGKGHDGLYQGLSTATKDTYDALHMQTLAPRSEQ ID NO: 11 (human CD3ζ intracellular domain):RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMA EAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR In some embodiments, the CAR comprises the intracellular signalling domains of sequenceidentical to SEQ ID NOs: 8 and 9, or variants thereof having at least 80% sequence identity toSEQ ID NOs: 8 and 9.In some embodiments, the CAR comprises the intracellular signalling domains of sequenceidentical to SEQ ID NOs: 10 and 11, or a variant thereof having at least 80% sequence identityto SEQ ID NOs: 10 and 11.In some embodiments, the CAR comprises the intracellular signalling domains of sequenceSEQ ID NOs: 8 and 9.In some embodiments, the CAR comprises the intracellular signalling domains of sequenceSEQ ID NOs: 10 and 11. A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%sequence identity to any one of SEQ ID NOs: 8 to 11, provided that the intracellular signallingdomain provides an effective intracellular T cell signalling domain which is able to provideactivation signals for T cells and / or co-stimulatory signalling. The CAR of the present invention may, for example, comprise an activatory intracellular signalling domain, for example CD3ζ, in combination with a further co-stimulatory intracellularsignalling domain, for example a CD28 co-stimulatory domain.In preferred embodiments, the CAR of the present invention comprises a human CD28 intracellular signalling domain and a human CD3ζ intracellular signalling domain. In some preferred embodiments, the intracellular portion (endodomain) of the CAR of the present invention consists of a human CD28 intracellular signalling domain and a human CD3ζ intracellular signalling domain. In other embodiments, the CAR of the present invention comprises a murine CD28 intracellular signalling domain and a murine CD3ζ intracellular signalling domain. In some embodiments, the intracellular portion (endodomain) of the CAR of the present invention consists of a murine CD28 intracellular signalling domain and a murine CD3ζ intracellular signalling domain. In some embodiments, the endodomain comprises a CD28 intracellular signalling domain. In some preferred embodiments, the CD28 intracellular signalling domain is linked to a CD28 transmembrane domain. In a preferred embodiment, the endodomain comprises a human CD28 intracellular signallingdomain, and a human CD3ζ intracellular signalling domain, wherein the CD28 intracellularsignalling domain is linked to a human CD28 transmembrane domain. CAR structure The CAR of the present invention may comprise: an antigen-binding domain, a spacer domain, a transmembrane domain, and an endodomain comprising one or more intracellular signalling domains. The skilled person would understand that linkers may be used between any of the domains. Suitable linker sequences are known in the art. A linker sequence may be, for example, an amino acid of SEQ ID NO: 20. SEQ ID NO: 20 (spacer peptide) SGSG In one embodiment, the CAR has the general structure:Integrin-binding peptide - IgG1 spacer – CD4 transmembrane domain – CD28 intracellulardomain - CD3ζ intracellular domain.In a further embodiment, the CAR has the general structure:Integrin-binding peptide – murine IgG1 spacer – murine CD4 transmembrane domain – murineCD28 intracellular domain – murine CD3ζ intracellular domain.In another embodiment, the CAR has the general structure:Integrin-binding peptide – IgG1 hinge – CD28 transmembrane domain – CD28 intracellulardomain - CD3ζ intracellular domain.In a further embodiment, the CAR has the general structure:Integrin-binding peptide – human IgG1 hinge – human CD28 transmembrane domain – humanCD28 intracellular domain – human CD3ζ intracellular domain.In another embodiment, the CAR has the general structure:Integrin-binding peptide – NWL spacer - CD28 transmembrane domain – CD28 intracellulardomain - CD3ζ intracellular domain.In a further embodiment, the CAR has the general structure:Integrin-binding peptide – human NWL spacer – human CD28 transmembrane domain –human CD28 intracellular domain – human CD3ζ intracellular domain.In another embodiment, the CAR has the general structure:Integrin-binding peptide – CH2CH3 spacer - CD28 transmembrane domain – CD28intracellular domain - CD3ζ intracellular domain.In a further embodiment, the CAR has the general structure:Integrin-binding peptide – human CH2CH3 spacer – human CD28 transmembrane domain –human CD28 intracellular domain – human CD3ζ intracellular domain.The CAR of the present invention may comprise or consist of an amino acid sequenceselected from the group consisting of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 13, andSEQ ID NO: 12, or a variant thereof with at least 80% sequence identity to any of SEQ ID NOs: 12-15. SEQ ID NO: 14 (RGDL-human CAR NWL): FETLRGDLRILSILRHQNLLKELQDSGSGKPVKEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVC EPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGS GLVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRST PPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNPLIKFWVLVVVGGVLACY SLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQ QGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRR GKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 15 (RGDL-human CAR CH2CH3): FETLRGDLRILSILRHQNLLKELQDSGSGKPVEPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLM IARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLIKFWVLVV VGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSR SADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEI GMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 13 (RGDL-human CAR hinge): FETLRGDLRILSILRHQNLLKELQDSGSGKPVEPKSCDKTHTCPPCPPLIKFWVLVVVGGVLACYSLL VTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQ NQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKG HDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 12 (RGDL-murine CAR): FETLRGDLRILSILRHQNLLKELQDSGSGDPVPRDGGCKPCICTVPEVSSVFIFPPKPKDVLTITLTP KVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNS AAFPAPIEKTISKTKGRPKAPQVCTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKN TQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGIVFLACVLGGSFGFL GFLGLCILCCVNSRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPARDFAAYRPLRAKFSRSAETAANLQ DPNQLYNELNLGRREEYDVLEKKRARDPEMGGKQQRRRNPQEGVYNALQKDKMAEAYSEIGTKGERRR GKGHDGLYQGLSTATKDTYDALHMQTLAPR In some preferred embodiments, the CAR comprises an amino acid sequence of SEQ ID NO: 14 or 15, or a variant thereof with at least 80% sequence identity to SEQ ID NO: 14 or 15. In some preferred embodiments, the CAR consists of an amino acid sequence of SEQ ID NO: 14 or 15. A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 12 to 15, provided that the CAR is able to i) bind integrinαvβ6 and alternatively integrin αvβ6 and αvβ8, and ii) induce T cell signalling.The CAR of the present invention may comprise or consist of an amino acid sequence selected from the group consisting of SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 43 and SEQ ID NO: 42, or a variant thereof with at least 80% sequence identity to SEQ ID NOs: 42- 45. SEQ ID NO: 44 (RGDE-human CAR NWL): MEFGLSWVFLVALLRGVQCFETLRGDERILSILRHQNLLKELQDSGSGKPVKEACPTGLYTHSGECCK ACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGY YQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECT RWADAECEEIPGRWITRSTPPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTD NPLIKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDF AAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQ KDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 45 (RGDE-human CAR CH2CH3): MEFGLSWVFLVALLRGVQCFETLRGDERILSILRHQNLLKELQDSGSGKPVEPKSPDKTHTCPPCPAP PVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGKLIKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQ PYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQ EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 43 (RGDE-human CAR hinge): MEFGLSWVFLVALLRGVQCFETLRGDERILSILRHQNLLKELQDSGSGKPVEPKSCDKTHTCPPCPPL IKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAY RSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDK MAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 42 (RGDE-murine CAR): MDFQVQIFSFLLISASVIMSRFETLRGDERILSILRHQNLLKELQDSGSGDPVPRDGGCKPCICTVPE VSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVS ELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVCTIPPPKEQMAKDKVSLTCMITDF FPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKS LSHSPGIVFLACVLGGSFGFLGFLGLCILCCVNSRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPARDF AAYRPLRAKFSRSAETAANLQDPNQLYNELNLGRREEYDVLEKKRARDPEMGGKQQRRRNPQEGVYNA LQKDKMAEAYSEIGTKGERRRGKGHDGLYQGLSTATKDTYDALHMQTLAPR In some embodiments, the CAR comprises an amino acid sequence of SEQ ID NO: 44 or 45,or a variant thereof with at least 80% sequence identity to SEQ ID NO: 44 or 45.In some embodiments, the CAR consists of an amino acid sequence of SEQ ID NO: 44 or 45. A variant sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 42 to 45, provided that the CAR is able to i) bind integrin αvβ6 and ii) induce T cell signalling. The CAR of the present invention may, when initially expressed in a cell, additionally comprise a signal peptide at the N-terminus. The CAR of the present invention may, for example comprise a polypeptide sequence of SEQ ID NOs: 12-15, or a variant of at least 80% sequence identity thereto, and further comprise a signal peptide of SEQ ID NO: 23 or 24 at the N- terminus. In an embodiment, the CAR of the present invention, when initially expressed in a cell, comprises a polypeptide sequence of SEQ ID NO: 12, or a variant of at least 80% sequence identity thereto, and additionally comprises a signal peptide of SEQ ID NO: 23 at the N- terminus. In preferred embodiments, the CAR of the present invention, when initially expressed in a cell,comprises a polynucleotide sequence of SEQ ID NOs: 13-15, or a variant of at least 80%sequence identity thereto, and additionally comprises a signal peptide of SEQ ID NO: 24. In a particularly preferred embodiment, the CAR of the present invention, when initially expressed in a cell, comprises a polynucleotide sequence of SEQ ID NO: 14, or a variant of at least 80% sequence identity thereto, and additionally comprises a signal peptide of SEQ ID NO: 24 at the N-terminus. In other embodiments, the CAR of the present invention may comprise a polypeptidesequence of SEQ ID NOs: 42-45, or a variant of at least 80% sequence identity thereto, andfurther comprise a signal peptide of SEQ ID NO: 23 or 24 at the N-terminus. In one embodiment, the CAR of the present invention, when initially expressed in a cell, comprises a polypeptide sequence of SEQ ID NO: 42, or a variant of at least 80% sequence identity thereto, and additionally comprises a signal peptide of SEQ ID NO: 23 at the N- terminus. In some embodiments, the CAR of the present invention, when initially expressed in a cell, comprises a polynucleotide sequence of SEQ ID NOs: 43-45, or a variant of at least 80% sequence identity thereto, and additionally comprises a signal peptide of SEQ ID NO: 24. Signal peptide Signal peptides, also known as leader peptides or signal sequences, are short peptides that are able to influence the targeting of a protein within a cell, for example targeting a protein to a secretion pathway. The CAR of the present invention may comprise a signal peptide. The CAR of the present invention may comprise a signal peptide at its N-terminus. In some embodiments, the CAR lacks a signal peptide. In some embodiments, the nucleotide sequence encoding the CAR lacks a nucleotide sequence encoding a signal peptide. The signal peptide may be derived from a naturally occurring signal peptide from a native protein. The signal peptide may be a synthetic signal peptide (Park et al., 2022, AppliedMicrobiology and Biotechnology 106, 3571–3582, https: / / doi.org / 10.1007 / s00253-022-11955-6). The signal peptide may be derived from a murine or human native protein. In some embodiments, the signal peptide is derived from a murine IgGκ signal sequence, or the signal peptide is derived from a human immunoglobulin heavy chain signal sequence. The CAR of the present invention may comprise a signal peptide sequence of SEQ ID NO: 23 or 24, or a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 23 or 24. SEQ ID NO: 23 (murine LK leader) MDFQVQIFSFLLISASVIMSR SEQ ID NO: 24 (human leader) MEFGLSWVFLVALLRGVQC Nucleic acid The present invention further provides a nucleic acid encoding a CAR as defined above.The nucleic acid encoding the CAR may comprise a polynucleotide sequence encoding achromogranin A peptide, or a fragment or derivative thereof. The chromogranin A peptide, orfragment or derivative thereof may have an amino acid sequence SEQ ID NO: 1, or asequence with at least 80% identity thereto. The polynucleotide sequence encoding the amino acid sequence SEQ ID NO: 1, or a sequence with at least 80% identity thereto, may be codon optimised, wherein the degeneracy of the genetic code is utilised to replace codons with codons encoding the same amino acid that are more efficiently transcribed. The nucleic acid sequence encoding the CAR may comprise a polynucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 1, or a sequence with at least 80% identity thereto, wherein said polynucleotide sequence consists of the polynucleotide sequence of SEQ ID NO: 21 or 22, or a variant thereof with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 21 or 22, wherein the variant sequence encodes the amino acid of SEQ ID NO: 1, or a sequence with at least 80% identity thereto. The nucleotide sequence encoding the CAR may comprise a polynucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 1, or a sequence with at least 80% identity thereto, wherein said polynucleotide sequence consists of the polynucleotide sequence of SEQ ID NO: 46, or a variant thereof with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 46, wherein the variant sequence encodes the amino acid of SEQ ID NO: 1, or a sequence with at least 80% identity thereto. SEQ ID NO: 21 (murine nucleotide sequence encoding RGDL peptide) ttcgagaccctgaggggcgacctgaggatcctgagcatcctgaggcaccagaacctgctgaaggagct gcaggac SEQ ID NO: 22 (human codon-optimised nucleotide sequence encoding RGDL peptide) ttcgagaccctgagaggcgacctgagaatcctgagcatcctgagacaccagaacctgctgaaggagct gcaggac SEQ ID NO: 46 (human nucleotide sequence encoding RGDL peptide) tttgagacactccgaggagatttgcggatcctttccattctgagacatcagaatttactgaaggagct ccaagac Where the CAR comprises an integrin-binding peptide comprising an RGDE sequence, a nucleic acid sequence encoding the CAR may comprise a polynucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 35, or a sequence with at least 80% identity thereto, wherein said polynucleotide sequence consists of the polynucleotide sequence of SEQ ID NO: 36 or 37, or a variant thereof with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 36 or 37, wherein the variant sequence encodes the amino acid of SEQ ID NO: 35, or a sequence with at least 80% identity thereto. The nucleotide sequence encoding the CAR may comprise a polynucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 1, or a sequence with at least 80% identity thereto, wherein said polynucleotide sequence consists of the polynucleotide sequence of SEQ ID NO: 47, or a variant thereof with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 47, wherein the variant sequence encodes the amino acid of SEQ ID NO: 1, or a sequence with at least 80% identity thereto. SEQ ID NO: 36 (murine nucleotide sequence encoding RGDE peptide) ttcgagaccctgaggggcgacgagaggatcctgagcatcctgaggcaccagaacctgctgaaggagct gcaggacSEQ ID NO: 37 (human codon-optimised nucleotide sequence encoding RGDE peptide)ttcgagaccctgaggggcgacgagaggatcctgagcatcctgaggcaccagaacctgctgaaggagct gcaggac SEQ ID NO: 47 (human nucleotide sequence encoding RGDE peptide) tttgagacactccgaggagatgaacggatcctttccattctgagacatcagaatttactgaaggagct ccaagac The nucleic acid encoding the CAR may comprise a polynucleotide sequence selected from the group consisting of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 17 and SEQ ID NO: 16,or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%sequence identity to any one of SEQ ID NOs: 16-19. The nucleic acid encoding the CAR may consist of a polynucleotide sequence selected from the group consisting of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 17 and SEQ ID NO: 16, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 16-19. In some preferred embodiments, the CAR may comprise a polynucleotide sequence of SEQID NO: 18 or 19, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%,97%, 98%, or 99% sequence identity to SEQ ID NO: 18 or 19.SEQ ID NO: 18 (RGDL-human CAR NWL) ttcgagaccctgagaggcgacctgagaatcctgagcatcctgagacaccagaacctgctgaaggagct gcaggacagcggcagcggcaaaccggtcaaagaggcctgccccaccggcctgtacacccacagcggag agtgctgcaaggcctgcaacctgggagagggcgtggcccagccttgcggcgccaatcagaccgtgtgc gagccctgcctggacagcgtgaccttcagcgacgtggtgtccgccaccgagccctgcaagccttgcac cgagtgtgtgggcctgcagagcatgagcgccccctgcgtggaagccgacgacgccgtgtgtagatgcg cctacggctactaccaggacgagacaaccggcagatgcgaggcctgtagagtgtgcgaggccggcagc ggcctggtgttcagttgtcaagacaagcagaataccgtgtgtgaagagtgccccgacggcacctacag cgacgaggccaaccacgtggacccctgcctgccctgcactgtgtgcgaggacaccgagcggcagctgc gcgagtgcacaagatgggccgacgccgagtgcgaagagatccccggcagatggatcaccagaagcacc ccccctgagggcagcgacagcaccgcccctagcacccaggaacctgaggcccctcccgagcaggacct gatcgcctctacagtggccggcgtggtgacaaccgtgatgggcagctctcagcccgtggtgacacggg gcaccaccgacaatcccttaattaaattgggtgctggtggtggttggtggagtcctggcttgctatag cttgctagtaacagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtg actacatgaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccacca cgcgacttcgcagcctatcgctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagca gggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaaga gacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaat gaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggagggg caaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcaca tgcaggccctgcctcctcgctaa SEQ ID NO: 19 (RGDL-human CAR CH2CH3) ttcgagaccctgagaggcgacctgagaatcctgagcatcctgagacaccagaacctgctgaaggagct gcaggacagcggcagcggcaaaccggtagagcccaagagccccgacaagacccacacctgtcccccct gtcctgcccctccagtggccggacctagcgtgttcctgttccccccaaagcccaaggacaccctgatg atcgcccggacccccgaagtgacctgcgtggtggtggacgtgtcccacgaggaccctgaagtgaagtt caattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagtacaaca gcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagaatacaag tgcaaggtctccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaagggccagcc ccgcgagccccaggtgtacacactgccccccagccgggacgagctgaccaagaaccaggtgtccctga cctgcctcgtgaaaggcttctaccccagcgatatcgccgtggaatgggagagcaacggccagcccgag aacaactacaagaccaccccccctgtgctggacagcgacggctcattcttcctgtacagcaagctgac cgtggacaagagccggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcaca accactacacccagaagtccctgagcctgagccccggcaagttaattaaattttgggtgctggtggtg gttggtggagtcctggcttgctatagcttgctagtaacagtggcctttattattttctgggtgaggag taagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgca agcattaccagccctatgccccaccacgcgacttcgcagcctatcgctccagagtgaagttcagcagg agcgcagacgcccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaag agaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaagga agaaccctcaggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagatt gggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccac caaggacacctacgacgcccttcacatgcaggccctgcctcctcgctaa SEQ ID NO: 17 (RGDL-human CAR hinge) ttcgagaccctgagaggcgacctgagaatcctgagcatcctgagacaccagaacctgctgaaggagct gcaggacagcggcagcggcaaaccggtcgagcccaagagctgcgacaagacccacacctgtcccccct gcccccccttaattaaattttgggtgctggtggtggttggtggagtcctggcttgctatagcttgcta gtaacagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacat gaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgact tcgcagcctatcgctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccag aaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtgg ccgggaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgc agaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaagggg cacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggc cctgcctcctcgctaa SEQ ID NO: 16 (RGDL-murine CAR) ttcgagaccctgaggggcgacctgaggatcctgagcatcctgaggcaccagaacctgctgaaggagct gcaggacagcggcagcggcgatcctgtgcccagggatggtggttgtaagccttgcatatgtacagtcc cagaagtatcatctgtcttcatcttccccccaaagcccaaggatgtgctcaccattactctgactcct aaggtcacgtgtgttgtggtagacatcagcaaggatgatcccgaggtccagttcagctggtttgtaga tgatgtggaggtgcacacagctcagacgcaaccccgggaggagcagttcaacagcactttccgctcag tcagtgaacttcccatcatgcaccaggactggctcaatggcaaggagttcaaatgcagggtcaacagt gcagctttccctgcccccatcgagaaaaccatctccaaaaccaaaggcagaccgaaggctccacaggt gtgcaccattccacctcccaaggagcagatggccaaggataaagtcagtctgacctgcatgataacag acttcttccctgaagacattactgtggagtggcagtggaatgggcagccagcggagaactacaagaac actcagcccatcatggacacagatggctcttacttcgtctacagcaagctcaatgtgcagaagagcaa ctgggaggcaggaaatactttcacctgctctgtgttacatgagggcctgcacaaccaccatactgaga agagcctctcccactctcctggtattgtgttcctggcttgcgtgctgggtggctccttcggctttctg ggtttccttgggctctgcatcctctgctgtgtcaatagtagaaggaacagactccttcaaagtgacta catgaacatgactccccggaggcctgggctcactcgaaagccttaccagccctacgcccctgccagag actttgcagcgtaccgccccctgagagcaaaattcagcaggagtgcagagactgctgccaacctgcag gaccccaaccagctctacaatgagctcaatctagggcgaagagaggaatatgacgtcttggagaagaa gcgggctcgggatccagagatgggaggcaaacagcagaggaggaggaacccccaggaaggcgtataca atgcactgcagaaagacaagatggcagaagcctacagtgagatcggcacaaaaggcgagaggcggaga ggcaaggggcacgatggcctttaccagggtctcagcactgccaccaaggacacctatgatgccctgca tatgcagaccctggcccctcgctaa The nucleic acid encoding the CAR may comprise a polynucleotide sequence selected from the group consisting of SEQ ID NO: 49, SEQ ID NO: 50, and SEQ ID NO: 48, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 48-50. The nucleic acid encoding the CAR may consist of a polynucleotide sequence selected fromthe group consisting of SEQ ID NO: 49, SEQ ID NO: 50, and SEQ ID NO: 48, or a variantthereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 48-50. In some preferred embodiments, the CAR may comprise a polynucleotide sequence of SEQID NO: 49 or 50, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%,97%, 98%, or 99% sequence identity to SEQ ID NO: 49 or 50.SEQ ID NO: 49 (RGDL-human CAR NWL) tttgagacactccgaggagatttgcggatcctttccattctgagacatcagaatttactgaaggagct ccaagacagcggcagcggcaaaccggtcaaagaggcctgccccaccggcctgtacacccacagcggag agtgctgcaaggcctgcaacctgggagagggcgtggcccagccttgcggcgccaatcagaccgtgtgc gagccctgcctggacagcgtgaccttcagcgacgtggtgtccgccaccgagccctgcaagccttgcac cgagtgtgtgggcctgcagagcatgagcgccccctgcgtggaagccgacgacgccgtgtgtagatgcg cctacggctactaccaggacgagacaaccggcagatgcgaggcctgtagagtgtgcgaggccggcagc ggcctggtgttcagttgtcaagacaagcagaataccgtgtgtgaagagtgccccgacggcacctacag cgacgaggccaaccacgtggacccctgcctgccctgcactgtgtgcgaggacaccgagcggcagctgc gcgagtgcacaagatgggccgacgccgagtgcgaagagatccccggcagatggatcaccagaagcacc ccccctgagggcagcgacagcaccgcccctagcacccaggaacctgaggcccctcccgagcaggacct gatcgcctctacagtggccggcgtggtgacaaccgtgatgggcagctctcagcccgtggtgacacggg gcaccaccgacaatcccttaattaaattgggtgctggtggtggttggtggagtcctggcttgctatag cttgctagtaacagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtg actacatgaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccacca cgcgacttcgcagcctatcgctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagca gggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaaga gacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaat gaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggagggg caaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcaca tgcaggccctgcctcctcgctaa SEQ ID NO: 50 (RGDL-human CAR CH2CH3) tttgagacactccgaggagatttgcggatcctttccattctgagacatcagaatttactgaaggagct ccaagacagcggcagcggcaaaccggtagagcccaagagccccgacaagacccacacctgtcccccct gtcctgcccctccagtggccggacctagcgtgttcctgttccccccaaagcccaaggacaccctgatg atcgcccggacccccgaagtgacctgcgtggtggtggacgtgtcccacgaggaccctgaagtgaagtt caattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagtacaaca gcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagaatacaag tgcaaggtctccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaagggccagcc ccgcgagccccaggtgtacacactgccccccagccgggacgagctgaccaagaaccaggtgtccctga cctgcctcgtgaaaggcttctaccccagcgatatcgccgtggaatgggagagcaacggccagcccgag aacaactacaagaccaccccccctgtgctggacagcgacggctcattcttcctgtacagcaagctgac cgtggacaagagccggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcaca accactacacccagaagtccctgagcctgagccccggcaagttaattaaattttgggtgctggtggtg gttggtggagtcctggcttgctatagcttgctagtaacagtggcctttattattttctgggtgaggag taagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgca agcattaccagccctatgccccaccacgcgacttcgcagcctatcgctccagagtgaagttcagcagg agcgcagacgcccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaag agaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaagga agaaccctcaggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagatt gggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccac caaggacacctacgacgcccttcacatgcaggccctgcctcctcgctaa SEQ ID NO: 48 (RGDL-human CAR hinge) tttgagacactccgaggagatttgcggatcctttccattctgagacatcagaatttactgaaggagct ccaagacagcggcagcggcaaaccggtcgagcccaagagctgcgacaagacccacacctgtcccccct gcccccccttaattaaattttgggtgctggtggtggttggtggagtcctggcttgctatagcttgcta gtaacagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacat gaacatgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgact tcgcagcctatcgctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccag aaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtgg ccgggaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgc agaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaagggg cacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggc cctgcctcctcgctaa The nucleic acid encoding the CAR may also be exemplified by the following further embodiments: The nucleic acid encoding the CAR may comprise a polynucleotide sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 55 and SEQ ID NO: 54, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 54-57. The nucleic acid encoding the CAR may consist of a polynucleotide sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 55 and SEQ ID NO: 54, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 54-57. In some preferred embodiments, the CAR may comprise a polynucleotide sequence of SEQ ID NO: 56 or 57, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 56 or 57. SEQ ID NO: 56 (RGDL-human CAR NWL) atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgctttgagacact ccgaggagatttgcggatcctttccattctgagacatcagaatttactgaaggagctccaagacagcg gcagcggcaaaccggtcaaagaggcctgccccaccggcctgtacacccacagcggagagtgctgcaag gcctgcaacctgggagagggcgtggcccagccttgcggcgccaatcagaccgtgtgcgagccctgcct ggacagcgtgaccttcagcgacgtggtgtccgccaccgagccctgcaagccttgcaccgagtgtgtgg gcctgcagagcatgagcgccccctgcgtggaagccgacgacgccgtgtgtagatgcgcctacggctac taccaggacgagacaaccggcagatgcgaggcctgtagagtgtgcgaggccggcagcggcctggtgtt cagttgtcaagacaagcagaataccgtgtgtgaagagtgccccgacggcacctacagcgacgaggcca accacgtggacccctgcctgccctgcactgtgtgcgaggacaccgagcggcagctgcgcgagtgcaca agatgggccgacgccgagtgcgaagagatccccggcagatggatcaccagaagcaccccccctgaggg cagcgacagcaccgcccctagcacccaggaacctgaggcccctcccgagcaggacctgatcgcctcta cagtggccggcgtggtgacaaccgtgatgggcagctctcagcccgtggtgacacggggcaccaccgac aatcccttaattaaattgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaa cagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacatgaac atgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgc agcctatcgctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaacc agctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgg gaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaa agataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacg atggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctg cctcctcgctaa SEQ ID NO: 57 (RGDL-human CAR CH2CH3) atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgctttgagacact ccgaggagatttgcggatcctttccattctgagacatcagaatttactgaaggagctccaagacagcg gcagcggcaaaccggtagagcccaagagccccgacaagacccacacctgtcccccctgtcctgcccct ccagtggccggacctagcgtgttcctgttccccccaaagcccaaggacaccctgatgatcgcccggac ccccgaagtgacctgcgtggtggtggacgtgtcccacgaggaccctgaagtgaagttcaattggtacg tggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagtacaacagcacctaccgg gtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagaatacaagtgcaaggtctc caacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcccc aggtgtacacactgccccccagccgggacgagctgaccaagaaccaggtgtccctgacctgcctcgtg aaaggcttctaccccagcgatatcgccgtggaatgggagagcaacggccagcccgagaacaactacaa gaccaccccccctgtgctggacagcgacggctcattcttcctgtacagcaagctgaccgtggacaaga gccggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcacaaccactacacc cagaagtccctgagcctgagccccggcaagttaattaaattttgggtgctggtggtggttggtggagt cctggcttgctatagcttgctagtaacagtggcctttattattttctgggtgaggagtaagaggagca ggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattaccag ccctatgccccaccacgcgacttcgcagcctatcgctccagagtgaagttcagcaggagcgcagacgc ccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacg atgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcag gaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaagg cgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacct acgacgcccttcacatgcaggccctgcctcctcgctaa SEQ ID NO: 55 (RGDL-human CAR hinge) atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgctttgagacact ccgaggagatttgcggatcctttccattctgagacatcagaatttactgaaggagctccaagacagcg gcagcggcaaaccggtcgagcccaagagctgcgacaagacccacacctgtcccccctgccccccctta attaaattttgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaacagtggc ctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactc cccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctat cgctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaaccagctcta taacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctg agatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataag atggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggcct ttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgcctcctc gctaa SEQ ID NO: 54 (RGDL-murine CAR) atggattttcaggtgcagattttcagcttcctgctaatcagtgcctcagtcataatgtctagattcga gaccctgaggggcgacctgaggatcctgagcatcctgaggcaccagaacctgctgaaggagctgcagg acagcggcagcggcgatcctgtgcccagggatggtggttgtaagccttgcatatgtacagtcccagaa gtatcatctgtcttcatcttccccccaaagcccaaggatgtgctcaccattactctgactcctaaggt cacgtgtgttgtggtagacatcagcaaggatgatcccgaggtccagttcagctggtttgtagatgatg tggaggtgcacacagctcagacgcaaccccgggaggagcagttcaacagcactttccgctcagtcagt gaacttcccatcatgcaccaggactggctcaatggcaaggagttcaaatgcagggtcaacagtgcagc tttccctgcccccatcgagaaaaccatctccaaaaccaaaggcagaccgaaggctccacaggtgtgca ccattccacctcccaaggagcagatggccaaggataaagtcagtctgacctgcatgataacagacttc ttccctgaagacattactgtggagtggcagtggaatgggcagccagcggagaactacaagaacactca gcccatcatggacacagatggctcttacttcgtctacagcaagctcaatgtgcagaagagcaactggg aggcaggaaatactttcacctgctctgtgttacatgagggcctgcacaaccaccatactgagaagagc ctctcccactctcctggtattgtgttcctggcttgcgtgctgggtggctccttcggctttctgggttt ccttgggctctgcatcctctgctgtgtcaatagtagaaggaacagactccttcaaagtgactacatga acatgactccccggaggcctgggctcactcgaaagccttaccagccctacgcccctgccagagacttt gcagcgtaccgccccctgagagcaaaattcagcaggagtgcagagactgctgccaacctgcaggaccc caaccagctctacaatgagctcaatctagggcgaagagaggaatatgacgtcttggagaagaagcggg ctcgggatccagagatgggaggcaaacagcagaggaggaggaacccccaggaaggcgtatacaatgca ctgcagaaagacaagatggcagaagcctacagtgagatcggcacaaaaggcgagaggcggagaggcaa ggggcacgatggcctttaccagggtctcagcactgccaccaaggacacctatgatgccctgcatatgc agaccctggcccctcgctaa The nucleic acid encoding the CAR may comprise a polynucleotide sequence selected from the group consisting of SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 39 and SEQ ID NO: 38, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 38-40.The nucleic acid encoding the CAR may consist of a polynucleotide sequence selected fromthe group consisting of SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 39 and SEQ ID NO: 38, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%sequence identity to any one of SEQ ID NOs: 38-40.In some preferred embodiments, the CAR may comprise a polynucleotide sequence of SEQ ID NO: 40 or 41, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 40 or 41. SEQ ID NO: 40 (RGDE-human CAR NWL (RGDE-hCAR NWL) nucleotide) atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgcttcgagaccct gaggggcgacgagaggatcctgagcatcctgaggcaccagaacctgctgaaggagctgcaggacagcg gcagcggcaaaccggtcaaagaggcctgccccaccggcctgtacacccacagcggagagtgctgcaag gcctgcaacctgggagagggcgtggcccagccttgcggcgccaatcagaccgtgtgcgagccctgcct ggacagcgtgaccttcagcgacgtggtgtccgccaccgagccctgcaagccttgcaccgagtgtgtgg gcctgcagagcatgagcgccccctgcgtggaagccgacgacgccgtgtgtagatgcgcctacggctac taccaggacgagacaaccggcagatgcgaggcctgtagagtgtgcgaggccggcagcggcctggtgtt cagttgtcaagacaagcagaataccgtgtgtgaagagtgccccgacggcacctacagcgacgaggcca accacgtggacccctgcctgccctgcactgtgtgcgaggacaccgagcggcagctgcgcgagtgcaca agatgggccgacgccgagtgcgaagagatccccggcagatggatcaccagaagcaccccccctgaggg cagcgacagcaccgcccctagcacccaggaacctgaggcccctcccgagcaggacctgatcgcctcta cagtggccggcgtggtgacaaccgtgatgggcagctctcagcccgtggtgacacggggcaccaccgac aatcccttaattaaattgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaa cagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacatgaac atgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgc agcctatcgctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaacc agctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgg gaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaa agataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacg atggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctg cctcctcgctaaSEQ ID NO: 41 (RGDE-human CAR CH2CH3 (RGDE-hCAR CH2CH3) nucleotide)atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgcttcgagaccct gaggggcgacgagaggatcctgagcatcctgaggcaccagaacctgctgaaggagctgcaggacagcg gcagcggcaaaccggtagagcccaagagccccgacaagacccacacctgtcccccctgtcctgcccct ccagtggccggacctagcgtgttcctgttccccccaaagcccaaggacaccctgatgatcgcccggac ccccgaagtgacctgcgtggtggtggacgtgtcccacgaggaccctgaagtgaagttcaattggtacg tggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagtacaacagcacctaccgg gtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagaatacaagtgcaaggtctc caacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcccc aggtgtacacactgccccccagccgggacgagctgaccaagaaccaggtgtccctgacctgcctcgtg aaaggcttctaccccagcgatatcgccgtggaatgggagagcaacggccagcccgagaacaactacaa gaccaccccccctgtgctggacagcgacggctcattcttcctgtacagcaagctgaccgtggacaaga gccggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcacaaccactacacc cagaagtccctgagcctgagccccggcaagttaattaaattttgggtgctggtggtggttggtggagt cctggcttgctatagcttgctagtaacagtggcctttattattttctgggtgaggagtaagaggagca ggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattaccag ccctatgccccaccacgcgacttcgcagcctatcgctccagagtgaagttcagcaggagcgcagacgc ccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacg atgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcag gaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaagg cgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacct acgacgcccttcacatgcaggccctgcctcctcgctaa SEQ ID NO: 39 (RGDE-human CAR hinge (RGDE-hCAR hinge) nucleotide) atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgcttcgagaccct gaggggcgacgagaggatcctgagcatcctgaggcaccagaacctgctgaaggagctgcaggacagcg gcagcggcaaaccggtcgagcccaagagctgcgacaagacccacacctgtcccccctgccccccctta attaaattgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaacagtggcct ttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccc cgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctatcg ctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaaccagctctata acgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgag atggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataagat ggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggccttt accagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgcctcctcgc taa SEQ ID NO: 38 (RGDE-murine CAR (RGDE-mCAR) nucleotide) atggattttcaggtgcagattttcagcttcctgctaatcagtgcctcagtcataatgtctagattcga gaccctgaggggcgacgagaggatcctgagcatcctgaggcaccagaacctgctgaaggagctgcagg acagcggcagcggcgatcctgtgcccagggatggtggttgtaagccttgcatatgtacagtcccagaa gtatcatctgtcttcatcttccccccaaagcccaaggatgtgctcaccattactctgactcctaaggt cacgtgtgttgtggtagacatcagcaaggatgatcccgaggtccagttcagctggtttgtagatgatg tggaggtgcacacagctcagacgcaaccccgggaggagcagttcaacagcactttccgctcagtcagt gaacttcccatcatgcaccaggactggctcaatggcaaggagttcaaatgcagggtcaacagtgcagc tttccctgcccccatcgagaaaaccatctccaaaaccaaaggcagaccgaaggctccacaggtgtgca ccattccacctcccaaggagcagatggccaaggataaagtcagtctgacctgcatgataacagacttc ttccctgaagacattactgtggagtggcagtggaatgggcagccagcggagaactacaagaacactca gcccatcatggacacagatggctcttacttcgtctacagcaagctcaatgtgcagaagagcaactggg aggcaggaaatactttcacctgctctgtgttacatgagggcctgcacaaccaccatactgagaagagc ctctcccactctcctggtattgtgttcctggcttgcgtgctgggtggctccttcggctttctgggttt ccttgggctctgcatcctctgctgtgtcaatagtagaaggaacagactccttcaaagtgactacatga acatgactccccggaggcctgggctcactcgaaagccttaccagccctacgcccctgccagagacttt gcagcgtaccgccccctgagagcaaaattcagcaggagtgcagagactgctgccaacctgcaggaccc caaccagctctacaatgagctcaatctagggcgaagagaggaatatgacgtcttggagaagaagcggg ctcgggatccagagatgggaggcaaacagcagaggaggaggaacccccaggaaggcgtatacaatgca ctgcagaaagacaagatggcagaagcctacagtgagatcggcacaaaaggcgagaggcggagaggcaa ggggcacgatggcctttaccagggtctcagcactgccaccaaggacacctatgatgccctgcatatgc agaccctggcccctcgctaa The nucleic acid encoding the CAR may comprise a polynucleotide sequence selected from the group consisting of SEQ ID NO: 52, SEQ ID NO: 53, and SEQ ID NO: 51, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 51-53. The nucleic acid encoding the CAR may consist of a polynucleotide sequence selected from the group consisting of SEQ ID NO: 52, SEQ ID NO: 53, and SEQ ID NO: 51, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 51-53. In some preferred embodiments, the CAR may comprise a polynucleotide sequence of SEQ ID NO: 52 or 53, or a variant thereof with at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 52 or 53.SEQ ID NO: 52 (RGDE-human CAR NWL (RGDE-hCAR NWL) nucleotide)atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgctttgagacact ccgaggagatgaacggatcctttccattctgagacatcagaatttactgaaggagctccaagacagcg gcagcggcaaaccggtcaaagaggcctgccccaccggcctgtacacccacagcggagagtgctgcaag gcctgcaacctgggagagggcgtggcccagccttgcggcgccaatcagaccgtgtgcgagccctgcct ggacagcgtgaccttcagcgacgtggtgtccgccaccgagccctgcaagccttgcaccgagtgtgtgg gcctgcagagcatgagcgccccctgcgtggaagccgacgacgccgtgtgtagatgcgcctacggctac taccaggacgagacaaccggcagatgcgaggcctgtagagtgtgcgaggccggcagcggcctggtgtt cagttgtcaagacaagcagaataccgtgtgtgaagagtgccccgacggcacctacagcgacgaggcca accacgtggacccctgcctgccctgcactgtgtgcgaggacaccgagcggcagctgcgcgagtgcaca agatgggccgacgccgagtgcgaagagatccccggcagatggatcaccagaagcaccccccctgaggg cagcgacagcaccgcccctagcacccaggaacctgaggcccctcccgagcaggacctgatcgcctcta cagtggccggcgtggtgacaaccgtgatgggcagctctcagcccgtggtgacacggggcaccaccgac aatcccttaattaaattgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaa cagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacatgaac atgactccccgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgc agcctatcgctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaacc agctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgg gaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaa agataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacg atggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctg cctcctcgctaaSEQ ID NO: 53 (RGDE-human CAR CH2CH3 (RGDE-hCAR CH2CH3) nucleotide)atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgctttgagacact ccgaggagatgaacggatcctttccattctgagacatcagaatttactgaaggagctccaagacagcg gcagcggcaaaccggtagagcccaagagccccgacaagacccacacctgtcccccctgtcctgcccct ccagtggccggacctagcgtgttcctgttccccccaaagcccaaggacaccctgatgatcgcccggac ccccgaagtgacctgcgtggtggtggacgtgtcccacgaggaccctgaagtgaagttcaattggtacg tggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagtacaacagcacctaccgg gtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagaatacaagtgcaaggtctc caacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcccc aggtgtacacactgccccccagccgggacgagctgaccaagaaccaggtgtccctgacctgcctcgtg aaaggcttctaccccagcgatatcgccgtggaatgggagagcaacggccagcccgagaacaactacaa gaccaccccccctgtgctggacagcgacggctcattcttcctgtacagcaagctgaccgtggacaaga gccggtggcagcagggcaacgtgttcagctgcagcgtgatgcacgaggccctgcacaaccactacacc cagaagtccctgagcctgagccccggcaagttaattaaattttgggtgctggtggtggttggtggagt cctggcttgctatagcttgctagtaacagtggcctttattattttctgggtgaggagtaagaggagca ggctcctgcacagtgactacatgaacatgactccccgccgccccgggcccacccgcaagcattaccag ccctatgccccaccacgcgacttcgcagcctatcgctccagagtgaagttcagcaggagcgcagacgc ccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacg atgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcag gaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaagg cgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacct acgacgcccttcacatgcaggccctgcctcctcgctaaSEQ ID NO: 51 (RGDE-human CAR hinge (RGDE-hCAR hinge) nucleotide)atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgctttgagacact ccgaggagatgaacggatcctttccattctgagacatcagaatttactgaaggagctccaagacagcg gcagcggcaaaccggtcgagcccaagagctgcgacaagacccacacctgtcccccctgccccccctta attaaattgggtgctggtggtggttggtggagtcctggcttgctatagcttgctagtaacagtggcct ttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccc cgccgccccgggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctatcg ctccagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaaccagctctata acgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgag atggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataagat ggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggccttt accagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgcctcctcgc taa The nucleotide sequence encoding the CAR of the present invention may additionally comprise a nucleotide sequence encoding a signal peptide. In some embodiments, the nucleotide sequence encoding the CAR of the present inventionmay additionally comprise a nucleotide sequence of SEQ ID NO: 33 or 34, or a sequence withat least 70% identity thereto. In some embodiments, the additional nucleotide sequence ofSEQ ID NO: 33 or 34, or a sequence with at least 70% sequence identity thereto, is linked at the 5’ end of the sequence encoding the CAR. SEQ ID NO: 33 (nucleotide encoding murine LK leader): atggattttcaggtgcagattttcagcttcctgctaatcagtgcctcagtcataatgtctaga SEQ ID NO: 34 (nucleotide encoding human leader): atggagttcggcctgagctgggtgttcctggtggccctgctgagaggcgtgcagtgc In some embodiments, the nucleotide sequence encoding the CAR of the invention comprises a sequence selected from any of SEQ ID NOs: 16-19, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 33 or 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In preferred embodiments, the nucleotide sequence encoding the CAR of the invention comprises a sequence of SEQ ID NO: 18 or 19, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequenceencoding the signal peptide is linked at the 5’ end of the CAR sequence.In a particularly preferred embodiment, the nucleotide sequence encoding the CAR of the invention comprises a sequence of SEQ ID NO: 18, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In some embodiments, the nucleotide sequence encoding the CAR of the invention comprises a sequence selected from any of SEQ ID NOs: 48-50, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 33 or 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In preferred embodiments, the nucleotide sequence encoding the CAR of the invention comprises a sequence of SEQ ID NO: 49 or 50, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In a particularly preferred embodiment, the nucleotide sequence encoding the CAR of the invention comprises a sequence of SEQ ID NO: 49, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In some embodiments, the nucleotide sequence encoding the CAR of the invention comprises a sequence selected from any of SEQ ID NOs: 38-41, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 33 or 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In some embodiments, the nucleotide sequence encoding the CAR of the invention comprises a sequence selected from any of SEQ ID NO: 40 or 41, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In one embodiment, the nucleotide sequence encoding the CAR of the invention comprises a sequence of SEQ ID NO: 40, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In some embodiments, the nucleotide sequence encoding the CAR of the invention comprises a sequence selected from any of SEQ ID NOs: 51-53, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 33 or 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In some embodiments, the nucleotide sequence encoding the CAR of the invention comprises a sequence selected from any of SEQ ID NO: 52 or 53, or a sequence with at least 70% identity thereto, and additionally comprises a nucleotide sequence of SEQ ID NO: 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. In one embodiment, the nucleotide sequence encoding the CAR of the invention comprises asequence of SEQ ID NO: 52, or a sequence with at least 70% identity thereto, and additionallycomprises a nucleotide sequence of SEQ ID NO: 34, or a sequence with at least 70% identity thereto encoding a signal peptide, wherein the nucleotide sequence encoding the signal peptide is linked at the 5’ end of the CAR sequence. The polynucleotide of the invention may comprise one or more expression control sequence. Suitably, the nucleic acid sequence encoding the CAR and / or any other polynucleotides of interest are operably linked to one or more expression control sequence. As used herein, the term “operably linked” means that parts (e.g. the nucleic acid sequence encoding the CAR and the one or more expression control sequence) are linked together in a manner which enables both to carry out their function substantially unhindered. As used herein an “expression control sequence” may refer to a nucleotide sequence which controls expression of a transgene, e.g. to facilitate and / or increase expression. The expression control sequence and the transgene may be in any suitable arrangement in the polynucleotide, providing that the expression control sequence is operably linked to the transgene (e.g. nucleic acid sequence encoding the CAR or any other nucleotide sequence of interest). In some embodiments, the expression control sequence is a promoter. Any suitable promoter may be used, the selection of which may be readily made by the skilled person. The promoter sequence may be constitutively active (i.e. operational in any host cell background), or alternatively may be active only in a specific host cell environment, thus allowing for targeted expression of the nucleotide of interest (e.g. CAR) in a particular cell type (e.g. a tissue-specific promoter). The promoter may show inducible expression in response to presence of another factor, for example a factor present in a host cell. In any event, where the vector is administered for therapy, it is preferred that the promoter should be functional in the target cell background. In some embodiments, the polynucleotide further comprises a promoter operably linked to the nucleic acid sequence encoding the CAR or other nucleotide of interest. In some embodiments, the promoter is a constitutive promoter. In one embodiment, the nucleotide sequence encoding the CAR is operably linked to one or more promoter(s). In one embodiment, the nucleotide sequences encoding the CAR and any other polynucleotide of interest are operably linked to one or more promoter(s). In one embodiment, the nucleotide sequences encoding the CAR and any other polynucleotide of interest are operably linked to the same promoter. The nucleotide sequences encoding the CAR and any other polynucleotide of interest may share a promoter such that their expression may be regulated by a single regulatory sequence.In one embodiment, the nucleotide sequences encoding the CAR and polynucleotide ofinterest are independently operably linked to one or more promoter(s). The nucleotide sequences encoding the polynucleotide of interest and the CAR may each beoperably linked to a separate promoter such that their expression may be independentlyregulated by independent regulatory sequences. In one embodiment, the nucleotide sequences encoding the polynucleotide of interest and the CAR are operably linked to separate promoter(s). In one embodiment, the polynucleotide of interest and the CAR are encoded in opposing directions. In one embodiment, the polynucleotide of interest and the CAR are encoded in opposing directions and are independently operably linked to separate promoters. In one embodiment, the polynucleotide of interest and the CAR are encoded in the same direction. In one embodiment, the promoter is selected from the group consisting of: a cytomegalovirus promoter (CMV), a human phosphoglycerate kinase promoter (PGK), an EF-1α promoter and an inducible NFAT promoter. In one embodiment, the promoter is a cytomegalovirus (CMV) promoter. In another embodiment, the promoter is a minimal cytomegalovirus (mCMV or minCMV)promoter (mCMV, see, for example, Amendola Nat Biotech.2005;23:108-116).In one embodiment, the promoter is human phosphoglycerate kinase (PGK) promoter. In one embodiment, the promoter is an EF-1α promoter. In one embodiment, the promoter is an an inducible NFAT promoter. The inducible modulemay be composed of a synthetic NFAT response element usually comprising repetitions ofthe consensus NFAT binding site placed upstream of a minimal promoter.It will be understood by a skilled person that numerous different polynucleotides and nucleicacids can encode the same polypeptide as a result of the degeneracy of the genetic code. Inaddition, it is to be understood that skilled persons may, using routine techniques, make nucleotide substitutions that do not affect the polypeptide sequence encoded by the polynucleotides described here to reflect the codon usage of any particular host organism in which the polypeptides are to be expressed. Nucleic acids according to the invention may comprise DNA or RNA. They may be single- stranded or double-stranded. They may also be polynucleotides which include within them synthetic or modified nucleotides. A number of different types of modification to oligonucleotides are known in the art. These include methylphosphonate andphosphorothioate backbones, addition of acridine or polylysine chains at the 3' and / or 5' endsof the molecule. For the purposes of the use as described herein, it is to be understood that the polynucleotides may be modified by any method available in the art. Such modificationsmay be carried out in order to enhance the in vivo activity or life span of polynucleotides ofinterest. The terms “variant”, “homologue” or “derivative” in relation to a nucleotide sequence include any substitution of, variation of, modification of, replacement of, deletion of or addition of one(or more) nucleic acid from or to the sequence.Vector A vector is a tool that allows or facilitates the transfer of an entity from one environment to another. The present invention further provides a vector comprising a nucleic acid sequence or nucleic acid construct of the invention. Suitably, said vector may be used to introduce said nucleic acid sequence or construct into a host cell, for example, so that the host cell expresses and / oris capable of expressing a CAR according to the invention. The vector may be used to maintainsaid nucleic acid within the cell. Vectors comprising polynucleotides of the invention may be introduced into cells using a variety of techniques known in the art, such as transfection, transduction and transformation. Transfection may refer to a general process of incorporating a nucleic acid into a cell and includes a process using a non-viral vector to deliver a polynucleotide to a cell. Transduction may refer to a process of incorporating a nucleic acid into a cell using a viral vector. Examples of vectors include, but are not limited to, plasmids, chromosomes, artificial chromosomes and viruses. The vector may also be, for example, a naked nucleic acid (e.g. DNA). The vector of the invention may be a viral vector. Examples of viral vectors include, retroviral,lentiviral, adenoviral, adeno-associated viral, baculoviral and herpes simplex viral vectors.Viral vectors may be used to introduce a nucleic acid sequence to a host cell via transduction. The vector of the invention may be non-viral. Non-viral vectors may be used to introduce a nucleic acid sequence to a host cell via DNA transfection. Typical transfection methods include electroporation, DNA biolistics, lipid-mediated transfection, compacted DNA-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic agent-mediated transfection, and cationic facial amphiphiles (CFAs). Cell The present invention further provides a cell comprising a CAR according to the present invention. The present invention further provides a population of cells comprising a CAR according to the present invention. The cell(s) may comprise a CAR polypeptide of the present invention, a polynucleotide encoding a CAR of the present invention, and / or a vector comprising a polynucleotide encoding a CAR of the present invention. The cell(s) may be an immune cell. The cell(s) may be a lymphocyte. The cell(s) may be a T cell, a natural killer (NK) cell, or a natural killer T (NKT) cell. T cells, also referred to as T cellsor T lymphocytes, are lymphocytes that play a key role in adaptive immunity. They aredistinguishable from other lymphocytes such as NK cells and B cells by the expression of thecell-surface T cell receptor (TCR). NKT cells express cell-surface T cell receptor (TCR) butshare some properties and activities of NK cells. There are many subsets of T cells, with a variety of activities and functions. T cells may be divided by the expression of CD4 or CD8. CD4+ T cells are known as T helper cells, and comprise multiple subsets including TH1, TH2, TH9, TH17, TH22, T follicular helper (Tfh), and Tregulatory (Treg) cells. CD8+ T cells are known as cytotoxic T cells or cytotoxic T-lymphocytes(CTLs), and comprise subsets including Tc1, Tc2, Tc9, Tc17, and Tc22. T cell subsets showlarge heterogeneity and may have significant overlap with other subsets. Conventional T helper cells (CD4+) promote the activity of other immune cells, including, among others, CD8+ T cells, NK cells, and B-cells. The type of immune cell activated depends on the subset of T helper cell activated, which will depend on the type of pathogen being responded to. CD4+ T cells are activated when they recognise peptide antigen presented by MHC class II molecules on the surface of antigen presenting cells (APCs).Regulatory T cells (Tregs) are a subset of CD4+ T cells that function to supress the immuneresponse, by inhibiting T cell proliferation and activation. They are important in inhibiting T cellactivation towards the end of an immune response, and in inhibiting autoreactive T cells thatescaped negative selection in the thymus. However, Tregs can also act as a barrier to effectiveantitumor immune response by preventing T cell activity in tumour sites.Cytolytic T cells (CTLs) are CD8+ T cells that can directly destroy target body cells that areinfected or malignant. CTLs identity such cells and are activated when they recognise peptide antigen presented by MHC Class I molecules on the surface of nucleated body cells. CTLs induce apoptosis by multiple mechanisms, including releasing perforin-containing granules that create pores in target cell membranes, and releasing granzymes which trigger apoptosis via a caspase cascade. CTLs also release pro-inflammatory cytokines which contribute to the local immune response including via macrophage activation. Memory T cells may be either CD4+ or CD8+. Memory T cells are a subpopulation of T cells that persist long-term after an immune response to a particular antigen has resolved. The subsequent activation of the immune response to a repeat occurrence of the antigen is rapid due to the quick expansion of this memory T cell population. Human memory cells aredistinguishable by the typical expression of CD45RO on the cell surface. A further subset ofhuman memory cells, termed stem memory cells, are distinguishable by the expression ofCD45RA on the cell surface rather than CD45RO. Gamma delta (γδ) T cells are an unconventional T cell that are found at lower abundance than the “classical” T cells. The “classical” T cells express heterodimeric T cell receptors (TCRs) comprising α and β TCR chains. The gamma delta T cells express heterodimeric T cell receptors formed instead from γ and δ TCR chains. Gamma delta T cells are activated in anon-MHC restricted manner, where the γδ TCR may be able to variably recognise markers ofcell stress, including metabolites, heat shock proteins or lipids and glycolipids presented bythe MHC-related CD1 protein depending on the gamma and delta chains present.Natural killer T (NKT) cells are T lymphocytes that function similarly to both innate natural killer (NK) cells and adaptive T cells. NKTs express a T cell receptor, which depending on the NKT subtype can be semi-invariant comprising Valpha14-Jalpha18 chains paired with Vbeta8.2,Vbeta7, or Vbeta2 in type I, or invariant, NKTs, or comprise a more diverse range of T cell receptors in type II, or variant, NKTs. These cells can recognise glycolipid antigen presented by CD1d molecules. Cytokine-Induced Killer (CIK) cells are a heterogenous population of cytotoxic T lymphocytes, which express CD3 and CD56. These cells do not require antigen-specific stimuli for activationand show non-MHC-restricted cytotoxicity (Cappuzello E. et al., Cytokine & Growth FactorReviews.2017;36:99-105).The cell provided by the present invention may be any of the T cell types described above.The cell of the present invention may be a natural killer (NK) cell. Natural killer (NK) cells are a cell of the innate immune system. NK cells can destroy cells that are infected or malignant in a peptide-MHC independent manner. NK cells are able to identify cells that have altered cell surface protein expression, including down-regulation of MHC class I molecules on the cell surface. An inhibitory signal is generated when NK cells recognise MHC class I via KIR family receptors. In the absence or reduction of this signal, and presence of activating signals from activation receptors, NK cells are activated and cytolysis of the target cell occurs. The cell of the present invention may be any cell type mentioned above. Suitably, the cell of the present invention is a cytolytic immune cell. In one embodiment, the cell of the present invention is a T cell. In another embodiment, the cell of the present invention is a natural killer (NK) cell. The present invention provides a method of making the cell of the invention. The method may comprise introducing the nucleotide and / or vector of the invention into the cell, for example by transfection or transduction.Suitably, the cell of the present invention may be from a sample (e.g. peripheral blood, bonemarrow or umbilical cord blood) isolated from a subject. The cell (e.g. the cytolytic immune cell or progenitor thereof) may be further separated from the sample by any suitable method known in the art, for example leukaphoresis, fluorescence-activated cell sorting (FACS) or magnetic-activated cell sorting (MACS). The sample may be obtained from a subject to be treated with the cell of the present invention, or the sample may be obtained from a third party not requiring treatment with the cell of the present invention. The cell of the present invention may be generated by a method comprising the following steps: (i) isolation of a cell-containing sample from a subject, or, provision of a cell-containing sample; (ii) transduction or transfection of the cell-containing sample with the vector of the invention, to provide a population of engineered cells. The cell(s) may be cultured prior to, or after, introduction of the vector of the present invention.The population of engineered cells may be further cultured after transduction or transfection.The population of engineered cells may be further separated from the cell-containing sample, using any suitable method known in the art. The population of engineered cells may be further treated to activate the cells to provide more effective function (e.g. anti-tumour and cytolytic activity). The steps may be performed in a closed and sterile cell culture system. The cell of the present invention may be used for adoptive cell transfer. As used herein the term “adoptive cell transfer” refers to the administration of a cell population to a patient. The cell may be isolated from a subject and the vector of the invention may be introduced by amethod described herein before the cell is administered to the patient.Adoptive cell transfer may be allogenic or autologous. By “autologous cell transfer” it is to be understood that the starting population of cells is obtained from the same subject as that to which the transduced cell population is administered. Autologous transfer is advantageous as it avoids problems associated with immunological incompatibility and is available to subjects irrespective of the availability of a genetically matched donor. By “allogeneic cell transfer” it is to be understood that the starting population of cells is obtained from a different subject as that to which the transduced cell population is administered. Optionally, the donor will be genetically matched to the subject to which the cells are administered to minimise the risk of immunological incompatibility. Alternatively, the donor may be mismatched and unrelated to the patient. Suitable doses of transduced cell populations are such as to be therapeutically and / or prophylactically effective. The dose to be administered may depend on the subject and condition to be treated, and may be readily determined by a skilled person. Safety switch In cell therapies, it may be desirable to have the ability to remove a donor cell population following administration to a subject. This is so that, should the donor cells produce undesirable or damaging effects in a subject, the cause of these effects (i.e. the donor cells)can be removed. Such effects might include, for example, an immune response in the subject,or some undesired off-target effect of the donor cells. Suicide switch Suicide switches are genes which cause induced toxicity in cells in which they are present. Examples include expression of enzymes that are particularly effective at converting a non- toxic drug to a toxic compound, or apoptotic genes which can be induced. An example suicide switch is the herpes simplex virus thymidine kinase (HSV-TK) (see, for example, US9005945B2). A non-toxic substrate (gangciclovir) is converted by HSV-TK in cells expressing the enzyme into chain-terminating gangciclovir triphosphate. Gangciclovir may be used to selectively kill cells expressing HSV-TV, leaving other cells unaffected. Other suicide switches include iCasp9 (see, for example, US9089520B2). Truncation of Caspase 9 and replacement of the caspase recruitment domain with a multimeric ligand binding region, allows Caspase 9 activity (i.e. apoptotic activity) to be activated through providing the ligand of the ligand binding region. In some embodiments, the nucleic acid or vector of the invention further encodes a suicide switch (e.g. a suicide switch described herein). In some embodiments, the nucleic acid or vector of the invention further encodes herpes simplex virus thymidine kinase (HSV-TK). In some embodiments, the cell of the invention further comprises a suicide switch (e.g. a suicide switch described herein). In some embodiments, the cell of the invention further comprises herpes simplex virus thymidine kinase (HSV-TK). Targetable moiety In some embodiments, the cell of the invention is genetically engineered to express a targetable moiety. Suitably, the targetable moiety is a cell-surface marker that can be targetedby a small molecule or biologic to enable removal, for example by killing the cell of theinvention. In some embodiments, the targetable moiety is a truncated human EGFR (tEGFR)or a CD20 polypeptide. Truncated human EGFR (tEGFR) lacks the intracellular signalling domain and extracellular ligand binding domain, but is still able to be targeted by well-known methods of targetingEGFR, including by anti-EGFR antibody cetuximab (see, for example, WO 2021 / 229075 A2). CD20 is a marker that has been a target of cancer therapies for treating malignant Blymphocytes, for example in non-Hodgkin lymphoma and chronic lymphocytic leukaemia(Pavlasova and Mraz.2020. Haematologica.). Accordingly, there are well known methods oftargeting CD20-positive cells in vivo in order to kill them. For example, Rituximab is anapproved monoclonal antibody that can kill CD20-positive cells in the body of a subject. Suitably, the safety switch may be a suicide switch or a targetable moiety. In some embodiments, the cell of the present invention comprises a safety switch. In some embodiments, the cell of the present invention comprises a polynucleotide sequence encoding a safety switch. Genetic engineering In some embodiments, the cell according to the present invention may be a genetically engineered cell. In some embodiments, the cell of the present invention is genetically engineered to comprise a nucleic acid encoding a CAR of the present invention. Suitably, the nucleic acid encoding the CAR is integrated into the genome of the cell. In some embodiments, the nucleic acid encoding the CAR is comprised within a vector that is integrated in the genome of the cell of the invention The nucleic acid encoding the CAR of the invention or the vector encoding said sequence may be integrated into the genome through any suitable means known in the art. In some embodiments, the nucleic acid or vector may be integrated into the genome by transposon-mediated integration, or nuclease mediated gene editing, such as CRISPR-Cas systems,ZFNs and TALENs. Transposon-mediated integration may be effected by the action of atransposase enzyme on a transposon nucleotide sequence that comprises at least two repeats that can bind to the transposase enzyme. In some embodiments, the vector comprising the nucleic acid encoding the CAR of the present invention may be a transposon suitable for integration by a transposon system, such as a Sleeping Beauty transposon system. In some embodiments, the transposon nucleotide sequence comprises the a nucleotide sequence encoding the CAR of the present invention, and at least two repeats that can bind to a transposase enzyme. In some embodiments, the transposon nucleotide sequence comprises (i) a nucleotide sequence encoding the CAR of the present invention, (ii) a nucleotide sequence encoding a safety switch, (iii) one or more regulatory elements that control the expression of the CAR and / or safety switch, and (iv) a pair of transposon repeat sequences. In some embodiments, the nucleotide sequence encoding the CAR (i) and the nucleotide sequence encoding the safety switch (ii) are fused such that the genes are transcribed as a single transcript, and the encoded CAR and safety switch polypeptides are separated by a self-cleaving T2A peptidebetween them. In some embodiments, the one or more regulatory elements (iii) may includeone or more promoters and / or enhancers, and / or post-transcriptional regulatory elementssuch as a polyA sequence and / or WPRE. In some embodiments, the pair of transposon repeatsequences are inverse repeat (IR) sequences. In some embodiments, the transposoncomprises, from 5’-3’, a first IR sequence, a promoter sequence, the nucleotide sequence encoding the CAR of the present invention, a nucleotide sequence encoding a self-cleaving T2A peptide, a nucleotide sequence encoding a safety switch, a WPRE sequence, a polyA sequence, and a second IR sequence. Pharmaceutical composition The present invention also relates to a pharmaceutical composition comprising a therapeutic agent of the invention, such as a nucleotide, vector, cell, or population of cells of the present invention. The pharmaceutical composition may comprise, in addition to the therapeutic agent, a pharmaceutically acceptable carrier, diluent or excipient. The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as (or in addition to) the carrier, excipient or diluent, any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), and other carrier agent(s). The pharmaceutical composition may optionally comprise one or more further pharmaceutically active polypeptides or compounds. Such a formulation may, for example, be in a form suitable for intravenous administration. Subject and use The CAR, nucleotide, vector, cell, population of cells, or pharmaceutical composition may be for use as a medicament. The CAR, nucleotide, vector, cell, population of cells, orpharmaceutical composition may be for use in treating or preventing cancer in a subject inneed thereof. The subject may be a patient. The patient may be a human patient. The patient may be a non- human animal. The patient may be afflicted with a cancer. Alternatively, the patient may be at risk of developing a cancer. The patient may be diagnosed with a cancer by any suitable means known to those of skill in the art. For example, patients may be diagnosed by imaging, such as computerised tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, ultrasound or X-ray, or they may be diagnosed with a biopsy, a physical exam, or via blood tests, such as blood smear, complete blood count, or analysis of circulating cancer biomarkers. The patient may have been previously determined to be at risk of developing a cancer. The increased risk may have been determined by genetic screening and / or by reviewing the patient’s family history. The patient may have been determined to express one or moregenetic markers indicative of an increased risk of developing a cancer.Suitably, a person skilled in the art will be aware of genetic risk factors (e.g. genetic markers) associated with increased risk of developing a cancer. The skilled person may use any suitable method or technique known in the art to determine whether the subject has an increased risk of developing a cancer. The subject may have previously received treatment for the cancer. The subject may be in remission from the cancer. The subject may be resistant to chemotherapy. The cancer may be a primary or secondary cancer. Secondary cancer may be the result of metastasis of a primary cancer to a further location in the body. Metastatic disease maypresent with a much lower survival rate than primary cancer, and be a significant cause ofcancer-related morbidity and mortality. αvβ6 integrin can be upregulated in several solid tumour types, including tumours of the pancreas, head and neck, skin, lung, oesophagus, stomach, colon, breast, uterine cervix, andfallopian tube / ovary (Saha A. et al., The Journal of Pathology. 2010;222:1:52-63). αvβ8 canbe upregulated in various carcinoma cells (McCarty J.H., Journal of Cell Science. 2020;133(12):jcs239434). αvβ6 and αvβ8 integrins have also been shown by the present inventors to be expressed on several human leukaemias and lymphomas, including T cell, B cell and myeloid malignancies (see Example 8). The cancer may be a solid tumour that has upregulated and / or overexpressed levels of αvβ6and / or αvβ8 integrin. Suitably, the αvβ6 and / or αvβ8 integrin may be upregulated and / oroverexpressed compared to corresponding non-cancerous cell types or tissues. The αvβ6 and αvβ8 integrin expression level of the cancer may have been previously determined, and / or the cancer may be a cancer type known in the art to express αvβ6 and αvβ8 integrin. Suitably, the αvβ6 and / or αvβ8 integrin may be upregulated and / or overexpressed at the RNA or protein level. Methods to determine whether a cancer expresses or overexpresses αvβ6 and / or αvβ8 integrin are known in the art, and include reverse transcription polymerase chain reaction (RT- PCR), Western blotting, flow cytometry, fluorescent microscopy, and immunohistochemistry. The cancer may be a solid tumour, also known as an organ tumour, or a liquid tumour, alsoknown as blood cancer or haematological malignancy. A solid tumour may refer to, forexample, a carcinoma, a sarcoma, or a lymphoma. Blood cancer may refer to, for example, a leukaemia, a myeloma, or a lymphoma. The cancer may be a solid tumour selected from the group consisting of lung cancer, breast cancer, oesophageal cancer, gastric cancer, colon cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, head and neck cancers, synovial sarcoma, angiosarcoma,osteosarcoma, thyroid cancer, endometrial cancer, neuroblastoma, rabdomyosarcoma, livercancer, melanoma, prostate cancer, renal cancer, soft tissue sarcoma, urothelial cancer, biliary cancer, glioblastoma, cervical cancer and colorectal cancer. Suitably, the cancer may be a solid tumour selected from the group consisting of melanoma, lung, ovarian and prostate cancer. The cancer may be a haematological malignancy selected from the group consisting of acute myeloid leukemia (AML), lymphoblastic leukemia, acute lymphoblastic leukemia(ALL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), primarymyelofibrosis, essential thrombocythemia, polycythemia vera, atypical chronic myeloid leukemia, chronic myeloid leukemia (CML), lymphoma, multiple myeloma, non Hodgkin lymphoma and Hodgkin lymphoma. In particular embodiments of the invention, the cancer may be selected from the group comprising lung cancer, ovarian cancer, prostate cancer, pancreatic cancer and melanoma. The pancreatic cancer may be pancreatic ductal adenocarcinoma (PDAC). Secondary cancers (metastases) are the development of malignant growths at a secondary location away from the primary site of the cancer. They most commonly develop due to cancer cells breaking away from the main tumour and entering the bloodstream or lymphatic system and establishing a tumour at a new location. The liver is one of the most common sites for metastasis, accounting for nearly 25% of metastatic cases. The double blood supply to the liver of the portal vein and the hepatic artery is hypothesised to increase the deposition of circulating cancer cells there according to the “mechanical and hemodynamic hypothesis”. The “seed-and-soil” hypothesis considers that some primary tumours selectively target the liver as a favourable metastatic location. The majority of liver metastases are carcinomas, particularly adenocarcinoma. In particular embodiments of the invention, the cancer may be metastatic disease. In some embodiments, the cancer may be metastatic pancreatic ductal adenocarcinoma, or metastatic melanoma. In some embodiments, the cancer may be liver metastases of pancreatic ductal adenocarcinoma. The invention provides the CAR, nucleotide, vector, cell, population of cells, and / or pharmaceutical composition of the invention for use in the treatment or prevention of cancer in a subject in need thereof. The invention provides the use of the CAR, nucleotide, vector, cell, population of cells, and / or pharmaceutical composition of the invention in the manufacture of a medicament for treating or preventing a cancer in a subject in need thereof. The invention provides a method for treating or preventing a cancer, wherein the nucleotide, vector, cell, population of cells, and / or pharmaceutical composition of the invention is administered to a subject in need thereof. The method of treating or preventing a cancer may involve: (i) isolating an immune cell-containing sample from a subject;(ii) transducing or transfecting said cell or population of said cells in the sample with a nucleic acid or vector of the invention; and (iii) administering the cell or population of cells from step (ii) to a subject. The subject of step (i) and step (iii) may be the same or different. Wherein the subject of step (i) and step (iii) are different, the subjects may be a HLA-matched. The method may further comprise additional steps of expanding the cell or population of cells from step (ii) to increase their number. The method may further comprise selecting cells for expression of the CAR of the present invention and / or other cell markers indicative of transduction / transfection efficacy, cell lineage, identity and / or activation status. The method may further comprise activation of the cell or cell population from step (ii) to improve their efficacy in tumour killing. The therapeutic applications provided by the invention may comprise administration of a therapeutically effective amount of the nucleotide, vector, cell, population of cells, and / or pharmaceutical composition of the invention. The term “therapeutically effective amount”, as used herein, refers to an amount of nucleotide, vector, cell, population of cells and / or pharmaceutical composition of the invention which is required to achieve an appreciable prevention or cure of a cancer; a prevention or delay of a tumour growth; and / or a reduction in severity or amelioration of one or more symptoms of a cancer. In one embodiment, wherein the cell comprising the CAR expresses the CAR on the surface of the cell, binding of the CAR to the binding target of the CAR activates intracellular signaling of the cell. In a further embodiment, binding of the CAR and the resulting intracellular signaling activates effector function in the cell of the invention. In one embodiment, the cell is a cytotoxic immune cell, and the effector function is a form of cell-mediated cytotoxicity. In one embodiment, binding of the CAR to a binding target when the CAR is expressed by a cell of the invention results in cytotoxic activity of the cell towards the cell expressing the binding target. In one embodiment, the CAR comprised by a cell of the invention is capable of binding totumour cells that express the avβ6 integrin, the avb8 integrin or both the avβ6 and avβ8integrins. In one embodiment, the CAR binding causes cytotoxic activity towards the tumour cell from the cell of the invention. In some embodiments, wherein the cell of the invention is a T-cell, the CAR binding causes T-cell mediated cytotoxicity and mediates killing of the tumour cell. In one embodiment, the CAR comprised by a cell of the invention is capable of binding to Treg cells that express avβ8 integrin. In one embodiment, the CAR binding causes cytotoxic activity towards the Treg cell. In some embodiments, wherein the cell of the invention is a T-cell, the CAR binding causes T-cell mediated cytotoxicity and mediates killing of the Treg cell. Treg cells can help promote and maintain an immunosuppressive tumour microenvironment, and negatively impact effector T cell function. Destruction of Treg cells by cells of the invention inthe tumour site may promote improved tumour killing.The invention provides a method for treating or preventing cancer, wherein a cell of the invention expressing a CAR is used to destroy tumour cells expressing avβ6 and / or avβ8 integrin. The invention provides a method for treating or preventing cancer, wherein a cell of the invention expressing a CAR is used to destroy T regulatory (Treg) cells expressing avβ8 integrin in the tumour site. The invention provides a method for treating or preventing cancer, wherein a cell of the invention expressing a CAR is used to destroy tumour cells expressing avβ6 and / or avβ8 integrin and to destroy T regulatory (Treg) cells expressing avβ8 integrin in the tumour site. Administration The nucleotide, vector, cell, population of cells, and / or pharmaceutical composition of the invention may be administered by a variety of routes that make the agent bioavailable. For example, the agent can be administered parenterally, intraperitoneally, intravenously, subcutaneously, transcutaneously, intramuscularly, and / or via local delivery for example by catheter or stent. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject and it will vary with the age, weight and response of the particular patient. The dosage is such that it is sufficient to have anti-tumour activity, such as to destroy tumour cells or reduce tumour growth. Variants, derivatives, analogues, homologues and fragments In addition to the specific proteins and polynucleotides mentioned herein, the present invention also encompasses the use of variants, derivatives, analogues, homologues and fragments thereof. In the context of the present invention, a variant of any given sequence is a sequence in which the specific sequence of residues (whether amino acid or nucleic acid residues) has been modified in such a manner that the polypeptide or polynucleotide in question substantially retains at least one of its endogenous functions. A variant sequence can be obtained byaddition, deletion, substitution, modification, replacement and / or variation of at least oneresidue present in the naturally-occurring protein. The term “derivative” as used herein, in relation to proteins or polypeptides of the present invention includes any substitution of, variation of, modification of, replacement of, deletion of and / or addition of one (or more) amino acid residues from or to the sequence providing that the resultant protein or polypeptide substantially retains at least one of its endogenous functions. The term “analogue” as used herein, in relation to polypeptides or polynucleotides includes any mimetic, that is, a chemical compound that possesses at least one of the endogenous functions of the polypeptides or polynucleotides which it mimics. Proteins used in the present invention may also have deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent protein. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and / or the amphipathic nature of the residues as long as the endogenous function is retained. For example, negatively charged amino acidsinclude aspartic acid and glutamic acid; positively charged amino acids include lysine andarginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include asparagine, glutamine, serine, threonine and tyrosine. A substitution may involve replacement of an amino acid for a similar amino acid (a conservative substitution). A similar amino acid is one which has a side chain moiety with related properties as grouped together, for example as shown below:(i) basic side chains: lysine (K), arginine (R), histidine (H);(ii) acidic side chains: aspartic acid (D) and glutamic acid (E); (iii) uncharged polar side chains: asparagine (N), glutamine (Q), serine (S), threonine (T) and tyrosine (Y); or (iv) non-polar side chains: glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), methionine (M), tryptophan (W) and cysteine (C). Variant sequences may comprise amino acid substitutions, additions, deletions and / or insertions. Conservative substitutions, additions or deletions may be made, for example according to the Table below. Amino acids in the same block in the second column and preferably in the same line in the third column may be substituted for each other: ALIPHATIC Non-polar G A PI L V Polar – uncharged C S T MN Q Polar - charged D EK R H AROMATIC F W Y The present invention also encompasses homologous substitution (substitution and replacement are both used herein to mean the interchange of an existing amino acid residue, with an alternative residue), e.g. like-for-like substitution such as basic for basic, acidic for acidic, polar for polar etc. Non-homologous substitution may also occur e.g. from one class of residue to another or alternatively involving the inclusion of unnatural amino acids, such as ornithine. The term “variant” as used herein may mean an entity having a certain homology with the wild type amino acid sequence or the wild type nucleotide sequence. The term “homology” can be equated with “identity”. A variant sequence may include an amino acid sequence which may be at least 50%, 55%, 65%, 75%, 85% or 90% identical, preferably at least 95%, at least 97%, or at least 99% identical to the subject sequence. Typically, the variants will comprise the same active sitesetc. as the subject amino acid sequence. Although homology can also be considered in termsof similarity (i.e. amino acid residues having similar chemical properties / functions), in the context of the present invention it is preferred to express homology in terms of sequence identity. A variant sequence may include a nucleotide sequence which may be at least 40%, 45%, 50%, 55%, 65%, 75%, 85% or 90% identical, preferably at least 95%, at least 97%, or at least 99% identical to the subject sequence. Although homology can also be considered in terms of similarity, in the context of the present invention it is preferred to express homology in terms of sequence identity. Preferably, reference to a sequence which has a percent identity to any one of the SEQ ID NOs detailed herein refers to a sequence which has the stated percent identity over the entire length of the SEQ ID NO referred to. Identity comparisons can be conducted by eye or, more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs can calculate percentage homology or identity between two or more sequences. Percentage homology may be calculated over contiguous sequences, i.e. one sequence is aligned with the other sequence and each amino acid in one sequence is directly compared with the corresponding amino acid in the other sequence, one residue at a time. This is called an “ungapped” alignment. Typically, such ungapped alignments are performed only over a relatively short number of residues. Although this is a very simple and consistent method, it fails to take into consideration that, for example, in an otherwise identical pair of sequences, one insertion or deletion in the nucleotide sequence may cause the following codons to be put out of alignment, thus potentially resulting in a large reduction in percent homology when a global alignment is performed. Consequently, most sequence comparison methods are designed to produce optimal alignments that take into consideration possible insertions and deletions without penalising unduly the overall homology score. This is achieved by inserting “gaps” in the sequence alignment to try to maximise local homology. However, these more complex methods assign “gap penalties” to each gap that occurs in the alignment so that, for the same number of identical amino acids, a sequence alignment with as few gaps as possible, reflecting higher relatedness between the two compared sequences, will achieve a higher score than one with many gaps. “Affine gap costs” are typically used that charge a relatively high cost for the existence of a gap and a smaller penalty for each subsequent residue in the gap. This is the most commonly used gap scoring system. Highgap penalties will of course produce optimised alignments with fewer gaps. Most alignmentprograms allow the gap penalties to be modified. However, it is preferred to use the default values when using such software for sequence comparisons. For example when using the GCG Wisconsin Bestfit package the default gap penalty for amino acid sequences is -12 for a gap and -4 for each extension. Calculation of maximum percentage homology therefore firstly requires the production of an optimal alignment, taking into consideration gap penalties. A suitable computer program for carrying out such an alignment is the GCG Wisconsin Bestfit package (University of Wisconsin, U.S.A.; Devereux et al. (1984) Nucleic Acids Res.12: 387). Examples of other software that can perform sequence comparisons include, but are not limited to, the BLASTpackage (see Ausubel et al. (1999) ibid – Ch.18), FASTA (Atschul et al. (1990) J. Mol. Biol.403-410) and the GENEWORKS suite of comparison tools. Both BLAST and FASTA are available for offline and online searching (see Ausubel et al. (1999) ibid, pages 7-58 to 7-60). However, for some applications, it is preferred to use the GCG Bestfit program. Another tool, called BLAST 2 Sequences is also available for comparing protein and nucleotide sequences (see FEMS Microbiol. Lett. (1999) 174: 247-50; FEMS Microbiol. Lett. (1999) 177: 187-8). Although the final percentage homology can be measured in terms of identity, the alignment process itself is typically not based on an all-or-nothing pair comparison. Instead, a scaled similarity score matrix is generally used that assigns scores to each pairwise comparison based on chemical similarity or evolutionary distance. An example of such a matrix commonlyused is the BLOSUM62 matrix – the default matrix for the BLAST suite of programs. GCG Wisconsin programs generally use either the public default values or a custom symbol comparison table if supplied (see the user manual for further details). For some applications,it is preferred to use the public default values for the GCG package, or in the case of othersoftware, the default matrix, such as BLOSUM62. Once the software has produced an optimal alignment, it is possible to calculate percentage homology, preferably percentage sequence identity. The software typically does this as part of the sequence comparison and generates a numerical result. “Fragments” are also variants and the term typically refers to a selected region of the polypeptide or polynucleotide that is of interest either functionally or, for example, in an assay. “Fragment” thus refers to an amino acid or nucleic acid sequence that is a portion of a full- length polypeptide or polynucleotide. Such variants may be prepared using standard recombinant DNA techniques such as site- directed mutagenesis. Where insertions are to be made, synthetic DNA encoding the insertion together with 5' and 3' flanking regions corresponding to the naturally-occurring sequence either side of the insertion site may be made. The flanking regions will contain convenient restriction sites corresponding to sites in the naturally-occurring sequence so that the sequence may be cut with the appropriate enzyme(s) and the synthetic DNA ligated into the cut. The DNA is then expressed in accordance with the invention to make the encoded protein. These methods are only illustrative of the numerous standard techniques known in the art for manipulation of DNA sequences and other known techniques may also be used. This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. Numeric ranges are inclusive of thenumbers defining the range. Unless otherwise indicated, any nucleic acid sequences arewritten left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively. It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The terms "comprising", "comprises" and "comprised of' as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms "comprising", "comprises" and "comprised of' also include the term "consisting of'. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. The invention will now be further described by way of Examples, which are meant to serve toassist one of ordinary skill in the art in carrying out the invention and are not intended in anyway to limit the scope of the invention. EXAMPLESExample 1 – Expression of the αv^^ / αv^^ integrins is indicative of poor prognosis in PDACand is of relevance for T cell therapy of solid tumorsTo validate the concept that αv^^ and αv^^ are relevant TAA of putative interest for CAR-Tcell therapy we first interrogated the TCGA / GTEx mRNA dataset. Individual expression ofαv^^ and αv^^ was analyzed across different tumors compared to their normal counterparts.αv^^ and αv^^ are both upregulated in PDAC, along with the CEA antigen, a known PDACassociated antigen exploited in immunotherapy approaches used as reference (heat map in Figure 1A). In addition to PDAC, also stomach adenocarcinoma (STAD) and ovarian (OV)cancer expressed increased αv^^ and αv^^ integrins levels when compared to normal tissues.Of note, in the case of additional other tumor types including cervical squamous cell carcinomaand endocervical adenocarcinoma (CESC) and glioblastoma (GBM) either αv^^ or αv^^showed increased levels compared to controls (Figure 1A). Thus, in contrast to the CEAantigen, αv^^ and αv^^ appear to be shared by a larger number of cancer histotypes. To moredeeply analyze the pattern of expression within PDAC, we directly compared expression dataof normal pancreas with those of PDAC samples (Figure 1B), including primary and metastaticliver lesions, obtained from the LIMET bio-bank of the Ospedale San Raffaele (Figure 1C).Data indicate that compared to controls, PDAC shows higher expression of both αv^^ andαv^^. Furthermore, elevated mRNA levels encoding these integrins were observed in primaryand metastatic Limet PDAC patients. Next, we interrogated the TCGA / GTEx data set to correlate integrin expression levels withobserved overall survival and disease-free survival. Patients with higher αv^^ and αv^^expression showed a worse prognosis as indicated by a shorter overall survival and disease-free survival (Figure 1D). A similar trend was observed when adopting CEA to stratify patients.Also in this case, higher CEA levels predicted worse prognosis. In addition to mRNA, proteinexpression was also upregulated within PDAC, compared to normal tissue (Figure 1E).Analysis of integrin expression during PDAC progression showed that av^^ expression was absent in normal pancreas, while it progressively increased in IPMN, and in primary andmetastatic lesions of PDAC (Figure 1F). Thus, αv^^ and αv^^ are upregulated in several othersolid tumors and phenocopied CEA, a well-known tumor-associated antigen in PDAC, therebyrepresenting valuable oncological targets.Example 2 – Generation of single αvβ6- or dual αvβ6 / αvβ8-reactive mCAR-T cellsWe previously found that the chromogranin A-derived peptide RGDE (peptide 39-63; RGDE:FETLRGDERILSILRHQNLLKELQD) recognizes av^^ with nanomolar affinity and highselectivity (Ki: 15.5 + / - 3.2 nM). The cDNA encoding for this peptide was used to substitutethe single chain variable fragment of an anti-CEA single chain within a second-generationCAR module (Chmielewski et al. Gastroenterology.2012;143(4):1095-107) and cloned at the5’-end of the CH2CH3 spacer (see scheme in Figure 2A). FACS analyses proved that the RGDE-mCAR was properly expressed on the surface of transduced primary T cells (Figure 2B). Next, we investigated the ability of RGDE-mCAR-T cells to react to immobilizedrecombinant human αv^^ integrin. T cells transduced with the RGDE-CAR or with an irrelevantCAR (CEA-mCAR) were cultured on immobilized αv^^ or as control on αv^^^or^αv^^. RGDE-mCAR and not CEA-mCAR-transduced T cells, adhered and increased in size to αv^^ andnot on αv^^^or^αv^^ (Figure 2C). In addition, only RGDE-CARTs on αv^^ produced detectableIFN-^ levels in culture supernatants (Figure 2D).In the context of CAR T cell therapy, a multiple antigen targeting approach is preferable to a single targeting one to limit tumor escape due to the selection of antigen-loss variants. We previously found that E / L substitution in amino acid 46 of the chromogranin A-derived RGDEpeptide (RGDL peptide: FETLRGDLRILSILRHQNLLKELQD) lowered the Ki to αv^^ by oneorder of magnitude (Ki:1.6+ / -0.3 nM) and transformed the peptide in a bi-selective ligand ableto bind also αv^^ (Ki:8.5 + / - 3.7 nM). Thus, we cloned the cDNA encoding for RGDL peptideat the 5’-end of the CH2CH3 spacer (see scheme in Figure 3A). The RGDL-mCAR was found to be properly expressed on the surface of transduced primary T cells (Figure 3B). RGDL- mCAR-T cells and not mock-transduced T cells proved capable of adhering and increasing insize in response to recombinant human and mouse αv^^ or αv^^^^and as not to αv^^^^adoptedas control). RGDL-mCAR-T cells did not respond to coated αv^^ or αv^^ in the presence ofan excess of free 5a-RGDL peptide, further proving specific interactions (Figure 3C). Inaddition, RGDL-CARTs and not mock or anti-CEA Ts produced detectable IFN-^ levels whencultured on αv^^ or αv^^ in culture supernatants (Figure 3D). The anti-RGDL 5A8 mAb, ableto directly bind the RGDL peptide, also induced RGDL-CAR Ts activation. Again IFN-g production was abrogated by the addition of an excess of free RGDL peptide (Figure 3D).Thus, RGDE-mCAR Ts react to αv^^ only, while RGDL-mCAR-Ts cells specifically recognizeboth αv^^ and αv^^ (of mouse and human origin).Next we cocultured RGDL-mCAR Ts or mock Ts with PDAC cells. Human BxPC-3 cells (αvβ6+ / αvβ8+), murine 5M7101 / GFP cells (αvβ6+ / αvβ8-), and human M4436 cells (avb6- / avb8- ) were adopted as representatives of αvβ6 / avb8-positive and -negative tumor cells (Figure4A). We found that RGDL-mCAR T cells expressed detectable intracellular IFN-^ expressionby 4 hours (Figure 4B, C), and produced IFN-^ in culture supernatants by 48 hours (Figure4D) in response to BXPC-3 or 5M7101 / GFP cells, but not to M4436 cells. In addition, RGDL- CAR-T cells proved specific cytotoxicity against 5M7101 / GFP by 48h (Figure 4E), and in longitudinal imaging (Figure 4F). Thus, data indicate that the CgA-derived RGDL peptidegrafted into a second-generation CAR backbone instructs recognition of αv^^ / αv^^ on mouseand human tumor cells. The finding that the peptide-moiety of these novel CAR-s confers CARTs cross-reactivity to both mouse and human target antigens grants unique opportunities in safety evaluation.Example 3 – RGDL-mCAR-T cell therapy of PDACWe then investigated whether the RGDL peptide labelled with the fluorescent IRDye800compound (5a-RGDL- IRDye800) and RGDL-mCAR T cells can recognize PDAC cells in vivo.To this purpose we adopted a chemically-stapled form of the RGDL peptide (5a peptidedescribed in Monieri et al). The 5M7101 / GFP PDAC cells were injected subcutaneously orinto the portal vein (Figure 5). Upon the development of palpable subcutaneous lesions or ofMRI-sizeable liver metastasis, the 5a-RGDL-IRDye800 peptide was injected i.v. and micewere imaged. The 5a-RGDL-IRDye800 peptide imaged subcutaneous tumor lesions in vivo(Figure 5A) and after tumor explantation (Figure 5B) in independent mice (Figure 5C).Furthermore, the 5a-RGDL-IRDye800 peptide efficiently identified MRI-detectable PDAC livermetastases (Figure 5D), which were also revealed by colocalization with the GFP signal. Of note, the signal detected in metastases-bearing mice was higher than that found in tumor-freemice (Figure 5D). These data support the hypothesis that the 5a-RGDL peptide can recognizePDAC cells also in vivo.Next, we investigated whether RGDL-mCAR-T cells can induce anti-tumor effects in vivo usingthe 5M7101 / GFP model of PDAC. 5M7101 / GFP cells were injected subcutaneously in mice.When tumors were measurable, mice were randomized, preconditioned with CTX (300 mg / kg;to facilitate T cell engraftment), and then left untreated (NT) or treated with an i.v. injection ofMock-transduced (Mock T) or RGDL-mCAR-T cells. While controls developed fast-growing tumors, RGDL-mCAR-T cells-treated mice showed delayed tumor growth (Figure 6A), withsignificantly smaller tumor AUC (Figure 6B). At the time of sacrifice mice were imaged (Figure6C). Significantly smaller tumor volumes were also identified by lower GFP-signals in mice treated with RGDL-mCAR-T cells compared to controls (Figure 6D), which is consistent with smaller tumor volumes. This was confirmed by H&E analysis of explanted tumors (Figure 6E,F). Interestingly, immunohistochemical analysis of tumor lesions identified lower αv^^expression in vivo (Figure 6G-H), possibly indicating tumor immune editing. Anti-tumortherapeutic effects were observed with no evidence of toxicity. Indeed, mouse weightappeared comparable in control untreated or anti-CEA-CAR-treated mice and RGDL-mCAR- T cell-treated mice (Figure 7A). Low amounts of inflammatory cells, prevalently of a lymphocytic nature, were found in H&E analyses of lungs, livers and kidneys treated mice (Figure 7B). In the lungs, signs of increased infiltration were found in RGDL-mCAR-T cell- treated mice, however this did not result in tissue alteration (Figure 7B). Thus, these data indicate that RGDL-mCAR-Ts control PDAC lesions in vivo, without detectable off-tumor effects.Example 4 – The RGDL-hCAR retargets human CAR-Ts to αvβ6 / β8Having found that the RGDL-mCAR allows retargeted T cells to control the growth of mouseαv^^ / αv^^ expressing PDAC, we next generated a human CAR molecule. To this aim, wecloned the sequence encoding for the RGDL peptide within a second-generation human CAR sequence (Figure 8A). The RGDL sequence was cloned at the 5’ of: i) the optimized IgG- derived spacer, namely CH2CH3, consisting of two Ig-like domains mutated in the residues key for the IgG1–FcgR interactions (Hombach, Hombach, and Abken Gene Ther.2010;17(10):1206-13); ii) the NGFR spacer (the long form), namely NWL (Casucci et al., FrontImmunol. 2018 Mar 21;9:507); and iii) a short IgG1-derived hinge, namely hinge (described inTable 2). The cDNA encoding for CD20 was also cloned into the RGDL plasmid backbone to providean additional transduction marker. An CD19 CAR in the NWL configuration was used ascontrol. PBMC were activated on CD3 / CD28-beads, transduced and expanded using IL-7 / IL- 15. FACS analyses were performed to trace CAR expression with the anti-NGFR Ab and theanti-CD20 mAb. Data depicted in Figure 8B indicate that CD19 and RGDL-based hCAR wereexpressed to similar extents. In the case of RGDL-hCAR in the NWL configuration, transduced cells expressed similar surface levels of the CAR and the CD20 marker gene. Transductionefficiency was comparable to that of RGDL-hCAR in the CH2CH3 and hinge configurationsaccording to CD20 expression (Figure 7B). The distribution of naïve and memorysubpopulations were comparable among transduced T cells (Figure 8C).Next, recognition of immobilized recombinant human αv^^ and αv^^ integrins was tested.RGDL-NWL and RGDL-CH2CH3 hCAR T cells, but not control Mock-Ts, showed a blastingphenotype by 24h and released significant levels of IFN^ in culture supernatant by 48h (Figure8D and E). In contrast, RGDL-CAR Ts in the hinge configuration failed to be activated (Figure8E). None of the CAR Ts produced IFN^ in response to human αv^^ likely due to the loweraffinity (Ki=2405 + / - 592 nM) of the RGDL peptide for this integrin (Figure 8E). Of note, RGDL-hCAR-Ts activation was inhibited by the addition of free RGDL peptide competitor (Figure 8D,E). RGDL-hCAR Ts recognized equally mouse and human αv^^ (Figure 8E). To investigatethe properties of a hCAR instructed by the RGDE peptide, we cloned the corresponding sequence within a second-generation human CAR sequence in the NWL configuration (Figure 14A). As additional control, we also exploited the RGEE mutant peptide, previously found to lack avb6 or avb8 binding properties (Nardelli et al., Chem. Commun.2019;55:14777-14780; Monieri et al. Int J Biol Sci. 2023;19(1):156-166), and prepared a RGEE-hCAR. We found RGDL, RGDE and RGEE-hCAR to be expressed in human T cells (Figure 14B). Only RGDL- hCAR Ts produced IFN-g in response to avb6 and avb8, while RGDE-hCARs only reacted to avb6 (Figure 14C). IFNg remained undetectable in Mock T and in RGEE-hCAR Ts (Figure 14C). Thus, the E to L amino acid substitution is critical to confer dual specificity to CAR-Ts. We next performed cocultures of RGDL-hCAR-T and primary (BxPC-3) or metastatic (T3M4)human PDAC cells, lung adenocarcinoma cells (H1975) expressing αv^^ and αv^^. We alsoused metastatic melanoma cells (MeWo), and ovarian carcinoma cells (IGROV-1) which onlyexpress av^^ and normal endothelial cells (HUVEC) that lack αv^^ and αv^^ expression(Figure 9A-B). We found that RGDL-hCAR Ts in the NWL configuration proved cytotoxic andreleased IFN-^ in culture supernatants when co-cultured with BxPC-3, T3M4, H1975, MeWoand IGROV-1 cells, and not in cocultures with HUVEC cells (Figure 9C, D). When comparingdifferent spacer configurations in co-culture with T3M4 cells, we found RGDL-NWL and RGDL-CH2CH3 hCAR Ts to have similar cytotoxicity and IFN-^ release, superior to that found inRGDL-Hinge CAR Ts cocultures (Figure 9E, F). This suggests that the presence of the NWL or CH2CH3 spacers contribute to integrin engagement by CAR-T cells. In conclusion, thesedata indicate that RGDL-driven human CAR-T cells can recognize αv^^ and / or αv^^-expressing tumor cells.Example 5 – RGDL-hCAR-Ts control lesions of primary and metastatic PDAC in vivoTo test the efficacy of RGDL-hCAR Ts in vivo, we xenografted primary (BxPC-3) and metastatic (T3M4) human PDAC cells in immunocompromised Nude-SCID-gamma chain deficient (NSG) mice. In the case of BxPC-3 tumors, mice received an i.v. injection of control(Mock), RGDL-hCAR T in the NWL or CH2CH3 configuration 3 days after tumor cell injection(Figure 10A). We found that both RGDL-NWL and RGDL-CH2CH3 hCAR-Ts significantlydelayed tumor progression compared to mock controls (Figure 10B). Therapeutic effects were observed in the absence of toxicity (Figure 10C). In the case of T3M4-derived tumors, micereceived i.v. injections of RGDL-NWL hCAR Ts 5 and 14 days after tumor challenge (Figure10D). Also in this case, RGDL-NWL hCAR T cells significantly controlled tumor developmentcompared to controls (Figure 10E) in the absence of toxicity (Figure 10F). Therapeuticresponse was paralleled with an increased frequency of circulating human CD45 cells in single or multiple NWL RGDL-hCAR T infusions in respect to control CD19 CAR (not shown).Protective responses were superior in the case of T3M4 cells, possibly because of therepeated injection of CAR-T cells. Overall, these data indicate that the RGDL peptide allowsthe retargeting of human T cells to αv^^ / αv^^ expressing PDAC instructing therapeuticresponses.Example 6 - RGDL-hCAR-Ts recognize av^^ / av^^ PDAC Patient-Derived Organoids (PDOs)PDOs provide an opportunity to validate target expression and therapy susceptibility PDOs provide an opportunity to validate target expression and therapy susceptibility (Peschke et al., EMBO Mol Med.2022;14(4):e14876; Tiriac et al., Cancer Discov.2018;8(9):1112-1129). First, we analyzed integrins expression by FACS using specific antibodies and the 5a-RGDL- IRDye680 conjugate. Representative images are shown in Figure 11A and B. Data indicatethat both αv^^ and αv^^ are detectable and that PDAC PDOs are specifically imaged by the5a-RGDL-IRDye680 conjugate (Figure 11A-B). Next, we set up co-cultures of PDAC PDOs and RGDL-NWL-hCAR Ts. We found that only RGDL-NWL-hCAR Ts and not CD19 CAR-Tssecreted IFN-^ in response to PDAC PDOs (Figure 11C). The abundance of IFN-^ wasproportional to the number of RGDL-hCAR Ts. RGDL-NWL-hCAR Ts also cause PDAC PDOs apoptotic cells death after 20h of coculture, indicated by caspase 3 / 7 activation (Figure 11D).We then investigated whether PDAC PDOs retained integrins expression in vivo, and whetherthis could be imaged by the 5a-RGDL-IRDye800 peptide conjugate. PDO were orthotopically injected and organs explanted. We adopted bioluminescence to image the growth of luciferase+ PDO-derived tumors in vivo. At day 30 after PDO injection, some of the micereceived an i.v. injection of 5a-RGDL-IRDye800 and 24h later were sacrificed to explant andimage the pancreas. As a control, some mice were injected with D-luciferin, but not with 5a-RGDL-IRDye800 conjugate. The results indicate that the luciferase signal was detectable inmice with PDO-derived orthotopic tumors (Figure 11E), as was the signal originated by 5a- RGDL-IRDye800. Luciferase and 5a-RGDL-IRDye800-derived signals remained withinbackground in tumor-free (healthy) pancreas (Figure 11E, F). Thus, 5a-RGDL-IRDye800 canimage integrin-expressing PDAC in vivo, supporting expression of active αv^^ / αv^^ in vivo.We thus treated NSG mice with orthotopic PDOs with RGDL-NWL CAR-Ts or with CD19 CAR Ts as control. Tumor monitoring indicated that only the former, and not the latter efficiently controlled PDAC PDOs growth in vivo (Figure 11G, H). Together data indicate that αv^^ / αv^^ can be exploited as PDAC targets of RGDL-CAR Ts against human PDAC.Example 7 - The RGDL peptide retargets human CAR-Ts against T-regulatory cellsPrevious studies have found that T-regulatory cells (Tregs), known to dampen inflammationand tumor-protective immunity (Scott et al., Front. Immunol. 2021; 12; Togashi, Shitara, andNishikawa, Nat Rev Clin Oncol. 2019;16(6):356-371), express αv^^, and by that favor intra-tumoral TGFβ activation (Dodagatta-Marri et al., Cell Rep.2021;36(1):109309; Lainé et al., Nat. Commun. 2021;12:6228). Tregs are enriched in PDAC lesions (Gao et al., EuropeanJournal of Inflammation. 2022;20; Wang et al., Oncogene. 2017;36:3048–3058), and Tregenrichment is associated with worse prognosis in PDAC patients (Cheng et al., Pancreatology.2016;16:6:1080-1084; C. Liu et al., Int J Oncol.2017;51:686-694; L. Liu et al., Cancer ImmunolImmunother.2016;65:73–82). Thus, we hypothesized that Tregs might represent additional targets of RGDL-CAR-T celltherapy. To validate this concept, we differentiated CD25+; Foxp3+ human T-reg cells in vitro(hTregs, Figure 12A) and tested αv^^ / αv^^ expression by 5a-RGDL-IRDye680 imaging(Figure 12B). CD25-; Foxp3- T conventional (Tconv) cells were used as control. We found that5a-RGDL-IRDye680, but not Cys-IRDye680, bound a significant fraction of hTregs, withminimal reactivity with Tconv (Figure 12B-C). T3M4 and IGROV-1 cells, used as positivecontrol, also bound the 5a-RGDL-IRDye680 conjugate. Prompted by these results, we askedwhether RGDL-hCAR Ts could target human Tregs. We cocultured CMTMR-loaded Tregs orTconv with RGDL-NWL or RGDL-CH2CH3 or CD19 hCAR Ts. We found that only RGDL-NWL or RGDL-CH2CH3 hCAR Ts reduced survival of Tregs and not of Tconv (Figure 12D). Together data indicate that the 5a-RGDL peptide identify human Tregs, which are specificallytargeted by RGDL-hCAR T cells.Thus RGDL-CAR Ts bear the unique potential of simultaneously targeting αv^^ / αv^^-expressing tumors and immunosuppressive T-regulatory cells within the tumormicroenvironment. This is predicted to ameliorate CAR-Ts efficacy in promoting tumor eradication.Example 8 – αvβ6 / β8 expression in blood cancerIn-silico analysis of integrin αvβ6 / β8 expression in the LL-100 blood cancer panel RNA-Seqdata was carried out. Integrin αvβ6 and αvβ8 are shown to be expressed on a number of bloodcancers in the LL-100 panel. Relative normalised expression levels are shown in Figure 13 Aand B. Disease and relative abbreviation are listed in Figure 13C.Example 9 – RGDL-hCAR-T cells efficiently control patient-derived PDAC tumors at differentdevelopment stages Patients Derived Organoids (PDOs) provide the opportunity to validate target expression and therapy susceptibility (Peschke et al.2022; Tiriac et al.2018). We investigated whether PDAC PDOs retained integrins expression in vivo, and whether this could be imaged by the 5a- RGDL-IRDye800 peptide conjugate. PDO were orthotopically injected and the tumor homing ability of the 5a-RGDL-IRDye800 conjugate tested. Intravenous administration of the 5a- RGDL-IRDye800 conjugate efficiently identified PDO-derived orthotopic tumors, allowing for their visualization (Figure 15A). Moreover, immunohistochemistry analysis revealed that αvβ6 and αvβ8 integrins are expressed by orthotopic PDAC PDO-derived tumor (Figure 15B).Given that PDAC PDOs retain αv^^ and αv^^ integrin expression in the orthotopic xenograftmodel and the 5a-RGDL-IRDye800 conjugate accumulates in vivo in the PDAC tumor, we treated immunodeficient NOD-SCID IL-2Rgamma (null) NSG mice challenged with orthotopic PDAC PDO tumors with multiple intravenous administration of RGDL-CAR Ts or CD19 CAR Ts as control (Figure 15C). Tumor monitoring by luciferase imaging indicated that only the former, and not the latter, efficiently controlled PDAC PDOs growth in vivo (Figure 15D-F). While CD19-treated mice reached the ethical endpoint at day 23, the RGDL CAR Ts efficiently controlled tumor growth until the end of experiments (day 96), eventually leading to complete tumor eradication. This leads to a significant survival benefit in RGDL-CAR Ts treated mice, with no sign of clinical evidence of toxicity (Figure 15G). We then challenged the RGDL-pepti CAR T cells with advanced-stage PDAC PDO orthotopic tumors. Tumors were allowed to grow for 15 days until they became detectable by non-invasive imaging (ultrasound echography)with an average diameter of 2 mm. Mice were subsequently treated with two intravenousadministrations of RGDL-NWL CAR Ts or CD19 CAR Ts as control (Figure 15H). Tumor monitoring by luciferase imaging indicated that RGDL-CAR Ts also controlled orthotopic PDAC PDO tumors in an advanced stage of the disease (Figure 15D-F). Anti-tumor activity was associated with significant expansion of CAR T cells in the circulating blood 10 days afteradoptive cell transfer (Figure 15L). These data indicate that RGDL-NWL CAR T cells areefficacious against orthotopic PDAC PDO tumors at different developmental stages andsuggest that αv^^ and αv^^ integrins can serve as viable targets for RGDL-CAR T cells inhuman PDAC therapy.Example 10 – RGDL-mCAR-T cell therapy efficiently controls PDAC liver metastasesWe tested RGDL-mCAR-T cells using a model of PDAC liver metastases. Intraportal injection of PDAC cells resulted in metastatic liver dissemination, detectable by non-invasive MRI byday 15 (Pocaterra et al. 2024). Upon diagnosis, mice were randomized, preconditioned withsublethal dose of irradiation (6Gy) and treated with an intravenous administration of either Mock-transduced (Mock) T cells or RGDL-mCAR-Ts. Follow-up MRI analysis revealed significantly reduced volumes of PDAC liver metastases in mice treated with RGDL-mCAR- Ts when compared to those receiving Mock Ts (Figure 16A). The reduction in metastatic load was accompanied by an increase in overall survival, extending the median survival from 27 days to 42 days, resulting in the complete remission of approximately 30% of the RGDL- mCAR-Ts treated mice (Figure 16B). Importantly, therapeutic effects were observed without evidence of severe toxicity. These findings demonstrate that RGDL-mCAR-T cells effectivelycontrol PDAC liver metastases in vivo without detectable off-tumor effects.We next investigated whether the therapeutic effects of RGDL-mCAR Ts correlated withchanges in the immune infiltrate of PDAC liver metastases. Leukocytes were isolated fromPDAC liver metastases and spleens of mice treated with either RGDL-mCAR-T or Mock T cells. Analysis revealed a significantly increased frequency of cytotoxic donor T cells in PDAC liver metastases, but not in the spleens, of mice treated with RGDL-mCAR-T cells comparedto controls (Figure 16C). These data indicate that RGDL-CAR T cells effectively exert cytotoxicactivity against PDAC liver metastases, leading to their rejection in relevant preclinical animal models.Example 11 – Targeting of RGDL- and RGDE-CAR T cells to αv^^ and αv^^ integrinsWe demonstrated that monospecific RGDE-CAR-Ts react specifically to recombinant αv^^integrin, whereas bispecific RGDL-CAR T cells recognized both αv^^ and αv^^ integrins. Incontrast, RGEE-CAR Ts do not recognize any integrins (Figure 14). This was confirmedthrough αvβ6- and αvβ8-specific T cell activation and cytokine release (IFN-γ). These findingswere further validated in co-colture experiments with tumor cells expressing different integrinpatterns. RGDL-CAR Ts efficiently killed IGROV-1 cells (αvβ6- and αvβ8+). Additionally,RGDL-CAR Ts exhibited cytotoxic activity against the T3M4 metPDAC cells (αvβ6+ and αvβ8+) (Figure 17A). As an additional control, the absence of cytotoxicity was confirmed with RGEE-CAR Ts. These data indicate that while human RGDE-CAR T cells can exert cytotoxic activity against tumor cells expressing αvβ6, RGDL-CAR T cells can recognize and kill tumor cells expressing either αvβ6 or αvβ8, thereby further expanding their potential clinical applications. This indicates that the E to L amino acid substitution confers dual specificity to CAR-Ts.Example 12 – RGDL-CAR T Cell specificity is genetically dependant on β6 and β8 integrinsTo further assess the antigen specificity mediated by RGDL-CAR Ts, we generated T3M4 cells genetically knock-out (KO) for β6 and β8 integrins taking advantage of the CRISPR / Cas9 technology. We validated the absence of αvβ6 and αvβ8 protein on the β6 / β8 KO cells through antibody staining (Figure 14B) and IRDye680-conjugated peptides staining (Figure 14C). Integrin β6 / β8 KO cells stained negative for both β6 and β8 integrins and completely lost the binding of 5a-RGDL peptide. Functionally, while RGDL-CAR Ts efficently killed T3M4 wild- type (WT) cells, their cytotoxic activity was completely lost against αvβ6 / αvβ8 KO (Figure 14D). These data demonstrate that the cytotoxic activity of RGDL-CAR Ts is genetically dependant on αvβ6 and αvβ8 antigens.Example 13 – Tumor-infiltrating human regulatory T cells are an additional target of RGDL-CAR T cellsThe targeting of human T regulatory cells (Tregs) was investigated in a xenografted andPBMC-reconstituted NSG mouse model. As depicted in Figure 18A, mice were challenged on the same day with subcutaneous (SC) injection of metastatic PDAC tumor cells (T3M4) and intravenous (IV) administration of total unfractionated PBMCs. After 4 days, mice where either left untreated (Control) or intravenously injected with RGDL-NWL CAR Ts. After 10 days, tumors and spleens were analyzed by flow cytometry. We found a significant reduction in peptide-binding Tregs following RGDL-CAR T cell treatment specifically in the tumor compartment in respect to the spleen (Figure 18B). Taken together, these data indicate that RGDL-CAR Ts have the unique potential to simultaneously target αv^^ / αv^^-expressing tumors and immunosuppressive T-regulatory cells within the tumor microenvironment.Example 14 - Expression of HSV-TK suicide gene in RGDL-pepti CAR T cells renders themsensitive to ganciclovir while preserving their function For the clinical implementation of RGDL-CAR T cells, we aimed to include a safety switch in the lentiviral vector, to allow us to manipulate RGDL-CAR T cells after in vivo administration in case of adverse events following CAR T cell infusion in patients. The suicide gene approach involves transferring a suicide gene into donor lymphocytes to enable the safe infusion of a CAR T cells, which can be selectively controlled in vivo if adverse events arise in patients. The herpes simplex virus thymidine kinase (HSV-TK) is the most extensively tested suicide gene in humans (Greco et al.2015). Expression of HSV-TK in donor lymphocytes confers lethal sensitivity to the anti-herpes drug ganciclovir. We therefore generated a lentiviral vector encoding both the RGDL-CAR and HSV-TK under two differentpromoters in opposite orientations (Figure 19A). In vitro, we compared the cytotoxic activity ofRGDL-CAR Ts with RGDL-CAR Ts also expressing the TK suicide gene and found that both cellular products demonstrated comparable cytotoxicity against T3M4 metastatic PDAC cells in vitro at different tumor to effector ratios (Figure 19B). We then validated the sensitivity of these CAR-T cells to the anti-herpes drug ganciclovir (GVC) and found that only CAR- transduced T cells (NWL+) in the RGDL-TK CAR T cell product were senstive to GVC, while RGDL-CAR T cells were not (Figure 19C-D). We subsequently tested the antitumor activity of RGDL-TK CAR T cells against orthotopic PDAC PDO tumors and found comparable anti-tumor efficacy between RGDL-TK and RGDL- CAR T cells. As an additional control, noevidence of tumor control was evident in the case of RGEE-CAR T cell treated mice, with tumor progression resembling that of non-treated (NT) mice. These data indicate that the addition of the HSV-TK suicide gene did not alter the function of RGDL CAR T cells in vitro or in vivo, while allowing for their depletion in the case of adverse events, as they are sensitive to the anti-herpes drug ganciclovir. This supports the potential clinical implementation of the RGDL-CAR T cells incorporating a safety switch.Example 15 – Non-viral sleeping beauty gene delivery systemThe polynucleotide sequence encoding an RGDL-CAR may be comprised in a non-viraldelivery system such as a transposon, such as a Sleeping Beauty (SB) vector. The RGDL-CAR is fused to a safety switch with T2A self-cleaving peptide sequence ensuring coordinated expression of both elements. The WPRE sequence is included to enhance post-transcriptional gene expression. A single promoter drives the expression of both the RGDL-CAR and the safety switch within the vector. Inverted repeats (IR) flanking the vector allow the integration into the target DNA via the transposase enzyme. Discussion We describe here the design and validation of novel peptide-driven CAR constructs able tobind active conformations of αv^^ and / or αv^^^and instruct cytotoxic effects against integrin-expressing targets. While the RGDE-CAR redirects T cells against avb6 only, the RGDL-CARconfers specificity to both αv^^ and / or αv^^^^TThe RGDL CAR is the first CAR construct capable of dual recognition of αv^^ and / orαv^^^using a single targeting moiety. Specificity is granted by a 25mer peptide derived from the chromogranin A 39-63 region and carrying an E to L amino-acid substitution in position46, capable of recognizing human and mouse av^^ and av^^ with high affinity and specificity(Nardelli et al., Chem. Commun. 2019;55:14777-14780; Monieri et al. Int J Biol Sci.2023;19(1):156-166) grafted within second-generation CAR backbones. Of note, given avb8is expressed by Tregs, the RGDL-CAR bears the ability to target both tumor and immunosuppressive Tregs.We showed that while RGDE-CAR-Ts only reacted to recombinant avb6 (mouse or humanorigin), human and mouse RGDL-CAR T cells recognized both αv^^ and αv^^ integrins(mouse or human origin). This was proven by αv^^ and αv^^-specific T cell activation andcytokine release (IFN-^). In contrast, RGDL-CAR Ts did not respond to αv^5. This is in linewith the reported Ki (inhibitory constant) of the 5a-RGDL peptide, which is in the 1-5 nM rangefor immobilized αv^6 and αv^8, and about 1000 higher (2741 nM) for αv^5 (Nardelli et al.,Chem. Commun. 2019;55:14777-14780). The finding that the RGDL-CAR does not confer retargeted T cells the ability to bind αv^5 confirms that linking the RGDL-peptide to spacer / hinge regions does not affect its specificity. Accordingly, coincubation with an excessof free RGDL peptide abrogated T cell activation and IFN-^ release in this assay. Furthermore,we found that RGDL-CAR T cells were activated also when seeded in wells coated the anti- RGDL mAb 5A8, suggesting that the peptide RGDL on the CAR molecule was exposed and accessible. Notably, RGDL-CAR-Ts recognized tumors expressing one or both integrins. This is of extreme relevance for CAR-T cell therapy. Indeed, the same CAR construct could be exploited against a variety of tumor types. In addition, CAR-Ts have reported to result in immunoediting and the selection of antigen-escape variants. The dual targeting activity might reduce such risk. When constructing the human CAR, we tested three different configurations. The RGDL was linked at the 5’ end of a) the CH2CH3 or b) the NWL spacers or c) to a short IgG1-hinge. Such constructs produced CARs with different length. Notably, while the three different CAR configurations were expressed to comparable extents, integrin-expressing tumors were best recognized by CAR-T with the RGDL-CH2CH3 or the NWL configuration compared to the short IgG1 hinge. Thus, the RGDL motif retargets T cells, with some differences depending on the configuration. Different diffusion / mobility of the CAR constructs or interaction with othermembrane-bound protein might possibly account for differences in T cell responses. As in thecase of RGDE-mCAR-Ts, also RGDE-hCAR-Ts only reacted to αv^^ and not to αv^^,underlying the unique dual (αv^^ and αv^^^ targeting features of the RGDL-CAR.As in the case of plastic-bound recombinant integrin, also recognition of membrane-bound integrins occurred according to species-agnostic mechanism. Indeed, integrin-expressing mouse tumor cells induced both RDGL-mCAR and RGDL-hCAR activation and vice-versa, as indicated by IFN-gamma release in culture supernatants. Such species agnostic reactivity provides an important advantage for the clinical translation of the newly designed CAR molecule, as it allows testing off-tumor toxicity in in-vivo settings. Upon in vivo infusion, RGDL- CAR Ts of either mouse or human origin proved able to control the growth of αv^^ / αv^^- expressing tumors. We did not find evidence of RGDL-CAR-T mediated toxicity in the model adopted so far, neither in syngenic nor xenogeneic settings.The finding that the RGDL-targeting peptide can bind to mouse αv^^ and αv^^ integrins withcomparable affinity to the human orthologs (Nardelli et al., Chem. Commun.2019;55:14777- 14780; Monieri et al. Int J Biol Sci.2023;19(1):156-166), and that human RGDL-CAR T cells recognize αv^^ / αv^^-expressing mouse cells indicate that safety of these cells can be studies in vivo in NSG mice. This represents a clear advantage over other cellular products of clinicalinterest. Of note, expression of αv^^ is proportionately greater in mice than in man, mostnotably in the gastrointestinal tract (Saha et al.2010). This allows stringent safety studies. The RGDL-derived constructs reported here bind both αv^^^and αv^^. This provides twoimportant advantages: 1) αv^^^and αv^^ can be found independently expressed on varioustumor hystotypes (in addition to PDAC), 2) αv^^ is expressed by tumor-infiltrating Tregs; and3) interfering with the RGD motif competes with the LAP-binding site, hindering TGF^ activation.Notably, we found that the 5a-RGDL conjugates identifies Tregs, and RGDL-CAR-Ts exertspecific cytotoxicity against Tregs in vitro. This opens the possibility that RGDL-CAR-Ts could directly target Treg cells in vivo, thus eliminating an important immunosuppressive subset, and possibly shaping a more favorable tumor microenvironment.The ability of RGDL-hCARTs to simultaneously target both tumor and Tregs should provideimportant advantages over other T cell products, and particularly in the settings of PDAC.Indeed, Treg representation is a negative predictor in PDAC patients (Cheng et al., Pancreatology.2016;16:6:1080-1084; C. Liu et al., Int J Oncol.2017;51:686-694; L. Liu et al., Cancer Immunol Immunother.2016;65:73–82), and Treg are found enriched in PDAC lesions (Gao et al., European Journal of Inflammation. 2022;20; Wang et al., Oncogene. 2017;36:3048–3058). Winding et al reported that αv^^+ tumors had significantly more Tregsthan non– αv^^-expressing ones, and that this was caused by local activation of inactive pro-TGF-^ to its bioactive immune-suppressive form (L. M. Whilding et al., Mol Ther. 2017;4;25(1):259-273).In addition, as αv^^ and αv^^ are overexpressed by PDAC(10.14309 / ctg.0000000000000395), contribute to latent TGF^ activation (Yang et al. 2007;Aluwihare et al.2009), and the suppression function of T-regs is at least partially mediated by the conversion of latent forms of TGF-β1 into bioactive TGF-β1 (Dodagatta-Marri et al., CellRep.2021;36(1):109309; Lainé et al., Nat. Commun.2021;12:6228) it is thus foreseeable thatRGDL-CAR Ts might prevent TGF^-Treg-mediated immunosuppression.Overall, taken together, data justify the evaluation of αv^^^αv^^-targeted CAR T cell immunotherapy for tumors in which these integrins are found upregulated. Given the properties of the RGDL targeting motif, RGDL-CAR Ts should provide direct anti-tumor effects,and concurrently reshape the tumor microenvironment.Materials and methodsCells, mice and reagents. Murine 5M7101 and M4436 PDAC cells were obtained from thespontaneous liver metastasis of Ptf1a-Cre KrasG12D, p53+ / - KCP heterozygous mice (Mortonet al.2010). Briefly, surgically resected tumor tissues were immediately transferred to culture medium (RPMI-1640 supplemented with 10% FBS) and minced under sterilized condition. Minced tumor tissues were grown as tumor explants in soft-agar plated culture dishes. After 48 hours, explants were supplemented with fresh media. One week after seeding or at the time of confluence, serial propagations were performed to enrich for epithelial cells. After serial propagations, homogenous epithelial cells from pancreatic tissues and metastatic nodules were obtained. The genetic background of the cells was confirmed, and H&E analyses of tumor lesions analyzed. Human BxPC-3 and T3M4 PDAC cells, Mewo metastatic melanomacells, the H1975 lung adenocarcinoma, the IGROV-1 ovarian cancer and normal endothelialHuvec cells were obtained . Cells were maintained in culture with RPMI 1640 medium (Gibco- Thermo Fisher Scientific) containing 10% heat-inactivated fetal bovine serum (FBS), 2 mMglutamine, 100 IU / mL penicillin, and 100 mg / mL streptomycin (all from Gibco). Cells were maintained in a humidified atmosphere containing 5% CO2 at 37°C.Tumor cells were routinely assessed for the absence of mycoplasma contamination. PDAC PDO were obtained and maintained as previously described (Peschke et al., EMBO Mol Med.2022;14(4):e14876). The isolation of Tregs (CD4+CD25hiCD127low) and CD4+conventional T cells (Tconv; CD25−CD127hiCD45RA+) from human peripheral blood was as previously described (https: / / doi.org / 10.1182 / blood-2016-07-727834), with the combined use of MACS (Miltenyi Biotec, Auburn, CA) and FACS (FACSAria II cell sorter; BD Biosciences, Franklin Lakes, NJ). Briefly, peripheral blood cells (PBMCs) were isolated from mononuclear cell buffy coats using by Ficoll gradient centrifugation. For iTregs, sorted CD4+, CD25+ T cells were stimulated with magnetic beads coated with an anti-CD3 / anti-CD28 mAb using 3:1 beads:T cells ratio and cultured in X-vivo medium, containing 10% human serum, 1% penicillin, 1% streptomycin, glutamine, and 100 nM rapamycin. After 2 days, cells were supplemented with 500 U / ml IL-2. After 14 days, activation beads were magnetically removed, and cells were kept in expansion until day 21 in the presence of IL-2 but without rapamycin. On day 21, their phenotype waschecked through cytometry evaluation. For Tconv, sorted CD4+, CD25- T cells werestimulated with anti-CD3 / anti-CD28 magnetic beads in 3:1 beads:T cells ratio and cultured in RPMI 10% FBS, 1% penicillin, 1% streptomycin, glutamine, and homeostatic cytokines IL-7 and IL-15 at a concentration of 5 ng / ml. After 6 days, activation beads were magneticallyremoved and cells were kept in expansion until day 21 in the presence of IL-7 and IL-15.Female 8-10-week-old C57BL / 6N mice or NOD.Cg-Prkdcscid Il2rgtm1Wjl (NSG) mice (Charles River Laboratories or Inotiv) were kept in the Institutional specific pathogen–freefacility within individually ventilated cages. Experiments were conducted according to EUGuideline and the approval of the Institutional Animal Care and Use Committee of IRCCS San Raffaele Scientific Institute and by the Italian Governmental Health Institute. Chemical reagents were mostly obtained from Sigma-Aldrich or Thermo Fisher Scientific. Generation of CAR constructs.To generate the murine RGDE and RGDL-CAR sequences (reported in Table 1 and 2), acDNA including the ChromograninA derived 25-mers RGDE or RGDL peptides, a syntheticlinker, a murine IgG-domain, a murine transmembrane CD4 domain and a murine intracellularCD28-CD3 signaling domain were generated by gene synthesis (GeneArt Thermofisher;Table 1 and 2). NcoI / SalI were included at the 5’ and 3’ respectively for cloning into the pBulletretroviral vector (as described in Chmielewski et al.2012).To generate the human RGDE or RGDL-CAR sequence, the RGDE or the RGDL sequenceswere cloned in frame at the 5’end of the CH2CH3 spaced (Hombach, Hombach, and AbkenGene Ther. 2010;17(10):1206-13) fused with CD28 transmembrane and costimulatorydomains, and a CD3zeta endodomain (Savoldo et al., J Clin Invest. 2011;121(5):1822-6).Where indicated the CH2CH3 domain was substituted with the cDNA encoding for a truncatedform of the nerve growth factor receptor devoid of the intracellular signaling domain (long wild type: NWL) or a short hinge domain (Casucci et al., Front Immunol.2018 Mar 21;9:507). Thehuman RGDL-CAR cDNAs were then cloned into a bidirectional lentiviral vector (kindlyprovided by Prof. Luigi Naldini, San Raffaele Telethon Institute for Gene Therapy, (Amendola Nat Biotech.2005;23:108-116). The cDNA encoding for the green fluorescent protein (GFP) marker gene was substituted with a cDNA encoding for truncated CD20 suicide. Briefly, CAR constructs were placed under the direct control of the human phosphoglycerate kinase (hPGK) promoter, and the CD20 gene under the control of a minimal core promoter derived from the cytomegalovirus (minCMV) in antisense orientation. Transient transfection of 293T packaging cells and viral preparation was performed as previously described (Casucci et al., Front Immunol.2018 Mar 21;9:507; Greco et al.2022). Mouse T cell engineering Retroviral plasmids were used to transfect Phoenix-Eco packaging cells to generate retrovirus. The pCL-ECO (IMGENEX) packaging plasmid was used to maximize production. Splenocytes were harvested, CD4 and CD8 T cells selected by negative selection and activated for 48h with Dynabeads™ Mouse T-Activator CD3 / CD28 (2:1 bead: cell ratio; Gibco-Thermo Fisher Scientific). Cells were then harvested, resuspended in viral supernatant (0.5x106cells / mL), plated on retronectin-coated 24-well plates (50 mg / mL), subjected to spin transduction (90 minutes / 2,000 rpm / 32°C), and incubated overnight at 37°C. After transduction, cells were harvested and expanded in IL-7 / IL-15 (10ng / ml). Cell transduction was monitored by FACS, after staining the cells with a PE-labeled anti-mouse IgG1 antibody (Southern Biotech). Controlcells were centrifuged in complete medium and expanded in cytokines (IL-7+, IL-15).Human T cell engineering Buffy coats from healthy donors were obtained through Ospedale San Raffaele. Peripheral blood mononuclear cells (PBMCs) were isolated with Lymphoprep density separation and activated with Dynabeads™ HumanT-Activator CD3 / CD28 (2:1 bead: total cell; Gibco-ThermoFisher Scientific). Forty-eight hours later, T lymphocytes were transduced with frozen virus ata 5-10 MOI. At day 6, beads were removed by magnetic separation and CAR T cells (Casucci et al., Front Immunol.2018 Mar 21;9:507; Greco et al.2022). CAR-T cells were then cultured in RPMI-1640, 10% FBS (Euroclone), 2 mM glutamine, 100 IU / mL of penicillin and 100 μg / mL of streptomycin) with IL-7 (10 ng / mL; PeproTech) and IL-15 (10 ng / ml, Peprotech, 200-07, 200-15). Cell transduction was traced by FACS at day 8 and 21, with a PE-labeled anti-NGFR antibody (Biolegend) or with a FITC-labeled anti-CD20 antibody (Biolegend).Flow Cytometry analysis. Tumor cells were stained with anti-αv^^ mouse mAb (clone10D5), anti-αv^^8 rabbit mAb (clone EM13309) followed by an AlexaFluor 488-goat anti- mouse or anti-rabbit IgG polyclonal antibody. Isotype control mouse mAb or rabbit IgGs were used as control. mCAR expression on transduced mouse T cells was determined by staining with an anti-mouse IgG1 (PE-labeled). Expression of the human CAR was instead determinedby an anti-CH2CH3 mAb, or an anti-NGFR mAb. In the case of the RGDL-CAR in the hinge configuration, transduction efficiency was defined with the anti-CD20 mAb, used as separate transduction marker gene. Primary T cells were surface stained with anti-CD4, CD8, CD44, CD62L, CD45RA mAb. Where indicated cells were also fixed and permeabilized, and further stained for intracellular cytokines as described previously (ref nostra). Dead cells were identified by Zombie Aqua viability kit (Biolegend). Flow cytometry data were acquired using one of the following instruments: BD FACS Canto II (BD Biosciences), Cytoflex S (Beckman Coulter). For data collection, the BD FacsDIVA Software (BD Biosciences) and the CytExpert software were used. Data analysis was performed using FlowJo software (Tree star Inc). Doublets were distinguished and excluded by plotting FSC area versus FSC height and data analysis was performed using FlowJo software. Fluorescent peptide-based binding studies and in vivo imaging.The 5a-RGDL was labeled with maleimide-activated IRDye800 as described previously(Monieri et al. 2023). The 5a-RGDL or the Cys control were labeled with IRDye680. Thebinding of peptide-IRDye conjugates to cells was measured in binding buffer (200nM; 25 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM MgCl2, 1 mM MnCl2, and 1% BSA) for 1 h at 37 °C. The cells were then washed three times, fixed, and analyzed to quantify fluorescence using an Odyssey CLx scanner (LI-Cor) or a Cytoflex S flow cytometer (Beckman Coulter). For in vivo studies, mice received a tail vein injection of 5a-RGDL-IRDye800 (~1 nmol) and were imaged after 24 h using an IVIS Spectrum CT Imaging System (PerkinElmer). In some experiments, selected organs were explanted and imaged. CAR-T cells in vitro validation. RGDE or RGDL-CAR T cells were seeded on immobilized recombinant integrins (Bio-techne,Milan, Italy) or co-cultured with target cells in complete RPMI 1640 medium. Human andmurine avb6, avb8 and human avb5 recombinant proteins were used to coat 96-well platesovernight at 4° at final concentration of 2 µg / ml in DPBS with magnesium and calcium. The following day, the plates were washed and incubated in DPBS (with magnesium and calcium)containing 2% BSA for 1 hour at RT. CAR T cells or control T cells were then plated at 1x106cells / ml, 200ul / well. In tumor-T cell cocultures, 104tumor cells were let adhere before theaddition of control or transduced T cells. After 48 hours, supernatants were collected and IFN-gamma levels quantified by enzyme-linked immunosorbent assay (ELISA). Cell viability was analyzed by MTT assay. In some instances, the ability of T cells to kill target cells was determined using the Incucyte Live Imaging system. When using the T3M4 cell line as target, cells were first transduced with a lentivirus expressing a nuclear-restricted red fluorescence protein (Nuclight Red, Essen Biosciences). In the case of PDAC PDOs, apoptosis was detected by the Incucyte-Caspase 3 / 7 dye (Essen Biosciences). Images were taken every 60minutes and fluorescent signals were quantified using Incucyte Live-Cell Imaging and Analysissoftware (Essen Biosciences). CAR-T cell therapy. Syngeneic and xenogeneic preclinical models were adopted. In syngeneic settings, 5M7101 / GFP cells (106) were injected subcutaneously into 8-10-week-old C57BL / 6N female mice. Five days after tumor cell injection, mice were preconditioned by an intraperitoneal injection of cyclophosphamide (300mg / kg). Two days later mice received an intravenous injection of 2-10x106transduced T cell. In xenogeneic settings, BxPC-3 (0.5 × 106) or T3M4 (0.75 × 106) tumor cells were injected subcutaneously. On the days indicated in individual experiments mice received 2-3×106transduced T cells by intravenous injection. Tumor growth was monitored by caliper over time. In the case of 5M7101 / GFP derived tumors, mice were imaged with IVIS Spectrum (PerkinElmer) for the detection of GFP fluorescence signal. DatasetsThe Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) RNAdatasets comprising different tumors and relative normal counterparts were interrogated withthe GEPIA2 tools (Tang et al., Nucleic Acids Res. 2019;47(W1):W556-W560). The HumanProtein Atlas dataset was adopted to investigate protein expression in tumors and normal tissues. Statistical analysis.Data were presented with their means+ / - SD or SEM as indicated in the description of theFigure. Statistical analyses were performed using GraphPad Prism software. Two-tailed unpaired t-test, one or two-way analysis of variance ANOVA were used. All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims. ASPECTS OF THE INVENTION The invention is further described by the following numbered paragraphs:1. A chimeric antigen receptor (CAR) comprising an antigen binding domain comprisinga chromogranin A (CgA) peptide or a fragment or derivative thereof.2. The CAR according to paragraph 1, wherein the chromogranin A is humanchromogranin A.3. The CAR according to paragraph 1 or 2, wherein the antigen binding domaincomprises a polypeptide comprising SEQ ID NO: 1; or a polypeptide with at least 80% sequence identity to SEQ ID NO: 1.4. The CAR according to paragraph 1 or 2, wherein the antigen binding domaincomprises a polypeptide comprising SEQ ID NO: 35; or a polypeptide with at least 80%sequence identity to SEQ ID NO: 35.5. The CAR according to any of paragraphs 1-4, wherein the chromogranin A peptide orfragment or derivative thereof comprises a RGDL or RGDE motif.6. The CAR according to paragraph 5, wherein the chromogranin A peptide or fragmentor derivative thereof additionally comprises a peptide sequence capable of forming an amphiphilic alpha helix, preferably wherein said peptide sequence is adjacent and to the immediate C-terminal side of the RGDL or RGDE motif.7. The CAR according to paragraph 5 or 6, wherein the chromogranin A peptide orfragment or derivative thereof comprises a RGDL motif and the antigen binding domain is capable of binding αvβ6 and αvβ8 integrins.8. The CAR according to any of paragraphs 1 to 7, wherein the CAR further comprises:a) a spacer; b) a transmembrane domain; and / or c) one or more intracellular signaling domains.9. The CAR according to paragraph 8, wherein the spacer comprises a truncated nervegrowth receptor domain (NWL), a CH2CH3 spacer, an IgG1 domain or an IgG1 hinge.10. The CAR according to paragraph 9, wherein the spacer comprises: i) a NWL domain which comprises SEQ ID NO: 4, or a sequence with at least 80% identity to SEQ ID NO: 4,ii) a CH2CH3 domain which comprises SEQ ID NO: 5, or a sequence with at least 80%identity to SEQ ID NO: 5, iii) an IgG1 hinge which comprises SEQ ID NO: 3, or a sequence with at least 80% identity to SEQ ID NO: 3, or iv) an IgG1 domain which comprises SEQ ID NO: 2, or a sequence with at least 80% identity to SEQ ID NO: 2.The CAR according to paragraph 9 or 10, wherein the spacer comprises a NWLdomain.The CAR according to paragraph 11, wherein the NWL domain comprises a sequencewhich comprises SEQ ID NO: 4, or a sequence with at least 80% identity to SEQ ID NO: 4.The CAR according to any of paragraphs 8-12, wherein the transmembrane domaincomprises a human CD28 transmembrane domain or a murine CD4 transmembrane domain.The CAR according to paragraph 13, wherein the transmembrane domain comprises:i) a human CD28 transmembrane domain which comprises SEQ ID NO: 7, or a sequence with at least 80% identity to SEQ ID NO: 7, or ii) a murine CD4 transmembrane domain which comprises SEQ ID NO: 6, or a sequence with at least 80% identity to SEQ ID NO: 6.The CAR according to any of paragraphs 8-14, wherein the one or more intracellularsignaling domains comprise a human CD28 intracellular signaling domain, a murineCD28 intracellular signaling domain, a human CD3ζ and / or a murine CD3ζ intracellularsignaling domain.The CAR according to paragraph 15, wherein the one or more intracellular signalingdomains comprise: a) a human: i) CD28 intracellular signaling domain which comprises SEQ ID NO: 10, or a sequence with at least 80% identity to SEQ ID NO: 10, and / orii) CD3ζ intracellular signaling domain which comprises SEQ ID NO: 11, or a sequencewith at least 80% identity to SEQ ID NO: 11, orb) a murine: iii) CD28 intracellular signaling domain which comprises SEQ ID NO: 8, or a sequence with at least 80% identity to SEQ ID NO: 8, and / or iv) CD3ζ intracellular signaling domain which comprises SEQ ID NO: 9, or a sequencewith at least 80% identity to SEQ ID NO: 9.17. The CAR according to any of paragraphs 8-16, wherein the CAR comprises:i) a NWL domain, a human CD28 transmembrane domain, a human CD28 intracellular signaling domain and a human CD3ζ intracellular signaling domain,ii) a CH2CH3 domain, a human CD28 transmembrane domain, a human CD28intracellular signaling domain and a human CD3ζ intracellular signaling domain,iii) an IgG1 hinge, a human CD28 transmembrane domain, a human CD28 intracellular signaling domain and a human CD3ζ intracellular signaling domain, oriv) an IgG1 domain, a murine CD4 transmembrane domain, a murine CD28 intracellular signaling domain, and a murine CD3ζ intracellular signalling domain.18. The CAR according to any preceding paragraph, wherein the CAR comprisesi) an amino acid sequence which comprises SEQ ID NO: 14, or a sequence with at least 80% sequence identity to SEQ ID NO: 14, ii) an amino acid sequence which comprises SEQ ID NO: 15, or a sequence with at least 80% sequence identity to SEQ ID NO: 15, iii) an amino acid sequence which comprises SEQ ID NO: 13, or a sequence with at least 80% sequence identity to SEQ ID NO: 13, iv) an amino acid sequence which comprises SEQ ID NO: 12, or a sequence with at least 80% sequence identity to SEQ ID NO: 12.19. The CAR according to any preceding paragraph, wherein the CAR comprises an aminoacid sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or a sequence with at least 80% sequence identity to SEQ ID NO 14 or SEQ ID NO: 15.20. The CAR according to any previous paragraph, wherein the CAR is able to induce Tcell signaling when bound to αvβ6 or αvβ8.21. A nucleic acid which encodes the CAR of any preceding paragraph.22. The nucleic acid of paragraph 21, wherein the nucleic acid comprises a polynucleotidesequence with at least 70% sequence identity to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 16 or SEQ ID NO: 17.23. The nucleic acid of paragraph 21 or 22, wherein the nucleic acid comprises apolynucleotide sequence of SEQ ID NO: 18 or SEQ ID NO: 19.24. A vector which comprises the nucleic acid of any of paragraphs 21-23.25. A cell which comprises the CAR of any of paragraphs 1-20, the nucleic acid of any ofparagraphs 21-23, and / or the vector of paragraph 24.26. The cell of paragraph 25, wherein the cell is an effector immune cell, optionally whereinthe cell is a T cell or NK cell.27. The cell of paragraph 25 or 26, wherein the cell is an autologous or allogenic cell.28. A composition comprising a plurality of cells according to any of paragraphs 25-27.29. A method for making a cell according to any of paragraph 25-27, which comprises thestep of transducing or transfecting a cell with a nucleic acid according to any of paragraphs 21-23 or a vector according to paragraph 24.30. A method for making a cell composition according to 28, which comprises the step oftransducing or transfecting a sample of cells from a subject ex vivo with a nucleic acidaccording to any of paragraphs 21-23 or a vector according to paragraph 24.31. A pharmaceutical composition comprising the nucleic acid of any of paragraphs 21-23,the vector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28, in combination with a pharmaceutically acceptable carrier, diluent orexcipient.32. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use as a medicament.33. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use in treating or preventing cancer in a subject in need thereof.34. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use in a method of treating or preventing cancer in a subject in needthereof.35. Use of a CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23,the vector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for the manufacture of a medicament for the treatment or prevention ofcancer.36. A method for treating or preventing cancer which comprises administering the CAR ofany of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, the vector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28to a subject in need thereof.37. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraphs 33-34, wherein the subject is a humanor an animal.38. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraphs 33-34 or 37, wherein the cancer is aprimary cancer or a secondary cancer.39. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraphs 33-34 or 37 and 38, wherein the canceris a blood cancer or a solid tumour.40. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraphs 33-34 or 37-39, wherein the cancer isany cancer selected from the group consisting of pancreatic cancer, stomach cancer, melanoma, lung cancer, ovarian cancer and prostate cancer.41. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraph 33-34 or 37-40, wherein the cancer ispancreatic ductal adenocarcinoma (PDAC).42. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraph 33-34 or 37-41, wherein the cancer isliver metastases of pancreatic ductal adenocarcinoma.43. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraph 33-34 or 37-40, wherein the cancer ismetastatic melanoma.44. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraph 33-34 or 37-43, wherein the CAR iscapable of specific binding to Tregs.45. The cell or pharmaceutical composition for use according to any of paragraphs 33-34or 37-44, the use according to claim 35, or the method according to paragraph 36,wherein the cell or pharmaceutical composition is administered systemically.46. The cell or pharmaceutical composition for use according to any of paragraphs 33-34or 37-44, the use according to claim 35, or the method according to paragraph 36,wherein the cell or pharmaceutical composition is administered intravenously.47. The use according to claim 40 or 41, wherein the cancer is pancreatic cancer and thecell or pharmaceutical composition is administered intrapancreatically.48. The use according to claim 42, wherein the cell or pharmaceutical composition isadministered intrahepatically. The invention is further described by the following numbered paragraphs:1. A chimeric antigen receptor (CAR) comprising an antigen binding domain comprisinga chromogranin A (CgA) peptide or a fragment or derivative thereof.2. The CAR according to paragraph 1, wherein the chromogranin A is humanchromogranin A.3. The CAR according to paragraph 1 or 2, wherein the antigen binding domaincomprises a polypeptide comprising SEQ ID NO: 1; or a polypeptide with at least 80% sequence identity to SEQ ID NO: 1.4. The CAR according to paragraph 1 or 2, wherein the antigen binding domaincomprises a polypeptide comprising SEQ ID NO: 35; or a polypeptide with at least 80% sequence identity to SEQ ID NO: 35.5. The CAR according to any of paragraphs 1-4, wherein the chromogranin A peptide orfragment or derivative thereof comprises a RGDL or RGDE motif.6. The CAR according to paragraph 5, wherein the chromogranin A peptide or fragmentor derivative thereof additionally comprises a peptide sequence capable of forming an amphiphilic alpha helix, preferably wherein said peptide sequence is adjacent and to the immediate C-terminal side of the RGDL or RGDE motif.7. The CAR according to paragraph 5 or 6, wherein the chromogranin A peptide orfragment or derivative thereof comprises a RGDL motif and the antigen binding domain is capable of binding αvβ6 and αvβ8 integrins.8. The CAR according to any of paragraphs 1 to 7, wherein the CAR further comprises:a) a spacer; b) a transmembrane domain; and / or c) one or more intracellular signaling domains.9. The CAR according to paragraph 8, wherein the spacer comprises a truncated nervegrowth receptor domain (NWL), a CH2CH3 spacer, an IgG1 domain or an IgG1 hinge.10. The CAR according to paragraph 9, wherein the spacer comprises: i) a NWL domain which comprises SEQ ID NO: 4, or a sequence with at least 80% identity to SEQ ID NO: 4, ii) a CH2CH3 domain which comprises SEQ ID NO: 5, or a sequence with at least 80% identity to SEQ ID NO: 5, iii) an IgG1 hinge which comprises SEQ ID NO: 3, or a sequence with at least 80% identity to SEQ ID NO: 3, oriv) an IgG1 domain which comprises SEQ ID NO: 2, or a sequence with at least 80%identity to SEQ ID NO: 2.The CAR according to paragraph 9 or 10, wherein the spacer comprises a NWLdomain.The CAR according to paragraph 11, wherein the NWL domain comprises a sequencewhich comprises SEQ ID NO: 4, or a sequence with at least 80% identity to SEQ ID NO: 4.The CAR according to any of paragraphs 8-12, wherein the transmembrane domaincomprises a human CD28 transmembrane domain or a murine CD4 transmembrane domain.The CAR according to paragraph 13, wherein the transmembrane domain comprises:i) a human CD28 transmembrane domain which comprises SEQ ID NO: 7, or a sequence with at least 80% identity to SEQ ID NO: 7, or ii) a murine CD4 transmembrane domain which comprises SEQ ID NO: 6, or a sequence with at least 80% identity to SEQ ID NO: 6.The CAR according to any of paragraphs 8-14, wherein the one or more intracellularsignaling domains comprise a human CD28 intracellular signaling domain, a murineCD28 intracellular signaling domain, a human CD3ζ and / or a murine CD3ζ intracellularsignaling domain.The CAR according to paragraph 15, wherein the one or more intracellular signalingdomains comprise: a) a human: i) CD28 intracellular signaling domain which comprises SEQ ID NO: 10, or a sequence with at least 80% identity to SEQ ID NO: 10, and / or ii) CD3ζ intracellular signaling domain which comprises SEQ ID NO: 11, or a sequence with at least 80% identity to SEQ ID NO: 11, or b) a murine: iii) CD28 intracellular signaling domain which comprises SEQ ID NO: 8, or a sequencewith at least 80% identity to SEQ ID NO: 8, and / or iv) CD3ζ intracellular signaling domain which comprises SEQ ID NO: 9, or a sequence with at least 80% identity to SEQ ID NO: 9.17. The CAR according to any of paragraphs 8-16, wherein the CAR comprises:i) a NWL domain, a human CD28 transmembrane domain, a human CD28 intracellular signaling domain and a human CD3ζ intracellular signaling domain, ii) a CH2CH3 domain, a human CD28 transmembrane domain, a human CD28 intracellular signaling domain and a human CD3ζ intracellular signaling domain, iii) an IgG1 hinge, a human CD28 transmembrane domain, a human CD28 intracellular signaling domain and a human CD3ζ intracellular signaling domain, or iv) an IgG1 domain, a murine CD4 transmembrane domain, a murine CD28 intracellular signaling domain, and a murine CD3ζ intracellular signalling domain.18. The CAR according to any preceding paragraph, wherein the CAR comprisesi) an amino acid sequence which comprises SEQ ID NO: 14, or a sequence with at least 80% sequence identity to SEQ ID NO: 14, ii) an amino acid sequence which comprises SEQ ID NO: 15, or a sequence with at least 80% sequence identity to SEQ ID NO: 15, iii) an amino acid sequence which comprises SEQ ID NO: 13, or a sequence with at least 80% sequence identity to SEQ ID NO: 13, iv) an amino acid sequence which comprises SEQ ID NO: 12, or a sequence with at least 80% sequence identity to SEQ ID NO: 12.19. The CAR according to any preceding paragraph, wherein the CAR comprises an aminoacid sequence of SEQ ID NO: 14 or SEQ ID NO: 15, or a sequence with at least 80% sequence identity to SEQ ID NO 14 or SEQ ID NO: 15.20. The CAR according to any previous paragraph, wherein the CAR is able to induce Tcell signaling when bound to αvβ6 or αvβ8.21. A nucleic acid which encodes the CAR of any preceding paragraph.22. The nucleic acid of paragraph 21, wherein the nucleic acid comprises a polynucleotidesequence with at least 70% sequence identity to SEQ ID NO: 49, SEQ ID NO: 50 orSEQ ID NO: 48.23. The nucleic acid of paragraph 21 or 22, wherein the nucleic acid comprises apolynucleotide sequence of SEQ ID NO: 49 or SEQ ID NO: 50.24. A vector which comprises the nucleic acid of any of paragraphs 21-23.25. A cell which comprises the CAR of any of paragraphs 1-20, the nucleic acid of any ofparagraphs 21-23, and / or the vector of paragraph 24.26. The cell of paragraph 25, wherein the cell is an effector immune cell, optionally whereinthe cell is a T cell or NK cell.27. The cell of paragraph 25 or 26, wherein the cell is an autologous or allogenic cell.28. A composition comprising a plurality of cells according to any of paragraphs 25-27.29. A method for making a cell according to any of paragraph 25-27, which comprises thestep of transducing or transfecting a cell with a nucleic acid according to any of paragraphs 21-23 or a vector according to paragraph 24.30. A method for making a cell composition according to 28, which comprises the step oftransducing or transfecting a sample of cells from a subject ex vivo with a nucleic acid according to any of paragraphs 21-23 or a vector according to paragraph 24.31. A pharmaceutical composition comprising the nucleic acid of any of paragraphs 21-23,the vector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28, in combination with a pharmaceutically acceptable carrier, diluent or excipient.32. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use as a medicament.33. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use in treating or preventing cancer in a subject in need thereof.34. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use in a method of treating or preventing cancer in a subject in need thereof.35. Use of a CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23,the vector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for the manufacture of a medicament for the treatment or prevention of cancer.36. A method for treating or preventing cancer which comprises administering the CAR ofany of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, the vector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 to a subject in need thereof.37. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use according to paragraphs 33-34, wherein the subject is a human or an animal.38. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use according to paragraphs 33-34 or 37, wherein the cancer is a primary cancer or a secondary cancer.39. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use according to paragraphs 33-34 or 37 and 38, wherein the cancer is a blood cancer or a solid tumour.40. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use according to paragraphs 33-34 or 37-39, wherein the cancer is any cancer selected from the group consisting of pancreatic cancer, stomach cancer, melanoma, lung cancer, ovarian cancer and prostate cancer.41. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use according to paragraph 33-34 or 37-40, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).42. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition ofparagraph 28 for use according to paragraph 33-34 or 37-41, wherein the cancer is liver metastases of pancreatic ductal adenocarcinoma.43. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use according to paragraph 33-34 or 37-40, wherein the cancer is metastatic melanoma.44. The CAR of any of paragraphs 1-20, the nucleic acid of any of paragraphs 21-23, thevector of paragraph 24, the cell of any of paragraphs 25-27, or the composition of paragraph 28 for use according to paragraph 33-34 or 37-43, wherein the CAR is capable of specific binding to Tregs.45. The cell or pharmaceutical composition for use according to any of paragraphs 33-34or 37-44, the use according to claim 35, or the method according to paragraph 36, wherein the cell or pharmaceutical composition is administered systemically.46. The cell or pharmaceutical composition for use according to any of paragraphs 33-34or 37-44, the use according to claim 35, or the method according to paragraph 36, wherein the cell or pharmaceutical composition is administered intravenously.47. The use according to claim 40 or 41, wherein the cancer is pancreatic cancer and thecell or pharmaceutical composition is administered intrapancreatically.48. The use according to claim 42, wherein the cell or pharmaceutical composition isadministered intrahepatically.

Claims

CLAIMS1. A chimeric antigen receptor (CAR) comprising an antigen binding domain comprisinga chromogranin A (CgA) peptide or a fragment or derivative thereof.

2. The CAR according to claim 1 wherein the antigen binding domain comprises apolypeptide comprising (i) SEQ ID NO: 1; or a polypeptide with at least 80% sequence identity to SEQ ID NO: 1; or (ii) SEQ ID NO: 35; or a polypeptide with at least 80% sequence identity to SEQ ID NO: 35.

3. The CAR according to any of claims 1 or 2, wherein the chromogranin A peptide orfragment or derivative thereof comprises a RGDL or RGDE motif.

4. The CAR according to claim 3, wherein the chromogranin A peptide or fragment orderivative thereof comprises a RGDL motif and the antigen binding domain is capable of binding αvβ6 and αvβ8 integrins.

5. The CAR according to any preceding claim, wherein the CAR comprises a NWLdomain spacer which comprises SEQ ID NO: 4, or a sequence with at least 80% identity to SEQ ID NO: 4.

6. The CAR according to any preceding claim, wherein the CAR comprises: a NWLspacer domain, a human CD28 transmembrane domain, a human CD28 intracellular signaling domain and a human CD3ζ intracellular signaling domain.

7. The CAR according to claim 6, wherein the CAR comprises an amino acid sequencewhich comprises SEQ ID NO: 14, or a sequence with at least 80% sequence identity to SEQ ID NO: 14.

8. The CAR according to any previous claim, wherein the CAR is able to induce T cellsignaling when bound to αvβ6 or αvβ8.

9. A nucleic acid which encodes the CAR of any preceding claim.

10. The nucleic acid according to claim 9, wherein the nucleic acid comprises apolynucleotide sequence with at least 70% sequence identity to SEQ ID NO: 49 or 56.

11. A vector which comprises the nucleic acid of any of claims 9 or 10.

12. A cell which comprises the CAR of any of claims 1-8, the nucleic acid of any of claims9-10, and / or the vector of claim 11, optionally wherein the cell is a T cell, an NK cell oran NKT cell.

13. The CAR of any of claims 1-8, the nucleic acid of any of claims 9-10, the vector ofclaim 11, the cell of claim 12 for use in treating or preventing cancer in a subject in need thereof.

14. The CAR, nucleic acid, vector or cell for use according to claim 13 wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

15. The CAR, nucleic acid, vector or cell for use according to claim 13 wherein the cancer is liver metastases of PDAC, metastatic melanoma, lung adenocarcinoma and ovariancancer.

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