Methods and materials for treating cancer

Abstract

This document provides methods and materials involved in treating cancer. For example, methods and materials for generating immune cells (e.g., T cells) that (1) can constitutively express one or more chimeric antigen receptors (CARs) having the ability to bind a cancer-specific antigen and (2) can express an agent that can target a cell of a tumor microenvironment (TME) when the CAR is activated (e.g., by binding to a cancer cell expressing that cancer-specific antigen) are provided. Also provided are methods and materials for using such CAR T cells in an adoptive cell therapy (e.g., a CAR T cell therapy) to treat a mammal (e.g., a human) having cancer.

Description

Attorney Docket No.07039-2320WO1 / 2024-189 METHODS AND MATERIALS FOR TREATING CANCER CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application Serial No. 63 / 672,613, filed on July 17, 2024. The disclosure of the prior application is considered part of, and is incorporated by reference in, the disclosure of this application. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named “07039-2320WO1_SL.xml.” The XML file, created on July 7, 2025, is 121,919 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD This document relates to methods and materials involved in treating cancer. For example, this document provides methods and materials for generating immune cells (e.g., T cells) that (1) can constitutively express one or more chimeric antigen receptors (CARs) having the ability to bind a cancer-specific antigen and (2) can conditionally express an agent that can target a cell of a tumor microenvironment (TME) when the CAR is activated (e.g., by binding to a cancer cell expressing that cancer-specific antigen). This document also provides methods and materials for using such CAR T cells in an adoptive cell therapy (e.g., a CAR T cell therapy) to treat a mammal (e.g., a human) having cancer. BACKGROUND CD19-directed CART (CART19) cell therapy has revolutionized the treatment of B cell malignancies, and several CART19 cell therapies have been FDA-approved for the treatment of large B cell lymphoma (Grupp et al., N. Engl. J. Med., 368:1509-1518 (2013); Kenderian et al., J. Am. Soc. Blood Marr. Transplant., 23:235-246 (2017); and Porter et al., Sci. Transl. Med., 7:303ra139 (2015)). However, the activity of CART cell therapy in solid tumors has been very limited to date, and objective responses are rarely seen (Martinez et al., Front. Immunol., 10:128 (2019); Ma et al., Int. J. Biol. Sci., 15:2548-2560 (2019); and Morgan et al., Front. Immunol., 9: 2493 (2018)). In particular,Attorney Docket No.07039-2320WO1 / 2024-189 it has been shown that CART cell activity can be inhibited by an immunosuppressive tumor microenvironment (TME) in solid tumors (Geyer et al., Cytotherapy, 18:1393-1409 (2016); Jain et al., Blood, 134:4105-4105 (2019); Jain et al., Blood, 134:2885-2885 (2019); Jain, J. Clin. Oncol., 31:2205-2218 (2013); Rodriguez-Garcia et al., Front. Immunol., 11:1109 (2020). and Sakemura et al., Leuk. Lymphoma, 62:2052-2063 (2021)), including CAFs (Kakarla et al., Immunotherapy, 4:1129-1138 (2012); Lakins et al., Nat. Commun., 9:948 (2018); and Tripathi et al., Cell Adhes. Migrat., 6:231-235 (2012)). SUMMARY This document provides methods and materials involved in treating cancer. For example, this document provides methods and materials for generating immune cells (e.g., T cells such as CAR T cells) that (1) can constitutively express one or more CARs having the ability to bind a cancer-specific antigen and (2) can conditionally express an agent that can target a cell of a TME when the CAR is activated (e.g., by binding to a cancer cell expressing that cancer-specific antigen). Such CAR T cells can be referred to as conditional CAR T cells. In some cases, a T cell can be engineered to contain nucleic acid (e.g., exogenous nucleic acid) including (a) a nucleic acid sequence encoding one or more CARs having the ability to bind a cancer-specific antigen that each are operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter to generate a conditional CAR T cell. As described herein, a conditional CAR T cell can be designed to include (a) a nucleic acid sequence encoding one or more CARs having the ability to bind a cancer-specific antigen that each are operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter such that activation of a constitutively expressed CAR (e.g., by binding to a cancer cell expressing that cancer-specific antigen) can activate the conditional promoter and drive expression of the agent that can target a cell of a TME. This document also provides nucleic acid constructs (e.g., viral vectors such as lentiviral vectors) that can be used to generate conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated). For example, nucleic acid constructs that containAttorney Docket No.07039-2320WO1 / 2024-189 (a) a nucleic acid sequence encoding one or more CARs having the ability to bind a cancer-specific antigen that each are operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter can be used to a generate conditional CAR T cells provided herein. This document also provides methods and materials for using conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated). For example, conditional CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated can be administered (e.g., in an adoptive cell therapy) to a mammal (e.g., a human) having cancer to treat the mammal’s cancer. As described herein, when a CAR present on a conditional CAR T cell provided herein is activated (e.g., by binding to an antigen targeted by an antigen-binding domain present in the CAR), the conditional CAR T cell can express an agent that can target a cell of a TME such that the agent that can target the TME can reduce or eliminate immunosuppressive elements of the TME. Having the ability to precisely and flexibly control CAR T cell function using conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) provides a unique and unrealized opportunity to treat cancer while minimizing or even eliminating adverse impacts such as cytokine release syndrome and on-target / off-tumor toxicity. In general, one aspect of this document features immune cells including (a) a nucleic acid sequence encoding a CAR having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter, where the immune cell expresses the CAR, and where the immune cell expresses the agent following binding of the CAR binds to the cancer-specific antigen. The immune cell can be a T cell, a natural killer (NK) cell, a macrophage, and a B cell.Attorney Docket No.07039-2320WO1 / 2024-189 The nucleic acid sequence encoding the CAR can be integrated into the genome of the immune cell. The nucleic acid sequence encoding the agent can be integrated into the genome of the immune cell. The CAR can be CLDN18.2-specific CAR, a BCMA- specific CAR, a CS1-specific CAR, and a HER2-specific CAR. The CAR can be a CLDN18.2-specific CAR, and the agent can be a FAP-specific CAR. The CAR can be a BCMA-specific CAR, and the agent can be a CS1-specific CAR. The agent can be the FAP-specific CAR, and the cell of the TME can be a FAP+cell. The agent can be a bi- specific T cell engager (BiTE). The BiTE can be a FAP-specific BiTE and a CS1-specific BiTE. The agent can be the FAP-specific BiTE, and the cell of the TME can be a FAP+cell. The inducible promotor can include two to ten nuclear factor of activated T cell (NFAT) response element consensus domains fused to a minimal IL-2 promoter. The NFAT response element consensus domain can include a nucleic acid sequence set forth in SEQ ID NO:105. The minimal IL-2 promoter can include a nucleic acid sequence set forth in SEQ ID NO:107. The cell can include a nucleic acid sequence encoding a synNotch receptor having the ability to bind the cancer-specific antigen that is operably linked to a constitutive promoter, where the synNotch receptor includes an intracellular GAL4 polypeptide. The inducible promoter can include one to five copies of an upstream activation sequence (UAS). The UAS can include a nucleic acid sequence set forth in SEQ ID NO:108. In some cases, the CAR can include a GPR50 polypeptide and a GAL4polypeptide. The constitutive promoter can be an EF1 promoter, a cytomegalovirus(CMV) promoter, or a phosphoglycerokinase (PGK) promoter. In another aspect, this document features methods for making an immune cell including (a) a nucleic acid sequence encoding a CAR having the ability to bind a cancer- specific antigen that is operably linked to a constitutive promoter and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter, where the immune cell expresses the CAR, and where the immune cell expresses the agent following binding of the CAR binds to the cancer-specific antigen. The methods can include, or consist essentially of, introducing the (a) and the (b) to an immune cell. The introducing can be done ex vivo. The (a) and the (b) can be present on a single nucleic acid construct. The (a) and the (b) can be present on separate nucleic acid constructs. When the (a) and the (b) are present on separate nucleic acid constructs, the (a) and the (b) can be introduced to the cell at the same time. When the (a)Attorney Docket No.07039-2320WO1 / 2024-189 and the (b) are present on separate nucleic acid constructs, the (a) and the (b) are introduced to the cell separately. In another aspect, this document features nucleic acid constructs including (a) a nucleic acid sequence encoding a chimeric antigen receptor (CAR) having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter. The CAR can be a CLDN18.2-specific CAR, a BCMA- specific CAR, a CS1-specific CAR, or a HER2-specific CAR. The CAR can be a CLDN18.2-specific CAR, and the agent can be a FAP-specific CAR. The CAR can be a BCMA-specific CAR, and the agent is a CS1-specific CAR. The CAR can include a 4-1BB signaling domain and a CD3 signaling domain. The agent can be a BiTE. The BiTEcan be a FAP-specific BiTE or a CS1-specific BiTE. The inducible promotor can include two to ten NFAT response element consensus domains fused to a minimal IL-2 promoter. The NFAT response element consensus domain can include a nucleic acid sequence set forth in SEQ ID NO:105. The minimal IL-2 promoter can include a nucleic acid sequence set forth in SEQ ID NO:107. The construct can include a nucleic acid sequence encoding a synNotch receptor having the ability to bind the cancer-specific antigen that is operably linked to a constitutive promoter, where the synNotch receptor includes an intracellular GAL4 polypeptide. The inducible promoter can include one to five copies of an UAS. The UAS can include a nucleic acid sequence set forth in SEQ ID NO:108. The CAR can include a GPR50 polypeptide and a GAL4 polypeptide. The nucleic acid construct can be in the form of a vector. The vector can be a viral vector. The viral vector can be alentiviral vector. The constitutive promoter can be an EF1 promoter, a CMV promoter,or a PGK promoter. In another aspect, this document features immune cells including a nucleic acid construct including (a) a nucleic acid sequence encoding a chimeric antigen receptor (CAR) having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter, where the immune cell (1) constitutively expresses the CAR and (2) expresses the agent that can target a cell of a TME when the CAR is activated by binding to a cancer cell expressing the cancer-Attorney Docket No.07039-2320WO1 / 2024-189 specific antigen. The immune cell can be a T cell, a NK cell, a macrophage, and a B cell. The immune cell can be obtained from a human. In another aspect, this document features methods for treating a mammal having cancer. The methods can include, or consist essentially of, administering, to a mammal having cancer, a composition containing an immune cell including (a) a nucleic acid sequence encoding a CAR having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter, where the immune cell expresses the CAR, and where the immune cell expresses the agent following binding of the CAR binds to the cancer-specific antigen and / or an immune cell including a nucleic acid construct including (a) a nucleic acid sequence encoding a chimeric antigen receptor (CAR) having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter, where the immune cell (1) constitutively expresses the CAR and (2) expresses the agent that can target a cell of a TME when the CAR is activated by binding to a cancer cell expressing the cancer-specific antigen. The mammal can be a human. The cancer can be a colorectal cancer, a multiple myeloma, a pancreatic cancer, an esophageal cancer, a breast cancer, or a prostate cancer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.Attorney Docket No.07039-2320WO1 / 2024-189 BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1C. Figure 1) A schematic of a generic nucleic acid construct including (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding a polypeptide that is operably linked to an inducible promoter. Additional elements shown include a Rev- responsive element (RRE), a central polypurine tract (cPPT), a T2A polypeptide (T2A), and an epidermal growth factor receptor polypeptide (EGFR). Figure 1B) A schematic of a nucleic acid construct including (a) a nucleic acid sequence encoding a CAR having the ability to bind a CD19 antigen (a CD19-CAR) that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an enhanced green fluorescent polypeptide (eGFP) that is operably linked to a series of 6 nuclear factor of activated T cell (NFAT) promoter response element consensus domains (6x NFAT RE) fused to a minimal IL2 promoter. Additional elements shown include a RRE, a cPPT, a T2A, and a EGFR. Figure 1C) Flow cytometric analysis of GFP expression in T cells transduced with lentiviral vectors including a nucleic acid construct shown in Figure 1B and co-cultured with CD19-expressing Nalm6 cells. Figures 2A-2B. Schematic of an exemplary conditional expression system where CAR activation of a CLDN18.2-specific CAR results in expression of a FAP-specific CAR. Figure 2A) A schematic of a nucleic acid that includes (a) a nucleic acid sequenceencoding a CLDN18.2-specific CAR including a 4-1BB signaling domain and a CD3signaling domain (also referred to as a BBz signaling domain) and a that is operably linked to a constitutive EF1a promoter, and (b) a nucleic acid sequence encoding a FAP- specific CAR that is operably linked to a 6x NFAT RE fused to a minimal IL-2 promoter. Figure 2B) When the constitutively expressed CLDN18.2-specific CAR is activated by binding to a cell expressing a CLDN18.2 polypeptide, the CAR activation induces a lymphocyte protein tyrosine kinase (Lck) polypeptide to phosphorylate tyrosine-basedimmunoreceptor motifs present in the CD3 signaling domain of the CLDN18.2-specificCAR, the phosphorylation of the CD3 signaling domain causes an increase ofintracellular Ca2+which activates a calcineurin polypeptide, the activated calcineurin polypeptide dephosphorylates a nuclear factor of activated T cells (NFAT) polypeptide, the dephosphorylated NFAT polypeptide translocates to the nucleus where it binds the 6x NFAT RE and drives expression of the FAP-specific CAR.Attorney Docket No.07039-2320WO1 / 2024-189 Figure 3. Schematic of an exemplary conditional expression system where CAR activation of a CLDN18.2-specific CAR results in expression of a FAP-specific CAR. When the constitutively expressed CLDN18.2-specific synNotch receptor is activated by binding to a cell expressing a CLDN18.2 polypeptide, the GAL4 polypeptide is cleaved from the synNotch receptor, the free GAL4 polypeptide translocates to the nucleus where it binds the upstream activation sequence (UAS) and drives expression of the FAP- specific CAR. Figure 4. Schematic of an exemplary conditional expression system where CAR activation of a CLDN18.2-specific CAR results in expression of a FAP-specific CAR. When a CLDN18.2-specific CAR fused to a GPR50 polypeptide followed by a GAL4 polypeptide is activated, the CAR activation causes an increase in intracellular Ca2+levels which activates a calpain polypeptide, the activated calpain polypeptide cleaves the GPR50 polypeptide thus releasing the GAL4 polypeptide, the free GAL4 polypeptide translocates to the nucleus where it binds the UAS and drives expression of the FAP- specific CAR. Figure 5. Schematic of an exemplary conditional expression system where CAR activation of a CLDN18.2-specific CAR results in expression of a FAP-specific CAR. When the constitutively expressed CLDN18.2-specific synNotch receptor (Claudin18.2- SynNotch) on a CAR T cell is activated by binding to a cell expressing a CLDN18.2 polypeptide, cleavage of GAL4 by -secretase is induced. Cleaved GAL4 translocates to the nucleus where it binds the UAS sequence upstream of the FAP5-BBz CAR gene, inducing its expression. Figures 6A-6B. Activation of Claudin18.2-SynNotch induced expression of UAS- FAP CAR. Figure 6A) Representative flow plots of Claudin18.2-SynNotch expression two days post-transduction of healthy donor T cells. Figure 6B) Induction of UAS-FAP CAR expression. Claudin18.2-SynNotch + UAS-FAP CART or untransduced T cells were unstimulated or were co-cultured with SNU-C2B WT (Claudin18.2-) or SNU-C2B- Claudin18.2+cells at 1:3 effector:target (E:T) ratios for 48 hours. Expression of FAP CAR was determined by flow cytometry using soluble FAP-PE conjugated protein. Figures 7A-7B. SynNotch inducible Claudin18.2 / FAP dual targeting CART cells successfully eliminated cancer cells and fibroblasts in vitro. Figure 7A) CAR and SynNotch expression was confirmed by flow cytometry using rabbit-anti-VHH-APC forAttorney Docket No.07039-2320WO1 / 2024-189 nanobody based CART cells (KGHH18-5-BBz), rabbit-anti-Myc-AF700 for SynNotch, and soluble FAP-PE for FAP5-BBz. Figure 7B) Cytotoxic activity of unstransduced T cells, KGHH18-5-BBz CART, FAP5-BBz CART, KGHH18-5-BBz / SynNotch CART, and FAP5-BBz / SynNotch CART against luciferase+Claudin18.2+SNU-C2B cells was assessed. Cytotoxic activity of cells against luciferase+WI-38 cells was determined for unstimulated SynNotch CART cells and SynNotch CART cells stimulated at a 3:1 ratio with SNU-C2B Claudin18.2+cancer. Different E:T ratios were cultured for 48 hours. Cytotoxicity was assessed by bioluminescence of residual live cells. Mean and SEM; *P < .05, **P < .005, ***P < .0005, ****P < .0001, two-way ANOVA; n = 3. Figures 8A-8D. SynNotch inducible Claudin18.2 / FAP dual targeting CART cells exhibited anti-tumor activity in vivo. Figure 8A) CAR and SynNotch expression was confirmed by flow cytometry using rabbit-anti-VHH-APC for nanobody based CART cells (KGHH18-5-BBz) and rabbit-anti-Myc-AF700 for SynNotch. A mix of 1x106Claudin18.2+SNU-C2B cancer cells and 10x106colorectal cancer-associated fibroblasts (CAF) were implanted subcutaneously in NSG mice and allowed to engraft. Intravenous infusion of 2.5x106KGHH18-5-BBz CART cells or KGHH18-15-BBz / SynNotch CART cells was administered upon tumor engraftment. Figure 7B) Tumor volume was monitored via caliper measurement. Figure 7C) Mouse weight was measured as a readout of wellness. Figure 7D) Kaplan-Meier survival curve. DETAILED DESCRIPTION This document provides methods and materials for generating conditional CAR T cells that (1) can constitutively express one or more CARs having the ability to bind a cancer-specific antigen and (2) can conditionally express an agent that can target a cell of a TME when the CAR is activated (e.g., by binding to a cancer cell expressing that cancer-specific antigen). In some cases, a conditional CAR T cell provided herein can be engineered to contain nucleic acid (e.g., exogenous nucleic acid) including (a) a nucleic acid sequence encoding one or more CARs having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter. For example, a conditional CAR T cell can be engineered to contain nucleic acid (e.g., exogenous nucleic acid) that includes (a) a nucleic acid sequence encoding oneAttorney Docket No.07039-2320WO1 / 2024-189 or more CARs having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter to generate a T cell that (1) can constitutively express one or more CARs having the ability to bind a cancer- specific antigen and (2) can conditionally express an agent that can target a cell of a TME when the CAR is activated (e.g., by binding to a cancer cell expressing that cancer- specific antigen). A conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can be any appropriate T cell. A T cell can be a naïve T cell. Examples of T cells that can be used to generate conditional CAR T cells as described herein include, without limitation, cytotoxic T cells (e.g., CD4+CTLs and / or CD8+CTLs). In some cases, conditional CAR T cells can be generated from T cells that were obtained from a mammal (e.g., a mammal having cancer) that is to be treated with the conditional CAR T cells. For example, T cells can be obtained from a mammal to be treated with the materials and method described herein. In some cases, the methods and materials provided herein can be used to generate a conditional CAR cell other than a conditional CAR T cell. For example, the methods and materials provide herein can be used to can a conditional CAR from an immune cell other than a T cell. Examples of cells that can be used to generate a condition CAR cell using the methods and materials provided herein include, without limitation, stem cells (e.g., induced pluripotent stems cells (iPSCs) and mesenchymal stem cells (MSCs)), natural killer (NK) cells, macrophages, and B cells. A conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can constitutively express any appropriate CAR having the ability to bind a cancer- specific antigen. A CAR that can be used to make a conditional CAR T cell described herein can include an antigen-binding domain, an optional hinge, a transmembrane domain, and one or more signaling domains. Examples of antigen-binding domains include, without limitation, an antigen-binding fragment (Fab), a variable region of anAttorney Docket No.07039-2320WO1 / 2024-189 antibody heavy (VH) chain, a variable region of a light (VL) chain, a single-domain antibody (sdAb, also known as a nanobody or a VHH), and a single chain variable fragment (scFv). A CAR having the ability to bind a cancer-specific antigen and that can be used to make a conditional CAR T cell described herein can bind any appropriate cancer-specific antigen. For example, a CAR having the ability to bind a cancer-specific antigen can include an antigen-binding domain having the ability to bind a cancer-specific antigen. In some cases, a cancer-specific antigen can be a cell surface cancer-specific antigen expressed by a cancer cell in a mammal having cancer. Examples of antigens that can be recognized by an antigen-binding domain in a CAR having the ability to bind a cancer- specific antigen as described herein include, without limitation, claudin 18 isoform 2 (CLDN18.2), cluster of differentiation 19 (CD19), mucin 1 (MUC-1), human epidermal growth factor receptor 2 (HER-2), estrogen receptor (ER), epidermal growth factor receptor (EGFR), alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, epithelial tumor antigen (ETA), melanoma-associated antigen (MAGE), CD33, CD123, CLL-1, E-Cadherin, folate receptor alpha, folate receptor beta, IL13R, EGFRviii, CD22, CD20, kappa light chain, lambda light chain, desmopressin, CD44v, CD45, CD30, CD5, CD7, CD2, CD38, BCMA, CD138, FAP, CS1 (also known as CD319, CRACC and SLAMF7), and C-met. In some cases, a CAR having the ability to bind a cancer-specific antigen can be a CAR that includes an antigen-binding domain that can target (e.g., can target and bind) a CLDN18.2 polypeptide, also referred to as a CLDN18.2-specific CAR. A CAR having the ability to bind a cancer-specific antigen and that can be used to make a conditional CAR T cell described herein can have any appropriate antigen- binding domain. When a CAR having the ability to bind a cancer-specific antigen is a CLDN18.2-specific CAR, the CLDN18.2-specific CAR can include any appropriate antigen-binding domain that can bind (e.g., specifically bind) to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide). For example, a CLDN18.2-specific CAR can include an antigen-binding domain that can bind (e.g., specifically bind) to a polypeptide comprising, consisting essentially of, or consisting of the amino acid set forth in any one of SEQ ID NOs:76-78 (see, e.g., Example 13). In some cases, a CLDN18.2-specific CAR provided herein can have the ability to bind to a CLDN18.2 polypeptide and can lack the ability to bind to other members of the claudin family (e.g., a CLDN1 polypeptide, aAttorney Docket No.07039-2320WO1 / 2024-189 CLDN2 polypeptide, a CLDN3 polypeptide, a CLDN4 polypeptide, a CLDN5 polypeptide, a CLDN6 polypeptide, a CLDN7 polypeptide, a CLDN8 polypeptide, a CLDN9 polypeptide, a CLDN10 polypeptide, a CLDN11 polypeptide, a CLDN12 polypeptide, a CLDN13 polypeptide, a CLDN14 polypeptide, a CLDN15 polypeptide, a CLDN16 polypeptide, a CLDN17 polypeptide, a CLDN18.1 polypeptide, a CLDN19 polypeptide, a CLDN20 polypeptide, a CLDN21 polypeptide, a CLDN22 polypeptide, and a CLDN23 polypeptide). For example, a CLDN18.2-specific CAR provided herein can have the ability to bind to a human CLDN18.2 polypeptide and can lack the ability to bind to one or more other human CLDN polypeptides (e.g., a human CLDN1 polypeptide, a human CLDN2 polypeptide, a human CLDN3 polypeptide, a human CLDN4 polypeptide, a human CLDN5 polypeptide, a human CLDN6 polypeptide, a human CLDN7 polypeptide, a human CLDN8 polypeptide, a human CLDN9 polypeptide, a human CLDN10 polypeptide, a human CLDN11 polypeptide, a human CLDN12 polypeptide, a human CLDN13 polypeptide, a human CLDN14 polypeptide, a human CLDN15 polypeptide, a human CLDN16 polypeptide, a human CLDN17 polypeptide, a human CLDN18.1 polypeptide, a human CLDN19 polypeptide, a human CLDN20 polypeptide, a human CLDN21 polypeptide, a human CLDN22 polypeptide, and a human CLDN23 polypeptide). In some cases, a CLDN18.2-specific CAR provided herein can be designed to include an antigen binding domain that includes at least one set of three CDRs (e.g., CDR1, CDR2, and CDR3) of an antigen binding domain provided herein (e.g., SEQ ID NOs:1-3, SEQ ID NOs:5-6, or SEQ ID NOs:9-11). For example, an antigen binding domain of a CAR targeting a CLDN18.2 polypeptide can be designed to include a VH domain described herein. In some cases, a CAR provided herein can be designed to include an antigen binding domain that includes two sets of three CDRs (e.g., CDR1, CDR2, and CDR3 of a heavy chain and CDR1, CDR2, and CDR3 of a light chain) of an antigen binding fragment provided herein (e.g., SEQ ID NOs: 13-15 and 16-18 or SEQ ID NOs: 21-23 and 24-26). For example, an antigen binding domain of a CAR targeting a CLDN18.2 polypeptide can be designed to include a VH domain described herein or a scFv antibody described herein. In some cases, a CLDN18.2-specific CAR can include a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of theAttorney Docket No.07039-2320WO1 / 2024-189 amino acid sequence set forth in SEQ ID NO:1, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:2, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:3. In some cases, a CLDN18.2-specific CAR can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 1. Table 1. Exemplary CDR sequences for an antigen binding domain that can bind a CLDN18.2 polypeptide.A CDR that can be included in an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:1- 3 is a CDR that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:1-3), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:1-3), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:1-3), provided that the CAR retains the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide). In some cases, an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:1-3 can include a heavy chain variable domain having the sequence set forth in SEQ ID NO:4. In some cases, a CLDN18.2-specific CAR can include a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:1, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:2, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:3. In some cases, a CLDN18.2-specific CAR can include CDRs thatAttorney Docket No.07039-2320WO1 / 2024-189 comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 2. Table 2. Exemplary CDR sequences for an antigen binding domain that can bind a CLDN18.2 polypeptide.A CDR that can be included in an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:5- 7 is a CDR that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:5-7), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:5-7), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:5-7), provided that the CAR retains the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide). In some cases, an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:5-7 can include a heavy chain variable domain having the sequence set forth in SEQ ID NO:8. In some cases, a CLDN18.2-specific CAR can include a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:9, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:10, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:11. In some cases, a CLDN18.2-specific CAR can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 3.Attorney Docket No.07039-2320WO1 / 2024-189 Table 3. Exemplary CDR sequences for an antigen binding domain that can bind a CLDN18.2 polypeptide.A CDR that can be included in an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:9- 11 is a CDR that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:9-11), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:9-11), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:9-11), provided that the CAR retains the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide). In some cases, an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:9-11 can include a heavy chain variable domain having the sequence set forth in SEQ ID NO:12. In some cases, CLDN18.2-specific CAR can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:13, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:14, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:15, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:16, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:17, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:18. In some cases, a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 4.Attorney Docket No.07039-2320WO1 / 2024-189 Table 4. Exemplary CDR sequences for an antigen binding domain that can bind a CLDN18.2 polypeptide.A CDR that can be included in an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:13-18 is a CDR that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:13-18), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:13-18), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:13-18), provided that the CAR retains the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide). In some cases, an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:13-15 and / or 16-18 can include an scFv having the sequence set forth in SEQ ID NO:19 or an scFv having the sequence set forth in SEQ ID NO:20. In some cases, CLDN18.2-specific CAR can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:21, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:22, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:23, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:24, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:25, and (iii) a CDR3 that comprises,Attorney Docket No.07039-2320WO1 / 2024-189 consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:26. In some cases, a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 5. Table 5. Exemplary CDR sequences for an antigen binding domain that can bind a CLDN18.2 polypeptide.A CDR that can be included in an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:21-26 is a CDR that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:21-26), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:21-26), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:21-26), provided that the CAR retains the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide). In some cases, an antigen binding domain of a CAR having the ability to bind to a CLDN18.2 polypeptide (e.g., a human CLDN18.2 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:21-23 and / or 24-26 can include an scFv having the sequence set forth in SEQ ID NO:27 or an scFv having the sequence set forth in SEQ ID NO:28. In some cases, a CAR having the ability to bind a cancer-specific antigen (e.g., a CLDN18.2-specific CAR) can include an optional hinge region. In some cases, a hinge region can be located between an antigen-binding domain and a transmembrane domain of a CAR. In some cases, a hinge region can provide a CAR with increased flexibility for the antigen-binding domain. For example, a hinge region can reduce spatial limitations ofAttorney Docket No.07039-2320WO1 / 2024-189 an antigen-binding domain of a CAR and its target antigen (e.g., to increase binding between an antigen-binding domain of a CAR and its target antigen). Examples of hinge regions that can be used as described herein include, without limitation, a membrane- proximal region from an IgG, a membrane-proximal region from CD8, and a membrane- proximal region from CD28. In some cases, a hinge region of a CAR can be as described elsewhere (see, e.g., U.S. Patent Application Publication No.2018 / 0000914 such as U.S. Patent Application Publication No.2018 / 0000914 at paragraph

[0168] , and Table 1; U.S. Patent Application Publication No.2017 / 0183418 such as U.S. Patent Application Publication No.2017 / 0183418 at paragraphs

[0034] ,

[0037] ,

[0040] , and Table 2; U.S. Patent Application Publication No.2017 / 0183413 such as U.S. Patent Application Publication No.2017 / 0183413 at paragraph

[0116] ; and U.S. Patent Application Publication No.2017 / 0145094 such as U.S. Patent Application Publication No. 2017 / 0145094 at paragraph

[0104] . A CAR having the ability to bind a cancer-specific antigen (e.g., a CLDN18.2- specific CAR) can include any appropriate transmembrane domain. A transmembrane domain can be located between an antigen-binding domain and a signaling domain of a CAR and / or located between a hinge and a signaling domain of a CAR. In some cases, a transmembrane domain can provide structural stability for the CAR. For example, a transmembrane domain can include a structure (e.g., a hydrophobic alpha helix structure) that can span a cell membrane and can anchor the CAR to the plasma membrane. Examples of transmembrane domains that can be used as described herein include,without limitation, CD3 transmembrane domains, CD4 transmembrane domains, CD8(e.g., a CD8 ) transmembrane domains, CD28 transmembrane domains, CD16transmembrane domains, and erythropoietin receptor transmembrane domains. In some cases, a transmembrane domain of a CAR can be as described elsewhere (see, e.g., U.S. Patent Application Publication No.2016 / 0120906 such as U.S. Patent Application Publication No.2016 / 0120906 at paragraphs

[0155] ,

[0161] ,

[0269] , Figure 4, and Figure 11; U.S. Patent Application Publication No.2019 / 0209616 such as U.S. Patent Application Publication No.2019 / 0209616 at paragraph

[0026] ; U.S. Patent ApplicationAttorney Docket No.07039-2320WO1 / 2024-189 paragraphs

[0116] –

[0118] ; U.S. Patent Application Publication No.2017 / 0183413 such as U.S. Patent Application Publication No.2017 / 0183413 at paragraphs

[0116] –

[0118] ; and U.S. Patent Application Publication No.2017 / 0145094 such as U.S. Patent Application Publication No.2017 / 0145094 at paragraphs

[0104] –

[0107] . A CAR having the ability to bind a cancer-specific antigen (e.g., a CLDN18.2- specific CAR) can include any appropriate signaling domain or combination of signaling domains (e.g., a combination of two, three, or four signaling domains). In some cases, a signaling domain of a CAR can be an intracellular signaling domain normally found within T cells or NK cells. In some cases, a CAR can include a signaling domain that renders a T cell expressing the CAR susceptible to senescence (e.g., susceptible to senescence upon reactivation). Examples of signaling domains that can be used asdescribed herein include, without limitation, BB signaling domains, 28 signalingdomains, CD2 signaling domains, CD3 signaling domains, CD28 signaling domains,Toll-like receptor (TLR) signaling domains (e.g., TLR3 or TLR4 signaling domains), CD27 intracellular signaling domains, OX40 (CD134) intracellular signaling domains, 4- 1BB (CD137) intracellular signaling domains, CD278 intracellular signaling domains, DAP10 intracellular signaling domains, DAP12 intracellular signaling domains, FceRly intracellular signaling domains, CD278 intracellular signaling domains, CD122 intracellular signaling domains, CD132 intracellular signaling domains, CD70 intracellular signaling domains, cytokine receptor intracellular signaling domains, and CD40 intracellular signaling domains. In some cases, a CAR for use as described hereincan be designed to be a first-generation CAR having a CD3 intracellular signalingdomain. In some cases, a CAR for use as described herein can be designed to be a second-generation CAR having a CD28 intracellular signaling domain followed by aCD3 intracellular signaling domain. In some cases, a CAR for use as described hereincan be designed to be a third generation CAR having (a) a CD28 intracellular signaling domain followed by (b) a CD27 intracellular signaling domain, an OX40 intracellularsignaling domains, or a 4-1BB intracellular signaling domain followed by (c) a CD3intracellular signaling domain. In some cases, the intracellular signaling domain(s) of a CAR can be as described elsewhere (see, e.g., U.S. Patent Application Publication No. 2018 / 0000914 such as U.S. Patent Application Publication No.2018 / 0000914 at paragraphs

[0164] –

[0167] ; and U.S. Patent Application Publication No.2017 / 0183413Attorney Docket No.07039-2320WO1 / 2024-189 such as U.S. Patent Application Publication No.2017 / 0183413 at paragraphs

[0112] –

[0115] . In some cases, a CAR having the ability to bind a cancer-specific antigen can be as set forth in Table 6. Table 6. Exemplary CARs having the ability to bind to a cancer-specific antigen.Attorney Docket No.07039-2320WO1 / 2024-189Any appropriate method can be used to constitutively express a CAR having the ability to bind a cancer-specific antigen in a conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated). In some cases, a conditional CAR T cell provided herein can be engineered to contain nucleic acid (e.g., exogenous nucleic acid) including a nucleic acid sequence encoding one or more CARs having the ability to bind a cancer- specific antigen that each are operably linked to a constitutive promoter. Each nucleic acid sequence encoding a CAR having the ability to bind a cancer-specific antigen can be operably linked to any appropriate constitutive promoter. In some cases, a constitutiveAttorney Docket No.07039-2320WO1 / 2024-189 promoter can be a naturally occurring promoter. In some cases, a constitutive promoter can be a recombinant promoter. In some cases, a continuative promoter can be a synthetic promoter. Examples of constitutive promoters that can be used to drive expression of a nucleic acid sequence encoding a CAR having the ability to bind a cancer-specific antigeninclude, without limitation, EF1 promoters, cytomegalovirus (CMV) promoters, andphosphoglycerokinase (PGK) promoters. A conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can conditionally express any appropriate agent that can target a cell of a TME. In some cases, an agent that can target a cell of TME can promote the reduction or elimination of cells such as fibroblasts (e.g., cancer-associated fibroblasts), immunosuppressive T cells, and / or gamma-delta T cells within the TME. An agent that can target a cell of a TME can be any appropriate type of molecule (e.g., polypeptides). In some cases, an agent that can target a cell of a TME can include an antigen-binding domain that can target a cell of a TME. Examples of agents that can include an antigen-binding domain and can target (e.g., can be designed to target) a cell of a TME include, without limitation, nanobodies, CARs, and T cell engagers (e.g., bi-specific T cells engagers (BiTEs). In some cases, an agent that can target a cell of a TME can include an antigen- binding domain having the ability to bind to an antigen expressed by that target cell. In some cases, such an antigen can be a cell surface antigen expressed by a cell present in a TME. Examples of antigens that can be recognized by an antigen-binding domain in an antigen-binding domain having the ability to bind a cell of a TME as described herein include, without limitation, fibroblast activation protein (FAP) polypeptides (e.g., FAP-alpha (FAP ) polypeptides) and CS1 polypeptides.In some cases, an agent that can target a cell of a TME can target a FAP+cell. Examples of FAP+cells include, without limitation, fibroblasts such as gastrointestinal fibroblasts bone marrow fibroblasts, lung fibroblasts, pancreatic fibroblasts, and colorectal fibroblasts. In some cases, an agent that can target a cell of a TME can target a CS1+cell. Examples of CS1+cells include, without limitation, bone marrow cells.Attorney Docket No.07039-2320WO1 / 2024-189 In some cases, an agent that can target a cell of a TME can include any appropriate antigen-binding domain that can bind (e.g., specifically bind) to a FAP polypeptide (e.g., a human FAP polypeptide). For example, an agent that can target a cell of a TME can include an antigen-binding domain that can bind (e.g., specifically bind) to a polypeptide comprising, consisting essentially of, or consisting of the amino acid set forth in any one of SEQ ID NOs:79-80 (see, e.g., Example 6). In some cases, an antigen-binding domain having the ability to bind a FAP polypeptide can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:29, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:30, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:31, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:32, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:33, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:34. In some cases, an antigen-binding domain having the ability to bind a FAP polypeptide (e.g., a human FAP polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 7. Table 7. Exemplary CDR sequences for an antigen binding domain that can bind a FAP polypeptide.An antigen binding domain having the ability to bind to a FAP polypeptide (e.g., a human FAP polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:29-34 is an antigen-binding domain that has zero, one, or twoAttorney Docket No.07039-2320WO1 / 2024-189 amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:29-34), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:29-34), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:29-34), provided that the antigen-binding domain retains the ability to bind to a FAP polypeptide (e.g., a human FAP polypeptide). In some cases, an antigen binding domain having the ability to bind to a FAP polypeptide (e.g., a human FAP polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:29-31 and / or 32-34 can include an scFv having the sequence set forth in SEQ ID NO:35 or an scFv having the sequence set forth in SEQ ID NO:36. In some cases, an antigen-binding domain having the ability to bind a FAP polypeptide can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:37, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:38, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:39, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:40, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:41, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:42. In some cases, an antigen-binding domain having the ability to bind a FAP polypeptide (e.g., a human FAP polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 8. Table 8. Exemplary CDR sequences for an antigen binding domain that can bind a FAP polypeptide.Attorney Docket No.07039-2320WO1 / 2024-189An antigen binding domain having the ability to bind to a FAP polypeptide (e.g., a human FAP polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:37-42 is an antigen-binding domain that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:37-42), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:37-42), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:37-42), provided that the antigen-binding domain retains the ability to bind to a FAP polypeptide (e.g., a human FAP polypeptide). In some cases, an antigen binding domain having the ability to bind to a FAP polypeptide (e.g., a human FAP polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:37-39 and / or 40-42 can include an scFv having the sequence set forth in SEQ ID NO:43 or an scFv having the sequence set forth in SEQ ID NO:44. In some cases, an agent that can target a cell of a TME can include any appropriate antigen-binding domain that can bind (e.g., specifically bind) to a CS1 polypeptide (e.g., a human CS1 polypeptide). For example, an agent that can target a cell of a TME can include an antigen-binding domain that can bind (e.g., specifically bind) to a polypeptide comprising, consisting essentially of, or consisting of the amino acid set forth in any one of SEQ ID NOs:81-82 (see, e.g., Example 10). In some cases, an antigen-binding domain having the ability to bind a CS1 polypeptide can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:45, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:46, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:47, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consistsAttorney Docket No.07039-2320WO1 / 2024-189 essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:48, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:49, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:50. In some cases, an antigen-binding domain having the ability to bind a CS1 polypeptide (e.g., a human CS1 polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 9. Table 9. Exemplary CDR sequences for an antigen binding domain that can bind a CS1 polypeptide.An antigen binding domain having the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:45-50 is an antigen-binding domain that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:45-50), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:45-50), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:45-50), provided that the antigen-binding domain retains the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide). In some cases, an antigen binding domain having the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:45-47 and / or 48-50 can include an scFv having the sequence set forth in SEQ ID NO:51 or an scFv having the sequence set forth in SEQ ID NO:52.Attorney Docket No.07039-2320WO1 / 2024-189 In some cases, an antigen-binding domain having the ability to bind a CS1 polypeptide can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:53, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:54, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:55, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:56, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:57, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:58. In some cases, an antigen-binding domain having the ability to bind a CS1 polypeptide (e.g., a human CS1 polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 10. Table 10. Exemplary CDR sequences for an antigen binding domain that can bind a CS1 polypeptide.An antigen binding domain having the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:53-58 is an antigen-binding domain that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:53-58), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:53-58), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ IDAttorney Docket No.07039-2320WO1 / 2024-189 NOs:53-58), provided that the antigen-binding domain retains the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide). In some cases, an antigen binding domain having the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:53-55 and / or 56-58 can include an scFv having the sequence set forth in SEQ ID NO:59 or an scFv having the sequence set forth in SEQ ID NO:60. In some cases, an antigen-binding domain having the ability to bind a CS1 polypeptide can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:61, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:62, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:63, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:64, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:65, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:66. In some cases, an antigen-binding domain having the ability to bind a CS1 polypeptide (e.g., a human CS1 polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 11. Table 11. Exemplary CDR sequences for an antigen binding domain that can bind a CS1 polypeptide.An antigen binding domain having the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide) that consists essentially of a CDR amino acid sequence set forthAttorney Docket No.07039-2320WO1 / 2024-189 in any one of SEQ ID NOs:61-66 is an antigen-binding domain that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:61-66), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:61-66), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:61-66), provided that the antigen-binding domain retains the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide). In some cases, an antigen binding domain having the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:61-63 and / or 64-66 can include an scFv having the sequence set forth in SEQ ID NO:67 or an scFv having the sequence set forth in SEQ ID NO:68. In some cases, an antigen-binding domain having the ability to bind a CS1 polypeptide can include (a) a heavy chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:69, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:70, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:71, and / or (b) a light chain variable domain comprising (i) a CDR1 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:72, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:73, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:74. In some cases, an antigen-binding domain having the ability to bind a CS1 polypeptide (e.g., a human CS1 polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 12. Table 12. Exemplary CDR sequences for an antigen binding domain that can bind a CS1 polypeptide.Attorney Docket No.07039-2320WO1 / 2024-189An antigen binding domain having the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:69-74 is an antigen-binding domain that has zero, one, or two amino acid substitutions within the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:69-74), has zero, one, two, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:69-74), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs:69-74), provided that the antigen-binding domain retains the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide). In some cases, an antigen binding domain having the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:69-71 and / or 72-74 can include an scFv having the sequence set forth in SEQ ID NO:75. When an agent that can target a cell of a TME is a CAR, the CAR having the ability to bind an antigen expressed by a cell of a TME can include an optional hinge region. In some cases, a hinge region can be located between an antigen-binding domain and a transmembrane domain of a CAR. In some cases, a hinge region can provide a CAR with increased flexibility for the antigen-binding domain. For example, a hinge region can reduce spatial limitations of an antigen-binding domain of a CAR and its target antigen (e.g., to increase binding between an antigen-binding domain of a CAR and its target antigen). Examples of hinge regions that can be used as described herein include, without limitation, a membrane-proximal region from an IgG, a membrane-proximal region from CD8, and a membrane-proximal region from CD28. In some cases, a hinge region of a CAR can be as described elsewhere (see, e.g., U.S. Patent Application Publication No. 2018 / 0000914 such as U.S. Patent Application Publication No.2018 / 0000914 at paragraph

[0168] , and Table 1; U.S. Patent Application Publication No.2017 / 0183418Attorney Docket No.07039-2320WO1 / 2024-189 such as U.S. Patent Application Publication No.2017 / 0183418 at paragraphs

[0034] ,

[0037] ,

[0040] , and Table 2; U.S. Patent Application Publication No.2017 / 0183413 such as U.S. Patent Application Publication No.2017 / 0183413 at paragraph

[0116] ; and U.S. Patent Application Publication No.2017 / 0145094 such as U.S. Patent Application Publication No.2017 / 0145094 at paragraph

[0104] . When an agent that can target a cell of a TME is a CAR, the CAR having the ability to bind an antigen expressed by a cell within a TME can include any appropriate transmembrane domain. A transmembrane domain can be located between an antigen- binding domain and a signaling domain of a CAR and / or located between a hinge and a signaling domain of a CAR. In some cases, a transmembrane domain can provide structural stability for the CAR. For example, a transmembrane domain can include a structure (e.g., a hydrophobic alpha helix structure) that can span a cell membrane and can anchor the CAR to the plasma membrane. Examples of transmembrane domains thatcan be used as described herein include, without limitation, CD3 transmembranedomains, CD4 transmembrane domains, CD8 (e.g., a CD8 ) transmembrane domains,CD28 transmembrane domains, CD16 transmembrane domains, and erythropoietin receptor transmembrane domains. In some cases, a transmembrane domain of a CAR can be as described elsewhere (see, e.g., U.S. Patent Application Publication No. 2016 / 0120906 such as U.S. Patent Application Publication No.2016 / 0120906 at paragraphs

[0155] ,

[0161] ,

[0269] , Figure 4, and Figure 11; U.S. Patent Application Publication No.2019 / 0209616 such as U.S. Patent Application Publication No. 2019 / 0209616 at paragraph

[0026] ; U.S. Patent Application Publication No. 2018 / 0000914 such as U.S. Patent Application Publication No.2018 / 0000914 at paragraphs

[0168] –

[0171] ; U.S. Patent Application Publication No.2017 / 0183418 such as U.S. Patent Application Publication No.2017 / 0183418 at paragraphs

[0116] –

[0118] ; U.S. Patent Application Publication No.2017 / 0183413 such as U.S. Patent Application Publication No.2017 / 0183413 at paragraphs

[0116] –

[0118] ; and U.S. Patent Application Publication No.2017 / 0145094 such as U.S. Patent Application Publication No. 2017 / 0145094 at paragraphs

[0104] –

[0107] . When an agent that can target a cell of a TME is a CAR, the CAR having the ability to bind an antigen expressed by a cell within a TME can include any appropriate signaling domain or combination of signaling domains (e.g., a combination of two, three,Attorney Docket No.07039-2320WO1 / 2024-189 or four signaling domains). In some cases, a signaling domain of a CAR can be an intracellular signaling domain normally found within T cells or NK cells. In some cases, a CAR can include a signaling domain that renders a T cell expressing the CAR susceptible to senescence (e.g., susceptible to senescence upon reactivation). Examples of signaling domains that can be used as described herein include, without limitation, BB signalingdomains, 28 signaling domains, CD2 signaling domains, CD3 signaling domains, CD28signaling domains, Toll-like receptor (TLR) signaling domains (e.g., TLR3 or TLR4 signaling domains), CD27 intracellular signaling domains, OX40 (CD134) intracellular signaling domains, 4-1BB (CD137) intracellular signaling domains, CD278 intracellular signaling domains, DAP10 intracellular signaling domains, DAP12 intracellular signaling domains, FceRly intracellular signaling domains, CD278 intracellular signaling domains, CD122 intracellular signaling domains, CD132 intracellular signaling domains, CD70 intracellular signaling domains, cytokine receptor intracellular signaling domains, and CD40 intracellular signaling domains. In some cases, a CAR for use as described herein can be designed to be a first-generation CAR having a CD3 intracellular signalingdomain. In some cases, a CAR for use as described herein can be designed to be a second-generation CAR having a CD28 intracellular signaling domain followed by a CD3 intracellular signaling domain. In some cases, a CAR for use as described hereincan be designed to be a third generation CAR having (a) a CD28 intracellular signaling domain followed by (b) a CD27 intracellular signaling domain, an OX40 intracellular signaling domains, or a 4-1BB intracellular signaling domain followed by (c) a CD3intracellular signaling domain. In some cases, the intracellular signaling domain(s) of a CAR can be as described elsewhere (see, e.g., U.S. Patent Application Publication No. 2018 / 0000914 such as U.S. Patent Application Publication No.2018 / 0000914 at paragraphs

[0164] –

[0167] ; and U.S. Patent Application Publication No.2017 / 0183413 such as U.S. Patent Application Publication No.2017 / 0183413 at paragraphs

[0112] –

[0115] . In some cases, a CAR having the ability to bind to an antigen expressed by a cell of a TME can be as set forth in Table 13. Table 13. Exemplary CARs having the ability to bind to an antigen expressed by a cell ofAttorney Docket No.07039-2320WO1 / 2024-189When an agent that can target a fibroblast cell of a TME is a T cell engager (e.g., a BiTE), the agent that can target a fibroblast cell of a TME can be any appropriate T cell engager. The term “T cell engager” as used herein refers to a polypeptide that includes two or more antigen binding domains (e.g., two, three, or four antigen binding domains) with one that binds to a T cell and has the ability to link two cells together with one being a T cell. In some cases, a T cell engager can be a BiTE. In general, a T cell engager provided herein can be designed to include at least one agent that can target a cell (e.g., a fibroblast) of a TME (e.g., an antigen binding domain having the ability to bind to a FAP polypeptide or an antigen binding domain having the ability to bind to a CS1 polypeptide) and at least one antigen binding domain having the ability to bind to an antigen expressed on the surface of a T cell. In some cases, a T cell engager described herein can link a cell (e.g., a fibroblast) of a TME (e.g., a FAP+cell or a CS1+cell) to a T cell via the two or more antigen binding domains of the T cell engager. When designing a T cell engager such as a BiTE to link a cell of a TME and a T cell, the T cell engager can include an agent that can target a cell of a TME and one or more (e.g., one, two, or three) antigen binding domains having the ability to bind to a polypeptide expressed on the surface of a T cell. For example, when designing a T cell engager to link a FAP+cell and a T cell, the T cell engager can include an antigen binding domain having the ability to bind to a FAP polypeptide and an antigen binding domain having the ability to bind to a polypeptide expressed on the surface of a T cell. For example, when designing a T cell engager to link a CS1+cell and a T cell, the T cell engager can include an antigen binding domain having the ability to bind to a CS1 polypeptide and an antigen binding domain having the ability to bind to a polypeptide expressed on the surface of a T cell. Examples of polypeptides expressed on the surface of a T cell that can be targeted by an antigen binding domain of a T cell engager provided herein include, without limitation, CD3 polypeptides, CD5 polypeptides, and CD28Attorney Docket No.07039-2320WO1 / 2024-189 polypeptides. Examples of antigen binding domains having the ability to bind to a polypeptide expressed on the surface of a T cell that can be used to make a T cell engager provided herein (e.g., a BiTE) include, without limitation, anti-CD3 scFvs, anti-CD3 VH domains, anti-CD5 scFvs, anti-CD5 VH domains, anti-CD28 scFvs, and anti-CD28 VH domains. Additional examples of amino acid sequences that can be used as antigen binding domains having the ability to bind to a polypeptide expressed on the surface of a T cell (e.g., CD3) can be as described in U.S. Patent No.6,750,325 (see, e.g., the sequence listing of U.S. Patent No.6,750,325). Any appropriate method can be used to trigger the conditional expression of a polypeptide (e.g., an agent that can target a cell of a TME) upon activation of a CAR designed to be constitutively expressed by a conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated). In some cases, a conditional CAR T cell provided herein can be engineered to contain nucleic acid (e.g., exogenous nucleic acid) including a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter. A nucleic acid sequence encoding an agent that can target a cell of a TME can be operably linked to any appropriate inducible promoter. Examples of inducible promoters that can be used to drive expression of a nucleic acid sequence encoding an agent that can target a cell of a TME include, without limitation, NFAT mediated expression systems, synNotch mediated expression systems, GPR50-mediated expression systems, , and UAS / GAL4 mediated expression systems. In some cases, an agent that can target a cell of a TME can be operably linked to an NFAT mediated expression system. For example, a conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can include (a) a nucleic acid sequence encoding a CAR having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an NFAT mediated expression system. For example, a conditional CAR T cell provided herein can include a constitutively expressed CAR that includes one or more signaling domains (e.g., 4-1BBAttorney Docket No.07039-2320WO1 / 2024-189signaling domain and a CD3 signaling domain) and can include a nucleic acid sequenceencoding an agent that can target a cell of a TME that is operably linked to a 6x NFAT RE fused to a minimal IL-2 promoter, such that the conditional CAR T cells express the agent that can target a cell of a TME when the CAR is activated. When the CAR having the ability to bind a cancer-specific antigen is bound to a cancer cell expressing the cancer-specific antigen, the CAR activation can induce a Lck polypeptide tophosphorylate the CD3 signaling domain of the CAR. The phosphorylation of the CD3signaling domain can cause an increase of intracellular Ca2+, which can activate a calcineurin polypeptide. The activated calcineurin polypeptide can dephosphorylate a NFAT polypeptide, and the dephosphorylated NFAT polypeptide can translocate to the nucleus where it can bind the 6xNFAT and drive expression of the agent that can target a cell of a TME. In some cases, a conditional CAR T cell provided herein can include (a) a nucleic acid sequence encoding a CLDN18.2-specific CAR operably linked to a constitutive promoter (e.g., an EF1a promoter), where the CLDN18.2-specific CARincludes a 4-1BB signaling domain and a CD3 signaling domain, and (b) a nucleic acidsequence encoding a FAP-specific CAR that is operably linked to a 6x NFAT RE fused to a minimal IL-2 promoter, such that the conditional CAR T cells (1) constitutively express a CLDN18.2-specific CAR, and (2) conditionally express the FAP-specific CAR when the CLDN18.2-specific CAR is activated. In some cases, an NFAT mediated expression system can be as shown in Figures 2A and 2B. In some cases, an agent that can target a cell of a TME can be operably linked to a synNotch mediated expression system. For example, a conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can include (a) a nucleic acid sequence encoding a CAR having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to a synNotch mediated expression system. For example, a conditional CAR T cell provided herein can include a constitutively expressed CAR having the ability to bind a cancer-specific antigen and a constitutively expressed synNotch receptor having the ability to bind to a cancer-specific antigen (e.g., the same cancer-specific antigen that is targeted by the CAR), and canAttorney Docket No.07039-2320WO1 / 2024-189 include a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to a UAS, such that the conditional CAR T cells conditionally express the agent that can target a cell of a TME when the synNotch receptor is activated. When an inducible promoter is a synNotch mediated expression system, a conditional CAR T cell can include (a) a nucleic acid sequence encoding a CAR having the ability to bind a cancer-specific antigen operably linked to a constitutive promoter (e.g., an EF1a promoter), (b) a nucleic acid sequence encoding a synNotch receptor having the ability to bind to a cancer-specific antigen (e.g., the same cancer-specific antigen that is targeted by the CAR) operably linked to a constitutive promoter, where the synNotch receptor includes an intracellular GAL4 polypeptide, and (c) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to a UAS, such that the conditional CAR T cells (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, (2) constitutively express a synNotch receptor having the ability to bind to a cancer-specific antigen (e.g., the same cancer-specific antigen that is targeted by the CAR), and (3) conditionally express the agent that can target a cell of a TME when the synNotch receptor is activated. When the synNotch receptor is bound to a cancer cell expressing the cancer-specific antigen, the GAL4 polypeptide can be cleaved from the synNotch receptor, and the free GAL4 polypeptide can translocate to the nucleus where it can bind the UAS and drive expression of the agent that can target a cell of a TME. In some cases, a conditional CAR T cell provided herein can include (a) a nucleic acid sequence encoding a CLDN18.2-specific CAR operably linked to a constitutive promoter (e.g., an EF1a promoter), (b) a nucleic acid sequence encoding a CLDN18.2-specific synNotch receptor operably linked to a constitutive promoter, where the synNotch receptor includes an intracellular GAL4 polypeptide, and (c) a nucleic acid sequence encoding a FAP-specific CAR that is operably linked to a UAS, such that the conditional CAR T cells (1) constitutively express a CLDN18.2-specific CAR, (2) constitutively express a CLDN18.2-specific synNotch receptor, and (3) conditionally express the FAP- specific CAR when the synNotch receptor is activated. In some cases, a synNotch mediated expression system can be as shown in Figure 3. In some cases, an agent that can target a cell of a TME can be operably linked to a GPR50-mediated expression system. For example, a conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having theAttorney Docket No.07039-2320WO1 / 2024-189 ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can include (a) a nucleic acid sequence encoding a CAR having the ability to bind a cancer-specific antigen fused to a GPR50 polypeptide that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to a GPR50-mediated expression system. For example, a conditional CAR T cell provided herein can include a constitutively expressed CAR having the ability to bind a cancer- specific antigen fused to a GPR50 polypeptide and a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to a GPR50-mediated expression system (e.g., a UAS such as a UAS fused to a minimal IL-2 promoter), such that the conditional CAR T cells conditionally express the agent that can target a cell of a TME when the GPR50-mediated expression system is activated when the CAR fused to a GPR50 polypeptide is activated. When the CAR having the ability to bind a cancer- specific antigen is bound to a cancer cell expressing the cancer-specific antigen, the GAL4 polypeptide is cleaved from the CAR, and the free GAL4 polypeptide translocates to the nucleus where it binds the UAS and drives expression of the agent that can target a cell of a TME. In some cases, a conditional CAR T cell provided herein can include (a) a nucleic acid sequence encoding a CLDN18.2-specific CAR fused to a GPR50 polypeptide followed by a GAL4 polypeptide operably linked to a constitutive promoter (e.g., an EF1a promoter), and (b) a nucleic acid sequence encoding a FAP-specific CAR that is operably linked to a UAS, such that the conditional CAR T cells (1) constitutively express a CLDN18.2-specific CAR fused to a GPR50 polypeptide followed by a GAL4 polypeptide, and (2) conditionally express the FAP-specific CAR when the CLDN18.2- specific CAR is activated. In some cases, a GPR50-mediated expression system can be as shown in Figure 4. Also provided herein are nucleic acid constructs that can be used to generate conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated). For example, nucleic acid constructs that contain (a) a nucleic acid sequence encoding one or more CARs having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent thatAttorney Docket No.07039-2320WO1 / 2024-189 can target a cell of a TME that is operably linked to an inducible promoter can be used to a generate conditional CAR T cells provided herein. A nucleic acid construct provided herein (e.g., a nucleic acid construct including (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter) can be any appropriate type of nucleic acid construct. In some cases, a nucleic acid construct can be a vector (e.g., a viral vector or a non-viral vector). When a nucleic acid construct is a viral vector, the viral vector can be based on any appropriate type of virus. In some cases, a viral vector that can include a nucleic acid construct provided herein can be a lentiviral vector or a retroviral vector. In some cases, (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter can be present on the same nucleic acid construct. In some cases, (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter can be present on separate nucleic acid constructs. Any appropriate method can be used to introduce (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter and / or (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter into a T cell to generate a conditional CAR T cell provided herein. For example, a nucleic acid construct provided herein (e.g., a nucleic acid construct including (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter and / or (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter) can be introduced into one or more T cells. In some cases, viral transduction can be used to introduce (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter and / or (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter into a non-dividing a cell. Nucleic acid can be introduced in a T cell using any appropriate method. In some cases, nucleic acid can beAttorney Docket No.07039-2320WO1 / 2024-189 introduced into a T cell by transduction (e.g., viral transduction using a retroviral vector such as a lentiviral vector) or transfection. In some cases, nucleic acid can be introduced ex vivo into one or more T cells. For example, ex vivo engineering of T cells can include transducing isolated T cells with a lentiviral vector containing (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter and / or (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter. In cases where T cells are engineered ex vivo to contain (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter and / or (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter, the T cells can be obtained from any appropriate source (e.g., a mammal such as the mammal to be treated or a donor mammal, or a cell line). In some cases, a conditional CAR T cell provided herein (e.g., a CAR T cell engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can be stimulated. In some cases, a T cell can be stimulated at the same time as being engineered to include (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter and / or (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter. For example, one or more T cells to be used in an adoptive cell therapy can be stimulated first, and can be engineered to include (a) a nucleic acid sequence encoding a CAR that is operably linked to a constitutive promoter and / or (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter second, or vice versa. A T cell can be stimulated using any appropriate method. For example, a T cell can be stimulated by contacting the T cell with one or more polypeptides. Examples of polypeptides that can be used to stimulate a T cell include, without limitation, CD3, CD28, inducible T cell co-stimulator (ICOS), CD137, CD2, OX40, CD27, TLR3, TLR4, TLR1, and TLR polypeptides . This document also provides methods and materials for treating cancer. For example, conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated)Attorney Docket No.07039-2320WO1 / 2024-189 can be administered (e.g., in an adoptive cell therapy such as a CAR T cell therapy) to a mammal (e.g., a human) having cancer to treat the mammal. In some cases, conditional CAR T cells provided herein can be used in an adoptive cell therapy to treat a mammal (e.g., a human) having cancer. In some cases, conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can be administered to a mammal (e.g., a human) having cancer to reduce the size of cancer within the mammal. For example, a mammal having cancer and in need of treatment thereof can be administered conditional CAR T cells provided herein to reduce the number of cancer cells in the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In another example, a mammal having cancer and in need of treatment thereof can be administered conditional CAR T cells provided herein to reduce the volume of one or more solid tumors in the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can be administered to a mammal (e.g., a human) having cancer to improve survival of the mammal. For example, a mammal having cancer and in need of treatment thereof can be administered conditional CAR T cells provided herein to improve the survival of a mammal having cancer by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In another example, a mammal having cancer and in need of treatment thereof can be administered conditional CAR T cells provided herein to improve the survival of a mammal having cancer by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more). Any appropriate amount (e.g., number) of conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) can be administered (e.g., in anAttorney Docket No.07039-2320WO1 / 2024-189 adoptive cell therapy such as a CAR T cell therapy) to a mammal (e.g., a human) having cancer. Any appropriate mammal (e.g., a human) having a cancer can be treated as described herein. Examples of mammals that can be treated as described herein include, without limitation, humans, non-human primates (e.g., monkeys), dogs, cats, horses, bovine species (e.g., cows), porcine species (e.g., pigs), sheep, mice, and rats. For example, a human having a cancer can be treated with conditional CAR T cells provided herein (e.g., T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) in, for example, an adoptive T cell therapy such as a CAR T cell therapy using the methods and materials described herein. When treating a mammal (e.g., a human) having a cancer as described herein, the cancer can be any appropriate cancer. In some cases, a cancer treated as described herein can include one or more solid tumors. In some cases, a cancer treated as described herein can be a blood cancer. In some cases, a cancer treated as described herein can be a primary cancer. In some cases, a cancer treated as described herein can be a metastatic cancer. In some cases, a cancer treated as described herein can be a refractory cancer. In some cases, a cancer treated as described herein can be a relapsed cancer. In some cases, a cancer treated as described herein can express a tumor-associated antigen (e.g., an antigenic substance produced by a cancer cell). Examples of cancers that can be treated as described herein include, without limitation, colorectal cancers (e.g., colorectal cancers having FAP+cells in the colorectal cancer TME), multiple myelomas (e.g., multiple myelomas having CS1+cells in the multiple myeloma TME), pancreatic cancers, esophageal cancers, breast cancers, and prostate cancers. In some cases, the methods described herein can include identifying a mammal (e.g., a human) as having a cancer. Any appropriate method can be used to identify a mammal having cancer. For example, imaging techniques and biopsy techniques can be used to identify mammals (e.g., humans) having cancer. In some cases, conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when theAttorney Docket No.07039-2320WO1 / 2024-189 CAR is activated) can be administered to a mammal (e.g., a human) having cancer as the sole active agent(s) to treat the cancer. In some cases, methods for treating a mammal (e.g., a human) as described herein (e.g., by administering conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated)) also can include administering to the mammal one or more (e.g., one, two, three, or more) additional agents used to treat cancer and / or performing one or more (e.g., one, two, three, or more) therapies used to treat cancer. For example, a combination therapy used to treat a mammal (e.g., a human) having cancer can include administering to the mammal conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) and administering to the mammal one or more (e.g., one, two, three, or more) additional agents used to treat cancer. In some cases, an additional anti-cancer agent that can be administered to a mammal can be a chemotherapeutic agent. In some cases, an additional anti-cancer agent that can be administered to a mammal can be a cytotoxic agent. In some cases, an additional anti-cancer agent that can be administered to a mammal can be an oncolytic viral therapy. In some cases, an additional anti-cancer agent that can be administered to a mammal can be an immune-checkpoint inhibitor (e.g., anti- PD-1 antibodies, PD-1 inhibitors, anti-PD-L1 antibodies, PD-L1 inhibitors and anti- CTLA-4 antibodies). Examples of additional anti-cancer agents that can be administered to a mammal (e.g., a human) having cancer to treat the mammal include, without limitation, enzalutamide, imanitib, gefitinib, erlotini, sunitinib, lapatinib, nilotinib, sorafenib, temsirolimus, everolimus, pazopanib, crizotinib, ruxolitinib, axitinib, bosutinib, cabozantinib, ponatinib, regorafenib, ibrutinib, trametinib, perifosine, bortezomib, carfilzomib, batimastat, ganetespib, obatoclax, navitoclax, taxol, paclitaxel, bevacizumab, cemiplimab, nivolumab, pembrolizumab, JTX-4014, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, INCMGA00012, AMP-224, AMP-514, avelumab, durvalumab, atezolizumab, KN035, CK-301, AUNP12, CA-170, BMS- 986189, ipilimumab, and any combinations thereof.Attorney Docket No.07039-2320WO1 / 2024-189 In cases where conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) are used in combination with additional anti-cancer agents, the one or more additional anti-cancer agents can be administered at the same time (e.g., in a single composition containing conditional CAR T cells provided herein and containing the one or more additional agents) or independently. For example, a composition including conditional CAR T cells provided herein can be administered first, and the one or more additional agents administered second, or vice versa. In some cases, a combination therapy used to treat a mammal (e.g., a human) having cancer can include administering to the mammal conditional CAR T cells provided herein (e.g., CAR T cells engineered to (1) constitutively express a CAR having the ability to bind a cancer-specific antigen, and (2) conditionally express an agent that can target a cell of a TME when the CAR is activated) and can include performing one or more (e.g., one, two, three, or more) therapies used to treat cancer. Examples of additional therapies that can be used to treat a mammal (e.g., a human) having cancer include, without limitation, radiation therapies, and / or surgeries. In cases where conditional CAR T cells provided herein are used in combination with one or more therapies used to treat a mammal (e.g., a human) having cancer, the one or more additional therapies can be performed at the same time or independently of the administration of the conditional CAR T cells provided herein. For example, conditional CAR T cells provided herein can be administered before, during, or after the one or more additional therapies are performed. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. EXAMPLES Example 1: Lentiviral Vector System with Constitutive CAR Expression and Inducible Cytokine Expression This Example describes the Design and characterization of an “all-in-one” Lentiviral vector system combining constitutive anti-CD19 CAR expression and inducible cytokines.Attorney Docket No.07039-2320WO1 / 2024-189 A modular “all-in-one” lentiviral vector system was designed to constitutively express a CAR, and to express a molecule (e.g., an agent that can target a cell of a TME) when that CAR was activated (e.g., by binding to an antigen targeted by an antigen- binding domain present in the CAR). A modular “all-in-one” lentiviral vector system was generated based on a clinically applied second generation vector designed to constitutively express a CAR in combination with NFAT-inducible cytokine expression (Zimmermann et al., Cancers, 12:375 (2020)). To verify the specificity and function of the system, a reporter construct was generated that consisted of an NFAT-sensitive minimal IL-2 promoter that induced enhanced green fluorescent protein (eGFP) upon CD19-CAR-specific activation. Co- culture of transduced T cells with CD19-expressing target cells (Nalm6 cells lines) led to CAR-activation dependent GFP expression, while non-transduced T cells remained GFP negative in the presence or absence of the target cells (Figure 1). The NFAT response element was effectively and selectively induced after CD19-CAR activation by CD19 antigen expressed on target cells and led to CAR-activation-dependent GFP expression. Additional lentiviral vector systems have been constructed that substituted theeGFP reporter with an NFAT-inducible cytokine (e.g., a TGF polypeptide, an IL-10polypeptide, or an IL-35 polypeptide), including their natural secretary signal peptide. Example 2: Conditional Dual-CAR T Cells Having CLDN18.2+Anti-Cancer Activity To generate a conditional dual-CAR T cell system, a synthetic Notch (SynNotch) receptor specific for Claudin18.2 (Claudin18.2-SynNotch) was constitutively expressed in T cells. Upon engagement with Claudin18.2 on the surface of target cells, the SynNotch receptor undergoes proteolytic cleavage by -secretase, resulting in the release of the intracellular GAL4 transcriptional activator domain. Cleaved GAL4 translocates to the nucleus and binds upstream activation sequences (UAS) to drive expression of a second CAR construct, FAP5-BBz, specific for fibroblast activation protein (FAP). A schematic representation of this inducible expression system is shown in Figure 5. Human T cells from healthy donors were transduced with constructs encoding the Claudin18.2-SynNotch receptor and UAS-driven FAP5-BBz CAR. Two days post- transduction, SynNotch receptor expression was confirmed via flow cytometry using anti-Attorney Docket No.07039-2320WO1 / 2024-189 Myc-AF700 (Figure 6A). To assess inducible FAP CAR expression, T cells were either left unstimulated or co-cultured with SNU-C2B WT or Claudin18.2+SNU-C2B cells at an E:T ratio of 1:3 for 48 hours. Expression of the FAP CAR was evaluated by flow cytometry using a soluble FAP-PE fusion protein (Figure 6B). Single targeting KGHH18-5-BBz (Claudin18.2-specific), FAP-BBz, Claudin18.2- SynNotch, and dual-CART cells co-expressing KGHH18-5-BBz (Claudin18.2-specific) and Claudin18.2-SynNotch were generated via lentivirus transduction. Expression of CAR constructs and the SynNotch receptor was validated by flow cytometry using rabbit anti-VHH-APC (for nanobody-based KGHH18-5-BBz), rabbit anti-Myc-AF700 (for SynNotch), and soluble FAP-PE (for FAP5-BBz) (Figure 7A). Cytotoxicity was measured against luciferase-expressing Claudin18.2+SNU-C2B cells and WI-38 fibroblasts using the following T cell groups: untransduced T cells, KGHH18-5-BBz CART cells, FAP5-BBz CART cells, KGHH18-5-BBz / SynNotch CART cells, and FAP5-BBz CART cells. For CAF targeting, WI-38 cells were co-cultured with unstimulated SynNotch CART cells or SynNotch CART cells previously activated with Claudin18.2+SNU-C2B cells at a 3:1 ratio. Co-cultures were maintained for 48 hours at varying E:T ratios. Target cell viability was quantified by measuring bioluminescence with mean and SEM reported. Statistical significance was assessed via two-way ANOVA (*P < .05, **P < .005, ***P < .0005, ****P < .0001; n = 3) (Figure 7B). To assess anti-tumor efficacy in vivo, NSG mice were implanted subcutaneously with a mixture of 1x106Claudin18.2+SNU-C2B cancer cells and 1x107colorectal cancer- associated fibroblasts. Following tumor engraftment, mice received an intravenous infusion of 2.5x106CART cells expressing either KGHH18-5-BBz alone or in combination with Claudin18.2-SynNotch. Prior to infusion, CAR and SynNotch expression in T cells was confirmed by flow cytometry using rabbit anti-VHH-APC and rabbit anti-Myc-AF700 antibodies (Figure 8A). Tumor volume was monitored using caliper measurements at regular intervals (Figure 8B), and body weight was tracked as an indicator of treatment-associated toxicity (Figure 8C). Overall survival was analyzed using Kaplan–Meier survival curves (Figure 8D).Attorney Docket No.07039-2320WO1 / 2024-189 Example 3: Exemplary Nanobodies Having the Ability to Bind a CLDN18.2 Polypeptide This Example provides the amino acid sequences of exemplary nanobodies having the ability to bind a CLDN18.2 polypeptide. The CDRs and framework sequences of each also are provided and delineated.Example 4: Exemplary scFvs Having the Ability to Bind a CLDN18.2 Polypeptide This Example provides structures of exemplary scFv’s having the ability to bind a CLDN18.2 polypeptide. The and framework sequences of each are provided anddelineated. Exemplary hu8e5 scFv VH domain + Linker + VL domain:Attorney Docket No.07039-2320WO1 / 2024-189 Exemplary hu8e5 scFv VL domain + Linker + VH domain: DIVMTQSPDSLAVSLGERATINCKSSQSLFNSGNQKNYLTWYQQKPGQPPKLLIY WASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNAYSFPYTFGGGTKLAttorney Docket No.07039-2320WO1 / 2024-189Attorney Docket No.07039-2320WO1 / 2024-189 AGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGC GCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCAC CAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC (SEQ ID NO:84) CAR designed using CDRs of Clone #2 (also referred to as K347):CD8 Signal Peptide + KGHH18-5 sdAb + CD8 Hinge + CD8 TransmembraneDomain + 4-1BB Intracellular Signaling Domain + CD3 Intracellular SignalingDomain MALPVTALLLPLALLLHAARPQVQLQESGGGLVQAGGSLRLSCAASGNISRYD YMGWYRQAPGKEREFVATIAYGATTYYADSVKGRFTISRDNAKNTVYLQMNSL KPEDTAVYYCAARWPGYYSHIYWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLS LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRK KLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQ GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:85) Nucleic acid sequence encoding a K347 CAR set forth in SEQ ID NO:85 ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGC CGCCAGGCCGCAGGTCCAACTTCAGGAATCTGGAGGAGGGCTTGTGCAGGCA GGAGGAAGTTTGCGACTCTCATGCGCTGCCTCTGGAAATATCTCACGCTATGA CTACATGGGTTGGTATCGACAAGCGCCCGGAAAGGAGAGGGAGTTCGTCGCA ACAATTGCCTACGGCGCTACTACCTACTACGCGGATTCCGTTAAAGGCCGGTT TACCATATCCCGGGATAATGCGAAGAACACAGTATATCTCCAGATGAACTCC CTGAAGCCCGAAGATACCGCCGTCTACTATTGCGCGGCACGGTGGCCGGGCT ATTATTCTCATATTTACTGGGGCCAGGGAACACAAGTGACTGTCAGTAGCACC ACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGC CCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCA CACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCCTTGGCCG GGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAAACGGAttorney Docket No.07039-2320WO1 / 2024-189 GGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTAC AAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGA AGGAGGATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGC GTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGA GAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGG GGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAG AAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGC CGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCA AGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC (SEQ ID NO:86) CAR designed using CDRs of Clone #3 (also referred to as K349):CD8 Signal Peptide + KGHH18-7 sdAb + + CD8 TransmembraneDomain + 4-1BB Intracellular Signaling + CD3 Intracellular SignalingDomain MALPVTALLLPLALLLHAARPQVQLQESGGGLVQAGGSLRLSCAASGNISGWP DMGWYRQAPGKEREFVAAINYGTTTNYADSVKGRFTISRDNAKNTVYLQMNSL KPEDTAVYYCAVAYRTITGLFYWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLS LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRK KLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQ GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:87) Nucleic acid sequence encoding a K349 CAR set forth in SEQ ID NO:87 ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGC CGCCAGGCCGCAGGTGCAGCTCCAGGAGTCCGGGGGAGGTCTTGTGCAGGCG GGCGGAAGTCTTCGCCTCTCTTGCGCTGCAAGCGGCAATATCTCAGGTTGGCC CGATATGGGTTGGTATCGCCAGGCCCCTGGTAAAGAGCGGGAATTCGTCGCT GCAATCAACTACGGCACTACTACGAATTACGCTGATTCCGTGAAAGGACGAT TCACCATCAGTCGGGACAATGCAAAAAATACCGTGTACCTGCAAATGAATAGAttorney Docket No.07039-2320WO1 / 2024-189 CTTGAAGCCAGAAGACACCGCTGTATATTATTGCGCCGTTGCTTACCGCACAA TTACCGGACTTTTCTACTGGGGCCAAGGGACGCAAGTAACTGTCTCTAGCACC ACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGC CCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCAAttorney Docket No.07039-2320WO1 / 2024-189 EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQ ALPPR (SEQ ID NO:89) Nucleic acid sequence encoding a K299-2 CAR set forth in SEQ ID NO:89 ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGCAttorney Docket No.07039-2320WO1 / 2024-189 CAR designed using CDRs of Clone #4 (also referred to as K300):CD8 Signal Peptide + hu8e5 scFv VL domain + scFv linker + hu8e5 scFv VH domainFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQE GLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR (SEQ ID NO:91) Nucleic acid sequence encoding a K300 CAR set forth in SEQ ID NO:91 ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGC CGCCAGGCCGGATATAGTCATGACTCAATCTCCCGACAGCCTTGCTGTCTCCC TCGGTGAAAGAGCAACAATCAACTGCAAATCTAGTCAATCTCTCTTTAATAGT GGCAACCAGAAGAATTACCTGACTTGGTACCAACAGAAGCCGGGGCAGCCCC CCAAGCTGTTGATATACTGGGCATCTACCCGCGAGAGCGGTGTTCCAGATAG GTTTAGCGGAAGTGGCAGCGGTACAGACTTTACTCTTACTATCAGCTCTCTGC AGGCTGAGGACGTAGCCGTCTACTACTGCCAAAACGCTTACAGTTTCCCATAT ACCTTTGGAGGTGGCACGAAACTCGAGATCAAAGGCGGTGGGGGGTCAGGTG GCGGCGGGAGCGGGGGAGGAGGCTCCCAGGTGCAACTGCAAGAGAGTGGGC CTGGCCTCGTGAAGCCGAGTCAAACTCTGTCTCTGACTTGCACTGTCAGTGGG GGTTCAATAAGCTCAGGTTACAATTGGCATTGGATTCGACAGCCCCCTGGAA AGGGATTGGAGTGGATCGGATACATACACTATACAGGATCTACTAACTACAA CCCCGCGCTCCGGTCACGAGTCACTATCAGCGTGGACACCAGCAAGAATCAA TTCTCCTTGAAATTGTCTTCTGTAACGGCGGCTGATACAGCCGTCTATTATTGTAttorney Docket No.07039-2320WO1 / 2024-189 GCAAGAATATATAATGGTAACAGCTTCCCTTATTGGGGACAGGGGACGACAG TAACTGTCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCAT CGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGG GGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGAttorney Docket No.07039-2320WO1 / 2024-189 Nucleic acid sequence encoding a K301 CAR set forth in SEQ ID NO:93 ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGC CGCCAGGCCGCAGGTTCAACTCCAGCAGCCAGGCGCCGAGCTGGTGAGGCCA GGCGCGTCCGTGAAACTGAGCTGCAAGGCAAGTGGCTACACGTTCACTTCCTAttorney Docket No.07039-2320WO1 / 2024-189CD8 Signal Peptide + GC-182 scFv VL domain + scFv linker + GC-182 scFv VHdomain + Hinge + CD8 Transmembrane Domain +Signaling + CD3 Intracellular Signaling DomainMALPVTALLLPLALLLHAARPDIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSG NQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAED LAVYYCQNDYSYPFTFGSGTKLEIKGGGGSGGGGSGGGGSQVQLQQPGAELVRP GASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKA TLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSSTTTP APRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCG VLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGC ELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRR KNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDA LHMQALPPR (SEQ ID NO:95) Nucleic acid sequence encoding a K302 CAR set forth in SEQ ID NO:95 ATGGCCTTACCAGTGACCGCCTTGCTCCTGCCGCTGGCCTTGCTGCTCCACGC CGCCAGGCCGGATATTGTTATGACTCAAAGCCCGTCATCACTTACGGTTACCG CCGGTGAAAAAGTTACAATGTCATGTAAGTCATCTCAATCTCTCCTGAATTCC GGAAATCAAAAAAACTACCTTACGTGGTATCAACAAAAACCCGGACAACCAC CTAAACTCCTTATATATTGGGCGTCTACTAGGGAGTCAGGAGTCCCCGATAGG TTCACTGGATCCGGAAGCGGTACAGACTTTACTCTCACTATCTCAAGTGTGCA GGCCGAGGATCTTGCAGTATATTATTGTCAAAACGATTATAGTTACCCATTCA CATTCGGCTCCGGAACGAAACTCGAGATCAAAGGCGGTGGGGGGTCAGGTGG CGGCGGGAGCGGGGGAGGAGGCTCCCAGGTTCAACTCCAGCAGCCAGGCGC CGAGCTGGTGAGGCCAGGCGCGTCCGTGAAACTGAGCTGCAAGGCAAGTGGC TACACGTTCACTTCCTACTGGATCAACTGGGTGAAGCAAAGACCTGGCCAAG GACTCGAGTGGATAGGGAATATCTATCCAAGTGATAGCTATACAAATTATAA CCAAAAATTTAAGGACAAGGCCACCCTTACGGTGGACAAAAGTAGTTCTACT GCCTACATGCAACTCAGTTCCCCTACTTCAGAGGACTCAGCAGTCTACTACTG CACTCGGTCCTGGAGAGGCAACTCATTTGACTATTGGGGCCAAGGGACGACA CTGACCGTCTCTAGTACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCAttorney Docket No.07039-2320WO1 / 2024-189 CCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGC GGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTAC ATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTAT CACCCTTTACTGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAAAttorney Docket No.07039-2320WO1 / 2024-189 KFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVY TERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQI AKALVNAQVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSD (SEQ ID NO:79) Example 7: Exemplary scFvs Having the Ability to Bind a FAP Polypeptide This Example provides structures of exemplary scFv’s having the ability to bind a FAP polypeptide. The each are provided and delineated.Exemplary FAP5 scFv VH domain + Linker + VL domain: QVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPR STNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCARTLTAPFAFWG QGTLVTVSAGSTSGSGKPGSGEGSTKGQIVLTQSPAIMSASPGEKVTMTCSASSG VNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDA ATYYCQQWSFNPPTFGGGTKLEIKR (SEQ ID NO:35) Exemplary FAP5 scFv VL domain + Linker + VH domain: QIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLA SGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKRGS TSGSGKPGSGEGSTKGQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLK QRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAV YFCARTLTAPFAFWGQGTLVTVSA (SEQ ID NO:36) Exemplary mFAP scFv VH domain + Linker + VL domain: QVQLKESGGGLVQPGGSLKLSCAASGFTFSSYGMSWVRQTADKRLELVATTNN NGGVTYYPDSVKGRFTISRDNAKNTLYLQMSSLQSEDTAMYYCARYGYYAMD YWGQGISVTVSSGGGGSGGGGSSGGGSDVLMTQTPLSLPVSLGDQASISCRSSQSAttorney Docket No.07039-2320WO1 / 2024-189Attorney Docket No.07039-2320WO1 / 2024-189Attorney Docket No.07039-2320WO1 / 2024-189 GTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCT GCCCCCTCGC (SEQ ID NO:98) CAR designed using a FAP5 scFv:Attorney Docket No.07039-2320WO1 / 2024-189 TTACGAACAACGGCATCAACTGGCTGAAGCAGCGGACCGGCCAGGGCCTGGA GTGGATCGGCGAAATATACCCCCGGTCCACAAACACTCTCTATAACGAGAAG TTTAAGGGCAAAGCAACTCTGACCGCGGACAGGTCCTCTAACACAGCCTATA TGGAGCTGAGAAGCTTGACGAGTGAGGACTCCGCTGTCTATTTTTGCGCCCGAAttorney Docket No.07039-2320WO1 / 2024-189KNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDA LHMQALPPR (SEQ ID NO:101) Nucleic acid sequence encoding a CAR designed using a mFAP scFv set forth in SEQ ID NO:101 ATGGCCCTGCCTGTGACAGCCCTGCTGCTGCCTCTGGCTCTGCTGCTGCATGC CGCTAGACCTCAGGTGCAGCTGAAAGAGTCCGGCGGAGGACTGGTGCAGCCT GGCGGATCTCTGAAGCTGAGCTGTGCTGCCAGCGGCTTCACCTTCAGCAGCTA CGGCATGAGCTGGGTGCGACAGACCGCCGACAAGAGACTGGAACTGGTGGCT ACCACCAACAACAACGGCGGCGTGACCTACTACCCCGACAGCGTGAAGGGCA GATTCACCATCTCCAGAGACAACGCCAAGAACACCCTGTACCTGCAGATGAG CAGCCTGCAGAGCGAGGACACCGCCATGTACTACTGCGCCAGATACGGCTAC TACGCCATGGATTACTGGGGCCAGGGCATCAGCGTGACCGTGTCTAGCGGAG GCGGCGGATCTGGCGGAGGGGGATCTAGTGGCGGAGGCTCTGACGTGCTGAT GACCCAGACACCTCTGAGCCTGCCAGTGTCCCTGGGCGACCAGGCCAGCATC AGCTGTAGAAGCAGCCAGAGCATCGTGCACAGCAACGGCAACACCTACCTGG AATGGTATCTGCAGAAGCCCGGCCAGAGCCCCAAGCTGCTGATCTACAAGGT GTCCAACAGATTCAGCGGCGTGCCCGACAGATTCTCCGGCAGCGGCTCTGGC ACCGACTTCACCGTGAAGATCTCCAGGGTGGAAGCCGAGGACCTGGGCGTGT ACTACTGTTTTCAAGGCAGCCACGTGCCCTACACCTTCGGCGGAGGCACCAA GCTGGAAATCAAGACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCC ACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGG CGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACAT CTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCA CCCTTTACTGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACC ATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGA TTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGAGTGAAGTTCAGCAGG AGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGC TCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCG GGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCT GTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGAttorney Docket No.07039-2320WO1 / 2024-189 GATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGG TCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTG CCCCCTCGC (SEQ ID NO:102) CAR designed using a mFAP scFv:Attorney Docket No.07039-2320WO1 / 2024-189 CGGCGGAGGACTGGTGCAGCCTGGCGGATCTCTGAAGCTGAGCTGTGCTGCC AGCGGCTTCACCTTCAGCAGCTACGGCATGAGCTGGGTGCGACAGACCGCCG ACAAGAGACTGGAACTGGTGGCTACCACCAACAACAACGGCGGCGTGACCTA CTACCCCGACAGCGTGAAGGGCAGATTCACCATCTCCAGAGACAACGCCAAG AACACCCTGTACCTGCAGATGAGCAGCCTGCAGAGCGAGGACACCGCCATGT ACTACTGCGCCAGATACGGCTACTACGCCATGGATTACTGGGGCCAGGGCAT CAGCGTGACCGTGACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCC ACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGG CGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACAT CTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCA CCCTTTACTGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACC ATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGA TTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGAGTGAAGTTCAGCAGG AGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGC TCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCG GGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCT GTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGG GATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGG TCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTG CCCCCTCGC (SEQ ID NO:104) Example 10: Exemplary CS1 Polypeptides This Example provides an amino acid sequence of a human CS1 polypeptide (SEQ ID NO:81). The boxed amino acid sequence of this human CS1 polypeptide depicts the extracellular domain (SEQ ID NO:82).Attorney Docket No.07039-2320WO1 / 2024-189 HSGENTEYDTIPHTNRTILKEDPANTVYSTVEIPKKMENPHSLLTMPDTPRLFAYE NVI (SEQ ID NO:81) Example 11: Exemplary scFvs Having the Ability to Bind a CS1 Polypeptide This Example provides structures of exemplary scFv’s having the ability to bind a CS1 polypeptide. The CDRs of each are provided and delineated. Exemplary CS1 scFv VH domain + Linker + VL domain: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEHVSAISPNGAT TYYADSVKGRFTISRDNSKNTLYLQMSSLRPEDTAVYYCVKGYNWNRFDYWGQGT LVTVSSGEGKSSGSGSESKASDIQMTQSPDSLAVSLGERATINCKSSQSVLYSSNN KNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSLQAEDV AVYYCQQYYSSWTFGQGTKLDIK (SEQ ID NO:51) Exemplary CS1 scFv VL domain + Linker + VH domain: ESKASDIQMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPP KLLIYWASTRESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSWTFGQ GTKLDIKSSGSGSEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKG LEHVSAISPNGATTYYADSVKGRFTISRDNSKNTLYLQMSSLRPEDTAVYYCVKGYN WNRFDYWGQGTLVTVSSGEGK (SEQ ID NO:52) Exemplary CS1 scFv VH domain + Linker + VL domain: ESKASEVQLLESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWV SGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDILYE WELPTFDYWGQGTLVTVSSSSGSGSNFMLTQPHSVSESPGKTVTISCTRSSGSIAS NYVQWYQQRPGSAPTTVIYEDNQRPSGVPDRFSGSIDSSSNSASLTISGLKTEDEA DYYCQSYDSSNVVFGGGTKLTVLGEGK (SEQ ID NO:59)Attorney Docket No.07039-2320WO1 / 2024-189 Exemplary CS1 scFv VL domain + Linker + VH domain: NFMLTQPHSVSESPGKTVTISCTRSSGSIASNYVQWYQQRPGSAPTTVIYEDNQR PSGVPDRFSGSIDSSSNSASLTISGLKTEDEADYYCQSYDSSNVVFGGGTKLTVLGAttorney Docket No.07039-2320WO1 / 2024-189 Example 12: Exemplary Sequences for use in an Inducible Promoter This Example provides exemplary nucleic acid sequences of elements that can be included in an inducible promoter described herein. Exemplary NFAT RE consensus domain (SEQ ID NO:105) ACGCCTTCTGTATGAAACAGTTTTTCCTCC Exemplary 6X NFAT RE (SEQ ID NO:106) ACGCCTTCTGTATGAAACAGTTTTTCCTCCACGCCTTCTGTATGAAACAGTTTT TCCTCCACGCCTTCTGTATGAAACAGTTTTTCCTCCACGCCTTCTGTATGAAAC AGTTTTTCCTCCACGCCTTCTGTATGAAACAGTTTTTCCTCCACGCCTTCTGTA TGAAACAGTTTTTCCTCC Exemplary minimal IL-2 promoter (SEQ ID NO:107) CATTTTGACACCCCCATAATATTTTTCCAGAATTAACAGTATAAATTGCATCT CTTGTTCAAGAGTTCCCTATCACTCTCTTTAATCACTACTCACAGTAACCTCAA CTCCTGC Exemplary UAS (SEQ ID NO:108) GGAGCACTGTCCTCCGAACG Exemplary sequence containing 5 copies of an UAS (SEQ ID NO:109) GGAGCACTGTCCTCCGAACGTCGGAGCACTGTCCTCCGAACGTCGGAGCACT GTCCTCCGAACGTCGGAGCACTGTCCTCCGAACGGAGCATGTCCTCCGAACG TCGGAGCACTGTCCTCCGAACG Example 13: Exemplary CLDN18.2 Polypeptides This Example provides an amino acid sequence of a human CLDN18.2 polypeptide (SEQ ID NO:76). The bolded amino acid sequence of this human CLDN18.2 polypeptide depicts the first CLDN18.2 extracellular loop (SEQ ID NO:77) and the boxed amino acid sequence of this human CLDN18.2 polypeptide depicts the second CLDN18.2 extracellular loop (SEQ ID NO:78).Attorney Docket No.07039-2320WO1 / 2024-189 MAVTACQGLGFVVSLIGIAGIIAATCMDQWSTQDLYNNPVTAVFNYQGLWRS CVRESSGFTECRGYFTLLGLPAMLQAVRALMIVGIVLGAIGLLVSIFALKCIRIG SMEDSAKANMTLTSGIMFIVSGLCAIAGVSVFANMLVTNFWMSTANMYTGMGG MVQTVQTRYTFGAALFVGWVAGGLTLIGGVMMCIACRGLAPEETNYKAVSYH ASGHSVAYKPGGFKASTGFGSNTKNKKIYDGGARTEDEVQSYPSKHDYV (SEQ ID NO:76) Example 14: Treating CLDN18.2+Cancer with Conditional Dual-CAR T cells A human having a CLDN18.2+cancer is administered conditional CAR T cells that (1) constitutively express a CLDN18.2-specific CAR, and (2) conditionally express a FAP-specific CAR when the CLDN18.2-specific CAR is activated. For example, a conditional CAR T cells can include (a) a nucleic acid sequence encoding a CLDN18.2- specific CAR that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding FAP-specific CAR that is operably linked to an inducible promoter to generate a CAR T cell that (1) can constitutively express CLDN18.2-specific CAR and (2) can express FAP-specific CAR when the CAR is activated (e.g., by binding to a cancer cell expressing that cancer-specific antigen). When an inducible promoter is a NFAT mediated expression system, a conditional CAR T cell can include (a) a nucleic acid sequence encoding a CLDN18.2-specific CAR operably linked to a constitutive promoter (e.g., an EF1a promoter), where theCLDN18.2-specific CAR includes a 4-1BB signaling domain and a CD3 signalingdomain, and (b) a nucleic acid sequence encoding a FAP-specific CAR that is operably linked to a 6x NFAT RE fused to a minimal IL-2 promoter, such that the conditional CAR T cells (1) constitutively express a CLDN18.2-specific CAR, and (2) conditionally express the FAP-specific CAR when the CAR is activated. When the CLDN18.2-specific CAR is bound to a cancer cell expressing a CLDN18.2 polypeptide, the CAR activationinduces a Lck polypeptide to phosphorylate the CD3 signaling domain of theCLDN18.2-specific CAR, the phosphorylation of the CD3 signaling domain causes anincrease of intracellular Ca2+which activates a calcineurin polypeptide, the activated calcineurin polypeptide dephosphorylates a NFAT polypeptide, and the dephosphorylatedAttorney Docket No.07039-2320WO1 / 2024-189 NFAT polypeptide translocates to the nucleus where it binds the 6xNFAT and drives expression of the FAP-specific CAR. When an inducible promoter is a synNotch mediated expression system, a conditional CAR T cell can include (a) a nucleic acid sequence encoding a CLDN18.2- specific CAR operably linked to a constitutive promoter (e.g., an EF1a promoter), (b) a nucleic acid sequence encoding a CLDN18.2-specific synNotch receptor operably linked to a constitutive promoter, where the synNotch receptor includes an intracellular GAL4 polypeptide, and (c) a nucleic acid sequence encoding a FAP-specific CAR that is operably linked to a UAS, such that the conditional CAR T cells (1) constitutively express a CLDN18.2-specific CAR, (2) constitutively express a CLDN18.2-specific synNotch receptor, and (3) conditionally express the FAP-specific CAR when the synNotch receptor is activated. When the CLDN18.2-specific synNotch receptor is bound to a cancer cell expressing a CLDN18.2 polypeptide, the GAL4 polypeptide is cleaved from the synNotch receptor, and the free GAL4 polypeptide translocates to the nucleus where it binds the UAS and drives expression of the FAP-CAR. When an inducible promoter is a GPR50-mediated expression system, a conditional CAR T cell can include (a) a nucleic acid sequence encoding a CLDN18.2- specific CAR fused to a GPR50 polypeptide followed by a GAL4 polypeptide operably linked to a constitutive promoter (e.g., an EF1a promoter), and (b) a nucleic acid sequence encoding a FAP-specific CAR that is operably linked to a UAS, such that the conditional CAR T cells (1) constitutively express a CLDN18.2-specific CAR fused to a GPR50 polypeptide followed by a GAL4 polypeptide, and (2) conditionally express the FAP-specific CAR when the CLDN18.2-specific CAR is activated. When the CLDN18.2-specific CAR is bound to a cancer cell expressing a CLDN18.2 polypeptide, the GAL4 polypeptide is cleaved from the CLDN18.2-specific CAR, and the free GAL4 polypeptide translocates to the nucleus where it binds the UAS and drives expression of the FAP-CAR. The conditional CAR T cells are dual-CAR T cells (e.g., CAR T cells containing both a CLDN18.2-specific CAR and a FAP-specific CAR only in the presence of CLDN18.2+cancer cells to induce acute killing of CLDN18.2+cancers with reduced off target effects.Attorney Docket No.07039-2320WO1 / 2024-189 Example 15: Exemplary Embodiments Embodiment 1. An immune cell comprising (a) a nucleic acid sequence encoding a chimeric antigen receptor (CAR) having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter and (b) a nucleic acid sequence encoding an agent that can target a cell of a tumor microenvironment (TME) that is operably linked to an inducible promoter, wherein said immune cell expresses said CAR, and wherein said immune cell expresses said agent following binding of said CAR binds to said cancer- specific antigen. Embodiment 2. The immune cell of embodiment 1, wherein said immune cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a macrophage, and a B cell. Embodiment 3. The immune cell of any one of embodiments 1-2, wherein said nucleic acid sequence encoding said CAR is integrated into the genome of said immune cell. The immune cell of any one of embodiments 1-3, wherein said nucleic acid sequence encoding said agent is integrated into the genome of said immune cell. Embodiment 5. The immune cell of any one of embodiments 1-4, wherein said CAR is selected from the group consisting of a CLDN18.2-specific CAR, a BCMA- specific CAR, a CS1-specific CAR, and a HER2-specific CAR. Embodiment 6. The immune cell of any one of embodiments 1-4, wherein said CAR is a CLDN18.2-specific CAR, and wherein said agent is a FAP-specific CAR. Embodiment 7. The immune cell of any one of embodiments 1-4, wherein said CAR is a BCMA-specific CAR, and wherein said agent is a CS1-specific CAR.Attorney Docket No.07039-2320WO1 / 2024-189 Embodiment 8. The immune cell of embodiment 7, wherein said agent is said FAP- specific CAR, and wherein said cell of said TME is a FAP+cell. Embodiment 9. The immune cell of any one of embodiments 1-5, wherein said agent is a bi-specific T cell engager (BiTE). Embodiment 10. The immune cell of embodiment 9, wherein said BiTE is selected from the group consisting of a FAP-specific BiTE and a CS1-specific BiTE. Embodiment 11. The immune cell of embodiment 10, wherein said agent is said FAP-specific BiTE, and wherein said cell of said TME is a FAP+cell. Embodiment 12. The immune cell of any one of embodiments 1-11, wherein said inducible promotor comprises two to ten nuclear factor of activated T cell (NFAT) response element consensus domains fused to a minimal IL-2 promoter. Embodiment 13. The immune cell of embodiment 12, wherein said NFAT response element consensus domain comprises a nucleic acid sequence set forth in SEQ ID NO:105. Embodiment 14. The immune cell of any one of embodiments 12-13, wherein said minimal IL-2 promoter comprises a nucleic acid sequence set forth in SEQ ID NO:107. Embodiment 15. The immune cell of any one of embodiments 1-14, wherein said cell comprises a nucleic acid sequence encoding a synNotch receptor having the ability to bind said cancer-specific antigen that is operably linked to a constitutive promoter, wherein said synNotch receptor comprises an intracellular GAL4 polypeptide. Embodiment 16. The immune cell of embodiment 15, wherein said inducible promoter comprises one to five copies of an upstream activation sequence (UAS).Attorney Docket No.07039-2320WO1 / 2024-189 Embodiment 17. The immune cell of embodiment 16, wherein said UAS comprises a nucleic acid sequence set forth in SEQ ID NO:108. Embodiment 18. The immune cell of any one of embodiments 1-15, wherein said CAR comprises a GPR50 polypeptide and a GAL4 polypeptide. Embodiment 19. The immune cell of embodiment 18, wherein said inducible promoter comprises one to five copies of an UAS. Embodiment 20. The immune cell of embodiment 19, wherein said UAS comprises a nucleic acid sequence set forth in SEQ ID NO:108. Embodiment 21. The immune cell of any one of embodiments 1-20, wherein saidconstitutive promoter is selected from the group consisting of an EF1 promoter, acytomegalovirus (CMV) promoter, and a phosphoglycerokinase (PGK) promoter. Embodiment 22. A method of making an immune cell of any one of embodiments 1- 21, said method comprising introducing said (a) and said (b) to said cell. Embodiment 23. The method of embodiment 22, wherein said introducing is done ex vivo. Embodiment 24. The method of any one of embodiments 22-23, wherein said (a) and said (b) are present on a single nucleic acid construct. Embodiment 25. The method of any one of embodiments 22-23, wherein said (a) and said (b) are present on separate nucleic acid constructs. Embodiment 26. The method of embodiment 25, wherein said (a) and said (b) are introduced to said cell at the same time.Attorney Docket No.07039-2320WO1 / 2024-189 Embodiment 27. The method of embodiment 25, wherein said (a) and said (b) are introduced to said cell separately. Embodiment 28. A nucleic acid construct comprising (a) a nucleic acid sequence encoding a chimeric antigen receptor (CAR) having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter. Embodiment 29. The nucleic acid construct of embodiment 28, wherein said CAR is selected from the group consisting of a CLDN18.2-specific CAR, a BCMA-specific CAR, a CS1-specific CAR, and a HER2-specific CAR. Embodiment 30. The nucleic acid construct of embodiment 28, wherein said CAR is a CLDN18.2-specific CAR, and wherein said agent is a FAP-specific CAR. Embodiment 31. The nucleic acid construct of embodiment 28, wherein said CAR is a BCMA-specific CAR, and wherein said agent is a CS1-specific CAR.The nucleic acid construct of any one of embodiments 28-31, wherein said CAR comprises a 4-1BB signaling domain and a CD3 signaling domain.Embodiment 33. The nucleic acid construct of any one of embodiments 28-29, wherein said agent is a BiTE. Embodiment 34. The nucleic acid construct of embodiment 33, wherein said BiTE is selected from the group consisting of a FAP-specific BiTE and a CS1-specific BiTE. Embodiment 35. The nucleic acid construct of any one of embodiments 28-34, wherein said inducible promotor comprises two to ten NFAT response element consensus domains fused to a minimal IL-2 promoter.Attorney Docket No.07039-2320WO1 / 2024-189 Embodiment 36. The nucleic acid construct of embodiment 35, wherein said NFAT response element consensus domain comprises a nucleic acid sequence set forth in SEQ ID NO:105. Embodiment 37. The nucleic acid construct of any one of embodiments 35-36, wherein said minimal IL-2 promoter comprises a nucleic acid sequence set forth in SEQ ID NO:107. Embodiment 38. The nucleic acid construct of any one of embodiments 28-34, wherein said construct comprises a nucleic acid sequence encoding a synNotch receptor having the ability to bind said cancer-specific antigen that is operably linked to a constitutive promoter, wherein said synNotch receptor comprises an intracellular GAL4 polypeptide. Embodiment 39. The nucleic acid construct of embodiment 38, wherein said inducible promoter comprises one to five copies of an UAS. Embodiment 40. The nucleic acid construct of embodiment 39, wherein said UAS comprises a nucleic acid sequence set forth in SEQ ID NO:108. Embodiment 41. The nucleic acid construct of any one of embodiments 28-34, wherein said CAR comprises a GPR50 polypeptide and a GAL4 polypeptide. Embodiment 42. The nucleic acid construct of embodiment 41, wherein said inducible promoter comprises one to five copies of an UAS. Embodiment 43. The nucleic acid construct of embodiment 42, wherein said UAS comprises a nucleic acid sequence set forth in SEQ ID NO:108. Embodiment 44. The nucleic acid construct of any one of embodiments 28-43, wherein said nucleic acid construct is in the form of a vector.Attorney Docket No.07039-2320WO1 / 2024-189 Embodiment 45. The nucleic acid construct of embodiment 44, wherein said vector is a viral vector. Embodiment 46. The nucleic acid construct of embodiment 44, wherein said viral vector is a lentiviral vector. Embodiment 47. The nucleic acid construct of any one of embodiments 28-46,wherein said constitutive promoter is selected from the group consisting of an EF1promoter, a CMV promoter, and a PGK promoter. Embodiment 48. An immune cell comprising a nucleic acid construct of any one of embodiments 28-47, wherein said immune cell (1) constitutively expresses said CAR and (2) expresses said agent that can target a cell of a TME when said CAR is activated by binding to a cancer cell expressing said cancer-specific antigen. Embodiment 49. The immune cell of clam 48, wherein said immune cell is selected from the group consisting of a T cell, a NK cell, a macrophage, and a B cell. Embodiment 50. The immune cell of any one of embodiments 48-49, wherein said immune cell is obtained from a human. Embodiment 51. A method for treating a mammal having cancer, wherein said method comprises administering, to said mammal, a composition comprising the immune cell of any one of embodiments 1-21 or embodiments 48-50. Embodiment 52. The method of embodiment 51, wherein said mammal is a human. Embodiment 53. The method of any one of embodiments 51-52, wherein said cancer is selected from the group consisting of a colorectal cancer, a multiple myeloma, a pancreatic cancer, an esophageal cancer, a breast cancer, and a prostate cancer.Attorney Docket No.07039-2320WO1 / 2024-189 Embodiment 54. The use of a composition comprising the immune cell of any one of embodiments 1-21 or embodiments 48-50 to treat a mammal having cancer. Embodiment 55. A composition comprising the immune cell of any one of embodiments 1-21 or embodiments 48-50 for use in the preparation of a medicament to treat a mammal having cancer. Embodiment 56. A composition comprising the immune cell of any one of embodiments 1-21 or embodiments 48-50 for use in the treatment of cancer. OTHER EMBODIMENTS It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.07039-2320WO1 / 2024-189 WHAT IS CLAIMED IS:

1. An immune cell comprising (a) a nucleic acid sequence encoding a chimeric antigen receptor (CAR) having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter and (b) a nucleic acid sequence encoding an agent that can target a cell of a tumor microenvironment (TME) that is operably linked to an inducible promoter, wherein said immune cell expresses said CAR, and wherein said immune cell expresses said agent following binding of said CAR binds to said cancer- specific antigen.

2. The immune cell of claim 1, wherein said immune cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a macrophage, and a B cell.

3. The immune cell of any one of claims 1-2, wherein said nucleic acid sequence encoding said CAR is integrated into the genome of said immune cell.

4. The immune cell of any one of claims 1-2, wherein said nucleic acid sequence encoding said agent is integrated into the genome of said immune cell.

5. The immune cell of any one of claims 1-2, wherein said CAR is selected from the group consisting of a CLDN18.2-specific CAR, a BCMA-specific CAR, a CS1-specific CAR, and a HER2-specific CAR.

6. The immune cell of any one of claims 1-2, wherein said CAR is a CLDN18.2- specific CAR, and wherein said agent is a FAP-specific CAR.

7. The immune cell of any one of claims 1-2, wherein said CAR is a BCMA-specific CAR, and wherein said agent is a CS1-specific CAR.

8. The immune cell of claim 7, wherein said agent is said FAP-specific CAR, and wherein said cell of said TME is a FAP+cell.Attorney Docket No.07039-2320WO1 / 2024-189 9. The immune cell of any one of claims 1-2, wherein said agent is a bi-specific T cell engager (BiTE).

10. The immune cell of claim 9, wherein said BiTE is selected from the group consisting of a FAP-specific BiTE and a CS1-specific BiTE.

11. The immune cell of claim 10, wherein said agent is said FAP-specific BiTE, and wherein said cell of said TME is a FAP+cell.

12. The immune cell of any one of claims 1-2, wherein said inducible promotor comprises two to ten nuclear factor of activated T cell (NFAT) response element consensus domains fused to a minimal IL-2 promoter.

13. The immune cell of claim 12, wherein said NFAT response element consensus domain comprises a nucleic acid sequence set forth in SEQ ID NO:

105.

14. The immune cell of any one of claims 12-13, wherein said minimal IL-2 promoter comprises a nucleic acid sequence set forth in SEQ ID NO:

107.

15. The immune cell of any one of claims 1-2, wherein said cell comprises a nucleic acid sequence encoding a synNotch receptor having the ability to bind said cancer- specific antigen that is operably linked to a constitutive promoter, wherein said synNotch receptor comprises an intracellular GAL4 polypeptide.

16. The immune cell of claim 15, wherein said inducible promoter comprises one to five copies of an upstream activation sequence (UAS).

17. The immune cell of claim 16, wherein said UAS comprises a nucleic acid sequence set forth in SEQ ID NO:

108.

18. The immune cell of any one of claims 1-2, wherein said CAR comprises a GPR50 polypeptide and a GAL4 polypeptide.Attorney Docket No.07039-2320WO1 / 2024-189 19. The immune cell of claim 18, wherein said inducible promoter comprises one to five copies of an UAS.

20. The immune cell of claim 19, wherein said UAS comprises a nucleic acid sequence set forth in SEQ ID NO:

108.

21. The immune cell of any one of claims 1-2, wherein said constitutive promoter isselected from the group consisting of an EF1 promoter, a cytomegalovirus (CMV)promoter, and a phosphoglycerokinase (PGK) promoter.

22. A method of making an immune cell of any one of claims 1-21, said method comprising introducing said (a) and said (b) to said cell.

23. The method of claim 22, wherein said introducing is done ex vivo. The method of any one of claims 22-23, wherein said (a) and said (b) are present on a single nucleic acid construct.

25. The method of any one of claims 22-23, wherein said (a) and said (b) are present on separate nucleic acid constructs.

26. The method of claim 25, wherein said (a) and said (b) are introduced to said cell at the same time.

27. The method of claim 25, wherein said (a) and said (b) are introduced to said cell separately.

28. A nucleic acid construct comprising (a) a nucleic acid sequence encoding a chimeric antigen receptor (CAR) having the ability to bind a cancer-specific antigen that is operably linked to a constitutive promoter, and (b) a nucleic acid sequence encoding an agent that can target a cell of a TME that is operably linked to an inducible promoter.Attorney Docket No.07039-2320WO1 / 2024-189 29. The nucleic acid construct of claim 28, wherein said CAR is selected from the group consisting of a CLDN18.2-specific CAR, a BCMA-specific CAR, a CS1-specific CAR, and a HER2-specific CAR.

30. The nucleic acid construct of claim 28, wherein said CAR is a CLDN18.2-specific CAR, and wherein said agent is a FAP-specific CAR.

31. The nucleic acid construct of claim 28, wherein said CAR is a BCMA-specific CAR, and wherein said agent is a CS1-specific CAR.

32. The nucleic acid construct of claim 28, wherein said CAR comprises a 4-1BBsignaling domain and a CD3 signaling domain.

33. The nucleic acid construct of claim 28, wherein said agent is a BiTE.

34. The nucleic acid construct of claim 33, wherein said BiTE is selected from the group consisting of a FAP-specific BiTE and a CS1-specific BiTE.

35. The nucleic acid construct of any one of claims 28-34, wherein said inducible promotor comprises two to ten NFAT response element consensus domains fused to a minimal IL-2 promoter.

36. The nucleic acid construct of claim 35, wherein said NFAT response element consensus domain comprises a nucleic acid sequence set forth in SEQ ID NO:

105.

37. The nucleic acid construct of any one of claims 35-36, wherein said minimal IL-2 promoter comprises a nucleic acid sequence set forth in SEQ ID NO:

107.

38. The nucleic acid construct of any one of claims 28-34, wherein said construct comprises a nucleic acid sequence encoding a synNotch receptor having the ability toAttorney Docket No.07039-2320WO1 / 2024-189 bind said cancer-specific antigen that is operably linked to a constitutive promoter, wherein said synNotch receptor comprises an intracellular GAL4 polypeptide.

39. The nucleic acid construct of claim 38, wherein said inducible promoter comprises one to five copies of an UAS.

40. The nucleic acid construct of claim 39, wherein said UAS comprises a nucleic acid sequence set forth in SEQ ID NO:

108.

41. The nucleic acid construct of any one of claims 28-34, wherein said CAR comprises a GPR50 polypeptide and a GAL4 polypeptide.

42. The nucleic acid construct of claim 41, wherein said inducible promoter comprises one to five copies of an UAS.

43. The nucleic acid construct of claim 42, wherein said UAS comprises a nucleic acid sequence set forth in SEQ ID NO:

108.

44. The nucleic acid construct of any one of claims 28-43, wherein said nucleic acid construct is in the form of a vector.

45. The nucleic acid construct of claim 44, wherein said vector is a viral vector.

46. The nucleic acid construct of claim 44, wherein said viral vector is a lentiviral vector.

47. The nucleic acid construct of any one of claims 28-46, wherein said constitutivepromoter is selected from the group consisting of an EF1 promoter, a CMV promoter,and a PGK promoter.

48. An immune cell comprising a nucleic acid construct of any one of claims 28-47, wherein said immune cell (1) constitutively expresses said CAR and (2) expresses saidAttorney Docket No.07039-2320WO1 / 2024-189 agent that can target a cell of a TME when said CAR is activated by binding to a cancer cell expressing said cancer-specific antigen.

49. The immune cell of clam 48, wherein said immune cell is selected from the group consisting of a T cell, a NK cell, a macrophage, and a B cell.

50. The immune cell of any one of claims 48-49, wherein said immune cell is obtained from a human.

51. A method for treating a mammal having cancer, wherein said method comprises administering, to said mammal, a composition comprising the immune cell of any one of claims 1-21 or claims 48-50.

52. The method of claim 51, wherein said mammal is a human.

53. The method of any one of claims 51-52, wherein said cancer is selected from the group consisting of a colorectal cancer, a multiple myeloma, a pancreatic cancer, an esophageal cancer, a breast cancer, and a prostate cancer.

54. The use of a composition comprising the immune cell of any one of claims 1-21 or claims 48-50 to treat a mammal having cancer.

55. A composition comprising the immune cell of any one of claims 1-21 or claims 48-50 for use in the preparation of a medicament to treat a mammal having cancer.

56. A composition comprising the immune cell of any one of claims 1-21 or claims 48-50 for use in the treatment of cancer.

Images