Methods and materials for treating cancer

Abstract

This document provides methods and materials for treating cancer in a mammal (e.g., a human). For example, provided herein are methods and materials for generating immune cells (e.g., T cells) that (1) can express one or more chimeric antigen receptors (CARs) having the ability to bind a cancer-specific antigen and (2) can express (e.g., express and secrete) one or more cell engagers having the ability to bind (i) an immunosuppressive cell of a tumor microenvironment (TME) and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. The cell engager(s) can activate innate immune cells and / or adaptive immune cells (e.g., macrophages or natural killer cells) to kill immunosuppressive cells (e.g., cancer-associated fibroblasts) within the TME.

Description

METHODS AND MATERIALS FOR TREATING CANCER CLAIM OF PRIORITYThis application claims the benefit of U. S. Patent Application Serial No.63 / 716.307, filed on November 5, 2024. The entire contents of which are hereby incorporated by reference.SEQUENCE LISTINGThis application contains a Sequence Listing that has been submitted electronically as an XML file named "07039-2344WO 1_SL_ST26. XML.” The XML file, created on November 4, 2025, is 337,638 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.TECHNICAL FIELDThis document relates to methods and materials for treating cancer in a mammal (e.g., a human). For example, this document provides methods and materials for generating immune cells (e.g., T cells) that (1) can express one or more chimeric antigen receptors (CARs) having the ability to bind a cancer-specific antigen and (2) can express (e.g., express and secrete) one or more cell engagers each having the ability to bind (i) an immunosuppressive cell of a tumor microenvironment (TME) and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. 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 CAR T (CART 19) 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., 7:303ral39 (2015)). However, the activity of CAR T 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,it has been shown that CAR T cell activity can be inhibited by an immunosuppressive 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 cancer-associated fibroblasts (CAFs) (Kakarla et al., Immunotherapy, 4:1129-1138 (2012); Lakins et al., Nat. Commun., 9:948 (2018); and Tripathi et al., CellAdhes. Migrat., 6:231-235 (2012)).SUMMARYThis document provides methods and materials for 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 express one or more CARs having the ability to bind a cancer-specific antigen and (2) can express (e.g., express and secrete) one or more cell engagers each having the ability to bind (i) an immunosuppressive cell of a TME and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME. 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 and (b) a nucleic acid sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME to generate a CAR T cell provided herein. As described herein, a CAR T cell provided herein can be designed to include (a) a nucleic acid sequence encoding one or more CARs having the ability to bind a cancer-specific antigen and (b) a nucleic acid sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME such that the CAR T cell can secrete the cell engager, and such that the cell engager can activate innate immune cells and / or adaptive immune cells within the TME to promote the killing of immunosuppressive cells (e.g.. CAFs) present within the TME.As demonstrated herein, CAR T cells engineered to express (e.g., express and secrete) one or more cell engagers each having the ability to bind (i) an immunosuppressive cell of a TME and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can reduce or eliminate the number of cancer cellsexpressing an antigen targeted by an antigen binding domain present in the CAR. Also as demonstrated herein, CAR T cells engineered to express (e.g., express and secrete) one or more cell engagers each having the ability to bind (i) an immunosuppressive cell of a TME and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can activate innate immune cells and / or adaptive immune cells (e.g., macrophages or natural killer cells) within the TME to target (e g., target and destroy) immunosuppressive cells (e.g., CAFs) present within the TME. For example, CAR T cells engineered to express a cell engager that can activate a macrophage within a TME can induce phagocytosis of immunosuppressive cells present within the TME. For example, CAR T cells engineered to express a cell engager that can activate natural killer (NK) cells within a TME can induce apoptosis of immunosuppressive cells within the TME.This document also provides nucleic acid sequences (e.g., nucleic acid constructs such as viral vectors) that can be used to generate CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express (e.g., express and secrete) a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME). For example, nucleic acid sequences that contain (a) a nucleotide sequence encoding one or more CARs having the ability to bind a cancer-specific antigen and (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can be used to a generate CAR T cells provided herein.This document also provides methods and materials for using CART cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express (e.g., express and secrete) a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME). For example, CAR T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME 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 describedherein, when a CAR present on a CAR T cell provided herein binds to a cancer cell (e.g., a cancer cell expressing an antigen targeted by an antigen binding domain present in the CAR), the CAR T cell can kill the cancer cell and / or express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME such that the innate immune cell is activated to target (e.g., target and destroy) immunosuppressive elements of the TME.Having the ability to reduce or eliminate cellular sources of immunosuppression of CAR T cells using CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability’ to bind a cancer-specific antigen and (2) express (e.g., express and secrete) a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) provides a unique and unrealized opportunity to improve the efficacy of immune cell-based therapies (e.g., CAR T cell therapy).In general, one aspect of this document features T cells that include (a) an exogenous nucleotide sequence encoding a CAR having the ability to bind to a cancer antigen and (b) an exogenous nucleotide sequence encoding a cell engager having the ability to bind to (1) an antigen of an immunosuppressive cell of a TME and (2) an antigen of an innate immune cell or an adaptive immune cell of the TME, where the T cells express the CAR, and where the T cells express and secrete the cell engager. The immunosuppressive cell can be a cancer-associated fibroblast (CAF), an immunosuppressive macrophage, an immunosuppressive monocyte, a regulatory T cell, or a gamma-delta T cell. The innate immune cell or adaptive immune cell can be a natural killer (NK) cell, a macrophage, or a T cell. The nucleotide sequence encoding the CAR can be integrated into the genome of the T cell. The nucleotide sequence encoding the cell engager can be integrated into the genome of the T cell. The CAR can be a BCMA-specific CAR or a CS 1- specific CAR. The antigen of the immunosuppressive cell can be a FAP polypeptide. The cell engager can include a nanobody (VHH) or a single chain variable fragment (scFv). The antigen of the innate immune cell or the adaptive immune cell can be a polypeptide selected from the group consisting of a Fc receptor, a signal regulatory protein alpha (SIRPa) polypeptide, a CD 16a polypeptide, an IL- 15 receptor, a NK. G2D polypeptide, a NKp30 polypeptide, aNKG3C polypeptide, ankp64 polypeptide, and a siglec-10 polypeptide. The antigen of the innate immune cell or the adaptive immune cell can be a Fc receptor. The cell engager also can have the ability’ to bind to a CD47 polypeptide. The CD47 polypeptide can be a human polypeptide. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:63-66. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in SEQ ID NO:67 or SEQ ID NO:68. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in SEQ ID NO:69 or SEQ ID NO:70. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-SIRPa binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:71-74. The cell engager can include an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL-15, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:75-78. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL-15 polypeptide, followed by an anti-CD16a binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in SEQ ID NO:79 or SEQ ID NO:80. The cell engager can include an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:81-84. The cell engager can include an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an IL-15polypeptide, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:85-88. The cell engager can include an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:89-92 and 103-106. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-CD16a binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:93-94. The cell engager can include an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:95-98. The cell engager can include an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:99- 102. The cell engager can include an IgK leader sequence, followed by an anti- CD16a binding molecule, followed by an IL-12, followed by an anti-FAP binding molecule. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL-12, followed by an anti-CD16a binding molecule. This document also features compositions including such T cells.In another aspect, this document features methods for making T cells that include (a) an exogenous nucleotide sequence encoding a CAR having the ability to bind to a cancer antigen and (b) an exogenous nucleotide sequence encoding a cell engager having the ability to bind to (1) an antigen of an immunosuppressive cell of a TME and (2) an antigen of an innate immune cell or an adaptive immune cell of the TME, where the T cell expresses the CAR, and where the T cell expresses and secretes the cell engager. The methods can include, or consist essentially of, introducing into a T cell (a) an exogenous nucleotide sequence encoding a CAR having the ability to bind to a cancer antigen and (b) an exogenous nucleotide sequence encoding a cell engager having the ability to bindto (1) an antigen of an immunosuppressive cell of aTME and (2) an antigen of an innate immune cell or an adaptive immune cell of the TME. The introducing can be done ex vivo or in 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) can be present on separate nucleic acid constructs, the (a) and the (b) can be introduced into the T cell at the same time. When the (a) and the (b) can be present on separate nucleic acid constructs, the (a) and the (b) can be introduced into the T cell separately.In another aspect, this document features nucleic acid constructs including a promotor sequence operably linked to a nucleic acid including (a) a nucleotide sequence encoding a CAR having the ability to bind to a cancer antigen, and (b) a nucleotide sequence encoding a cell engager having the ability to bind to (1) an antigen of an immunosuppressive cell of a TME and (2) an antigen of an innate immune cell or an adaptive immune cell of the TME, where the (a) and the (b) are separated by a nucleotide sequence encoding a 2A polypeptide. The nucleic acid construct can be in the form of a viral vector. The viral vector can be a lentiviral vector or a retroviral vector. The promoter can be an EFla promoter or a CMV promoter. The 2A polypeptide can be a P2A polypeptide, a T2A polypeptide, a E2A polypeptide, or a F2A polypeptide. The CAR can be a BCMA-specific CAR or a CS1 -specific CAR. The antigen of the immunosuppressive cell can be a FAP polypeptide. The cell engager can include a VHH or a scFv. The antigen of the innate immune cell or the adaptive immune cell can be a polypeptide selected from the group consisting of a Fc receptor, a SIRPa polypeptide, a CD16a polypeptide, an IL-15 receptor, aNKG2D polypeptide, aNKp30 polypeptide, a NKG3C polypeptide, ankp64 polypeptide, and a siglec-IO polypeptide. The nucleic acid construct also can include a nucleotide sequence encoding a polypeptide having the abi li ty to bind a second antigen of the immunosuppressive cell. The second antigen of the immunosuppressive cell can be a CD47 polypeptide. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:63-66. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule. The cell engager can comprise, consistessentially of, or consist of a sequence set forth in SEQ ID NO:67 or SEQ ID NO:68. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in SEQ ID NO:69 or SEQ ID NO:70. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-SIRPa binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:71-74. The cell engager can include an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL-15, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:75-78. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL-15 polypeptide, followed by an anti-CD16a binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in SEQ ID NO:79 or SEQ ID NO: 80. The cell engager can include an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:81-84. The cell engager can include an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:85-88. The cell engager can include an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:89-92 and 103-106. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-CD16a binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs: 93-94. The cell engager can include an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs: 95-98. The cell engager can include an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an anti-FAP binding molecule. The cell engager can comprise, consist essentially of, or consist of a sequence set forth in any one of SEQ ID NOs:99-102. The cell engager can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL-12 polypeptide, followed by an anti-CD16a binding molecule. The cell engager can include an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL-12 polypeptide, followed by an anti-FAP binding molecule. This document also features compositions including such nucleic acid constructs.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 including T cells that include (a) an exogenous nucleotide sequence encoding a CAR having the ability to bind to a cancer antigen and (b) an exogenous nucleotide sequence encoding a cell engager having the ability- to bind to (1) an antigen of an immunosuppressive cell of a TME and (2) an antigen of an innate immune cell or an adaptive immune cell of the TME, where the T cells express the CAR, and where the T cells express and secrete the cell engager or a composition including nucleic acid constructs including a promotor sequence operably linked to a nucleic acid including (a) a nucleotide sequence encoding a CAR having the ability to bind to a cancer antigen, and (b) a nucleotide sequence encoding a cell engager having the ability to bind to (1) an antigen of an immunosuppressive cell of a TME and (2) an antigen of an innate immune cell or an adaptive immune cell of the TME, where the (a) and the (b) are separated by a nucleotide sequence encoding a 2A polypeptide. The mammal can be a human. The cancer can be a multiple myeloma, a pancreatic cancer, a breast cancer, or a leukemia. The number of cancer cells within the mammal can be reduced following the administering step.In another aspect, this document features methods for activating an innate immune cell or an adaptive immune cell in a TME of a cancer. The methods can include, or consist essentially of, administering, to a mammal having cancer, a composition including T cells that include (a) an exogenous nucleotide sequence encoding a CAR having the ability to bind to a cancer antigen and (b) an exogenous nucleotide sequence encoding a cell engager having the ability to bind to (1) an antigen of an immunosuppressive cell of a TME and (2) an antigen of an innate immune cell or an adaptive immune cell of the TME,where the T cells express the CAR, and where the T cells express and secrete the cell engager or a composition including nucleic acid constructs including a promotor sequence operably linked to a nucleic acid including (a) a nucleotide sequence encoding a CAR having the ability to bind to a cancer antigen, and (b) a nucleotide sequence encoding a cell engager having the ability to bind to (1) an antigen of an immunosuppressive cell of a TME and (2) an antigen of an innate immune cell or an adaptive immune cell of the TME, where the (a) and the (b) are separated by a nucleotide sequence encoding a 2A polypeptide. The mammal can be a human. The cancer can be a multiple myeloma, a pancreatic cancer, a breast cancer, or a leukemia. The innate immune cell or the adaptive immune cell can be a natural killer (NK) cell, a macrophage, or a T cell.Unless otherw ise 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.BRIEF DESCRIPTION OF THE DRAWINGSFigure 1. Schematic showing structural components of a full IgG antibody, a single chain variable fragment (scFv), a heavy chain only antibody, a heavy chain antibody fused to fragment crystallizable region of an antibody (VHH-Fc), and a nanobody (VHH).Figures 2A-2B. Schematics showing the structure and function of anti-fibroblast activation protein (FAP) VHH-Fc in the tumor microenvironment (TME). Figure 2A) Schematic showing structures of an anti-FAP heavy chain only antibody and a secretedanti-FAP VHH-Fc. Figure 2B) To induce localized killing of cancer-associated fibroblasts (CAFs) in the TME, anti-FAP VHH-Fcs (aFAP VHH-Fc) were designed to bind to FAP via their VHH domains and to Fc-receptors on innate immune cells in the TME via their Fc regions. The Fc regions of monoclonal antibodies can bind to the Fc receptors on the innate immune cells.Figure 3. Schematic demonstrating the function of VHH-Fc in the TME. The CAR T cells kill tumor cells; and natural killer (NK) cells and / or macrophages kill the CAF cells. CAFs can cause TME immunosuppression, leading to the survival of cancer cells. CAR T cells kill cancer cells expressing a specific tumor antigen and secrete anti-FAP VHH-Fcs. The Fc regions of the VHH-Fcs can bind to and activate Fc-receptors on innate immune cells.Figures 4A-4D. Schematics showing that combined targeting of CAFs and blocking CD47 / signal regulatory' protein alpha (SIRPa) interactions can promote phagocytosis in the TME and enhance the anti-CAF and anti-tumor efficacy. Figure 4A) Binding of CD47 to SIRPa, an inhibitory receptor on macrophages and other myeloid cells, blocks the VHH-Fc receptor-mediated functions (e.g., phagocytosis). To overcome this anti -phagocytosis signal, CAR T cells were engineered to secrete one or more molecules in the TME that can block the CD47-SIRPa interactions. Figure 4B) CAR T cells were engineered to secrete anti-FAP VHH-Fcs and anti-CD47 VHHs or anti-CD47 scFvs. Figure 4C) CAR T cells were engineered to secrete anti-SIRPa-FAP VHH bispecific macrophage engagers (BiMEs). Figure 4D) CAR T cells were engineered to secrete anti-FAP VHH-Fcs, and either an anti-SIRPa VHH or a scFv.Figure 5. Schematic of an exemplary construct including a nucleotide sequence encoding a CAR, followed by aP2A sequence, followed by a nucleotide sequence encoding an aFAP -VHH-Fc. T cells were transduced with a lenti viral vector containing the construct to generate aFAP -VHH-Fc secreting CAR T cells.Figure 6. Schematic of exemplary constructs. CAR: A construct encoding only a CAR (without any secreted phagocytosis-inducing molecules) was designed as a control. A number of constructs encoding both a CAR and a phagocytosis-inducing molecule were also designed. CAR + VHH-Fc: A construct encoding both a CAR and a VHH-Fc where the nucleotide sequence encoding the CAR and the nucleotide sequence encoding the VHH-Fc are separated by a nucleotide sequence encoding a P2A polypeptide. CAR +VHH-Fc + CD47 VHH: A construct encoding a CAR, a VHH-Fc, and a CD47-VHH where a nucleotide sequence encoding the CAR and a nucleotide sequence encoding the VHH-Fc are separated by a first nucleotide sequence encoding a P2A polypeptide, and the nucleotide sequence encoding the VHH-Fc and a nucleotide sequence encoding the CD47-VHH are separated by a second nucleotide sequence encoding a P2A polypeptide.CAR + SIRPa scFv-FAP VHH BiME: A construct encoding both a CAR and a SIRPa scFv-FAP VHH where the nucleotide sequence encoding the CAR and the nucleotide sequence encoding the SIRPa scFv-FAP VHH are separated by a nucleotide sequence encoding a P2A polypeptide. CAR + SIRPa VHH-FAP VHH: A construct encoding both a CAR and a SIRPa VHH-FAP VHH where the nucleotide sequence encoding the CAR and the nucleotide sequence encoding the SIRPa VHH-FAP VHH are separated by a nucleotide sequence encoding a P2A polypeptide. CAR + VHH-Fc + SIRPa scFv: A construct encoding a CAR, a VHH-Fc, and a SIRPa scFv where a nucleotide sequence encoding the CAR and a nucleotide sequence encoding the VHH-Fc are separated by a first nucleotide sequence encoding a P2A polypeptide, and the nucleotide sequence encoding the VHH-Fc and a nucleotide sequence encoding the SIRPa scFv are separated by a second nucleotide sequence encoding a P2A polypeptide. CAR + VHH-Fc + SIRPa VHH: A construct encoding a CAR. a VHH-Fc. and a SIRPa VHH where a nucleotide sequence encoding the CAR and a nucleotide sequence encoding the VHH-Fc are separated by a first nucleotide sequence encoding a P2A polypeptide, and the nucleotide sequence encoding the VHH-Fc and a nucleotide sequence encoding the SIRPa VHH are separated by a second nucleotide sequence encoding a P2A polypeptide. Secreted phagocytosis-inducing molecules can induce macrophages, monocytes, or NK cells to target CAFs in the TME. Anti-FAP VHHs and VHH-Fcs target FAP and Fc receptors on the innate immune cells in the TME. Anti-CD47 VHH targets anti-phagocytic CD47 molecules that are highly expressed on tumor cells. SIRPa scFv or VHHs target SIRPa on the innate immune cells.Figures 7A-7C. Size exclusion chromatography (SEC) purification of secreted phagocytosis-inducing molecules. Figure 7A) Eluted and Ni-NTA resin purified anti-CD47 VHH polypeptides were further purified using SEC on a SuperDex 200 column. Figures 7B and 7C) Eluted and Ni-NTA resin purified anti-FAP VHH-Fc polypeptides(Figures 7B) and anti-SIRPa-FAP VHH polypeptides (Figure 7C) were further purified using SEC on a SuperDex 75 column.Figures 8A-8C. Phagocytosis-inducing molecules successfully bound the target antigens. Figure 8A) The concentration of VHH-Fc, CD47 VHH, and SIRPa-FAP BiME in HEK293F supernatant increased over time. Supernatants of UTD HEK293F cells, or those transduced with VHH-Fc, CD47, or SIRPa-FAP BiME constructs were collected, purified via Ni-NTA resins, and subjected to SEC on days 0, 3, and 6 post-transduction. Polypeptide concentration was calculated using A260 / A280 absorbance readings, and normalization was performed in protopam. Figure 8B) Flow cytometric histograms demonstrate secondary His-tag detection of SEC purified anti-FAP VHH-Fc or anti-FAP VHH that were bound to FAP expressing WI38 cells. Figure 8C) Flow cytometric histograms demonstrate His-tag detection of SEC purified anti-CD47 VHH that were bound to CD47 on Nalm6 cells.Figure 9. Primary human T cells transduced with constructs described herein successfully expressed BCMA-specific CARs. The constructs used for this experiment include, BCMA, BCMA P2A VHH-Fc, BCMA P2A VHH-Fc P2A CD47 VHH, BCMA SIRPa-FAP BiME, and BCMA P2A mCherry VHH.Figures 10A-10B. BCMA-specific CAR T cells (with or without secretion of phagocytosis-inducing molecules) killed BCMA+tumor cells. Figure 10A) A luciferasebased cytotoxic assay was performed for untransduced T cells (UTD), BCMA, and BCMA-specific CAR T cells secreting phagocytosis-inducing molecules, which were each co-cultured with BCMA expressing OPM-2 cells for 24 and 48 hours. The killing ability of CAR T cells transduced with plasmids encoding only a CAR was relatively similar to that of CAR T cells transduced to express CAR and phagocytosis-inducing molecules. Figure 10B) Luciferase-based cytotoxicity assay was performed for UTD, BCMA, and BCMA-specific CAR T cells secreting phagocytosis-inducing molecules, which were each co-cultured with luciferase⁺ MM1S for 24, 48, and 72 hours. Killing percent was measured as the percentage luminescence of the target cells.Figure 11. CAR T cells secreting phagocytosis-inducing molecules induced killing of WI38 cells when co-cultured with innate immune cells. CAR T cells secreting VHH-Fcs, SIRPa-FAP VHH, or VHH-Fcs and CD47 were used to test the killing ability of the secreted phagocytosis-inducing molecules on the FAP⁺ WI38 cells. CAR T cells designedto both express CARs and secrete phagocytosis-inducing molecules (SIRPa-FAP VHH or VHH-Fcs + CD47) were able to kill FAP+cells. Killing was assessed 24 and 48 hours after co-culture.Figure 12. BCMA-specific CAR T cells secreting phagocytosis-inducing molecules induced macrophage (CD14+) expansion. CAR T cells secreting phagocytosis-inducing molecules (VHH-Fcs, SIRPa-FAP VHH, or VHH-Fcs and CD47) were cocultured with differentiated MO macrophages and target cells (WI38 FAP+cells or WI38 FAP+cells and OPM-2 cells) for 72 hours. Macrophage proliferation (CD3‘ and CD14+cells) was assessed as a measure of macrophage activation.Figures 13A-13B. BCMA-specific CAR T cells secreting phagocytosis-inducing molecules led to lower expression of macrophage inhibitory markers. CAR T cells secreting phagocytosis-inducing molecules (VHH-Fcs, SIRPa-FAP VHH, or VHH-Fcs + CD47) were co-cultured with differentiated M2 (inhibitory) macrophages and target cells (WI38 FAP+cells or WI38 FAP+cells, and OPM-2 cells) for 2 days. Figure 13A) Macrophage activation (CD206⁻) was assessed as a measure of macrophage polarization to pro-inflammatory subtypes. Figure 13B) Macrophage activation (CD163⁻) was assessed as a measure of macrophage polarization to pro-inflammatory subtypes.Figure 14. BCMA-specific CAR T cells secreting phagocytosis-inducing molecules led to higher expression of macrophage activation markers. CAR T cells secreting phagocytosis-inducing molecules (VHH-Fcs, SIRPa-FAP VHH, or VHH-Fcs + CD47) were co-cultured with differentiated M2 (inhibitory) macrophages and target cells (WI38 FAP+cells or WI38 FAP+cells and OPM-2 cells) for 2 days. Macrophage activation (CD86+) was assessed as a measure of macrophage polarization to pro-inflammatory subtypes.Figures 15A-15B. Anti-FAP tri-specific NK cell engagers (STriKEs). Figure 15A) aCD16-IL-15-aFAP STriKEs were designed to induce localized killing of TME-resident CAFs by binding to FAP via their VHH domains and binding to CD 16a and Fc-gamma receptors on NK cells, IL-15 receptors, macrophages, or other innate immune cells. The binding induces activation of the innate immune cell and killing of the target cells. Figure 15B) CAFs can lead to TME immunosuppression and cancer cell survival. CAR T cells can kill the cancer cells expressing a specific tumor antigen and secrete anti-FAP-IL-15-anti-CD16 STriKEs. Anti-CD16 and IL-15 regions of the STriKEs can bind to andactivate the NK cells via their CD16a receptors and IL-15 receptors, respectively. Thus, using the STriKEs, CAR T cells kill tumor cells, while NK cells kill the CAFs in the TME.Figure 16. Schematics of exemplary nucleic acid constructs encoding both a BCMA-specific CAR and an anti-FAP STriKE. Representative constructs for generating BCMA-specific CAR T cells secreting VHH-STriKEs and scFv-STriKEs are shown. VHH-STriKEs and scFv-STriKEs target FAP and NK cell activating receptors including IL-15 and CD16a (signal 1 and 2, respectively). BCMA-specific CAR T cells without secretion (top panel, CAR construct), and BCMA-specific CAR T cells secreting IL-15 (middle panel, CAR + IL-15 construct) were designed to serve as controls.Figures 17A-17B. SEC purification of STriKEs. Figure 17A) Eluted and Ni-NTA resin purified VHH-STriKE polypeptides were further purified with SEC on a SuperDex 75 column. Figure 17B) Eluted and Ni-NTA resin purified scFv-STriKE polypeptides were further purified with SEC on a SuperDex 75 column.Figure 18. Primary human T cells transduced with constructs described herein successfully expressed BCMA-specific CARs. The constructs used in this experiment include BCMA, BCMA P2A IL-15, BCMA P2A VHH-STriKE, BCMA P2A scFv-STriKE, and BCMA P2A mCherry VHH.Figures 19A-19C. Secreted STriKEs successfully bound the target antigens. Figure 19A) The concentration of scFv-STriKE and VHH-STriKE in HEK293F supernatant increased over time. Supernatants of UTD HEK293F cells, or those transduced with BCMA CAR scFv-STriKE or BCMA CAR VHH-STriKE were collected, purified via Ni-NTA resins, and subjected to SEC on days 0, 3. and 6 posttransduction. Polypeptide concentration was calculated using A260 / A280 absorbance readings, and normalization was performed in protopam. Figure 19B) Flow cytometric histograms demonstrating secondary His-tag detection of SEC purified scFv-STriKEs or VHH-STriKEs that were bound to WI38 cells expressing FAP. Figure 19C) Flow cytometric histograms demonstrating His-tag detection of SEC purified scFv-STriKEs and VHH-STriKEs that were bound to primary NK cells.Figures 20A-20C. BCMA-specific CAR T cells (with or without secretion of phagocytosis-inducing molecules) killed the target tumor cells. Figure 20A) Luciferasebased cytotoxicity assay was performed for UTD, BCMA, and BCMA-specific CAR Tcells secreting NK cell activating proteins (BCMA scFv-STriKE) or IL- 15 (BCMA VHH-STriKE), which were co-cultured with luciferase OPM-2 cells for 24, 48, and 72 hours. Killing percentage was measured as the percentage luminescence of the target cells. Figure 20B) Luciferase-based cytotoxicity assay was performed for UTD, BCMA, and BCMA-specific CAR T cells secreting NK cell activating proteins (BCMA scFv-STriKE or BCMA VHH-STriKE) or IL-15, which were co-cultured with luciferase+MM1S cells for 24, 48, and 72 hours. Killing percentage was measured as the percentage luminescence of the target cells. Figure 20C) Luciferase-based cytotoxicity assay was performed for UTD, BCMA or BCMA-specific CAR T cells secreting IL-15. scFv-STriKEs, or VHH-STriKEs, which were co-cultured with luciferase+WI38 cells expressing FAP and with or without NK cells for 24, 48, and 72 hours. Killing percentage was measured as the percentage luminescence of the target cells.Figure 21. NK cells were incubated with GFP’ WI38 cells, and either UTD, BCMA-specific CAR T, or BCMA-specific CAR T cells secreting IL- 15 or VHH-STriKEs for 48 hours at a 2:1:1 ratio, and the expression of NK activation markers CD25+and CD69+was assessed by flow cytometry. NK cells were identified as CD3⁻ CD56+cells. Live / dead aqua staining was used to distinguish live versus dead cells. NK cells alone or with WI38 were used as controls to compare the NK cell phenotypes in the presence of the VHH-STriKE or IL-15 polypeptides.Figures 22A-22B. BCMA-specific CAR T cells secreting STriKEs led to increased NK cell activation. Flow cytometric analysis showed increased expression of CD25 (Figure 22A) and CD69 (Figure 22B) after 24 and 48 hours of co-culturing NK cells with target cells and CAR T cells secreting STRIKES (376 = VHH-STriKE, 377 = scFv-STriKE), or with purified free-floating STriKEs at Ipg / mL. NK cells w ere identified as CD3⁻ CD56+cells. Live / dead aqua staining w as used to distinguish live versus dead cells. NK cells alone or with WI38 were used as controls to compare the NK cell phenotypes in the presence of the sTriKE polypeptides.Figure 23. BCMA-specific CAR T cells secreting VHH-STriKEs led to increased expression of degranulation markers. NK cells were co-cultured with BCMA-specific CAR T cells secreting polypeptides, and the target cells (WI38 cells) at an effector / target ratio of 2: 1: 1. Cells were stained with FITC-conjugated anti-CD107a (H4A3, BioLegend) at the beginning of a 4-hour incubation. One hour after the addition of anti-CD107a, cellswere given golgi stop (1:1,500) and golgi plug (1: 1,000; both from BD Biosciences), followed by a 3-hour incubation. Cells were then stained with alive / dead fixable aqua staining kit (catalog no.: L-34966, Thermo Fisher Scientific), anti-CD56, and anti-CD3. The cells were fixed in 2% paraformaldehyde (Thermo Fisher Scientific) and permeabilized (eBioscience permeabilization medium). The permeabilized cells were stained with BV421 -conjugated IFNy (4S. B3, BioLegend), and were evaluated using a flow cy tometry’ on a three-laser CytoFLEX (Beckman Coulter, Chaska, MN, USA). All analyses were performed using FlowJo X10.0.7r2 software (Ashland, OR, USA).Figures 24A-24B. Effects of VHH-STriKEs on CD8 T cells. The number of CD3+CD8+T cells (UTD cells, BCMA-specific CAR T cells, or BCMA-specific CAR T cells secreting IL-15 or VHH-STriKEs) was calculated using a flow cytometry after 48 hours of co-culturing with the NK cells and WI38 cells + / - OPM-2 tumor cells ( 1:2:1 or 1: 2:1:1 ratios were used depending on whether OPM-2 cells were added or not). Figure 24A) VHH-STriKEs did not induce disproportionate CD8 T cell polarization. Figure 24B) VHH-STriKEs did not induce disproportionate CD8 T cell proliferation.Figure 25. Schematic showing the function of an anti-FAP VHH-Fc (top panel) and an anti-FAP STriKE (bottom panel).Figure 26. Schematic showing that an Fc receptor or an IL-15 / CD16 STriKE can lead to immune cell modulation and activation.Figure 27. Primary human T cells transduced with constructs described herein successfully expressed BCMA-specific CARs. The constructs used in this experiment include BCMA, BCMA P2A VHH-Fc, BCMA P2A IL-15, BCMA VHH-STriKE, BCMA scFv-STnKE, BCMA P2A VHH-Fc P2A CD47 VHH, and BCMA P2A mCherry VHH.Figure 28. Addition of VHH-Fcs activated NK cells. Flow cytometric analysis showed increased expression of NK cell activation markers CD25 and CD69 after 24 hours of co-culturing the NK cells and the target cells with the purified secreted VHH-Fc polypeptides at varying different concentrations (1, 2, 5, and 10 pg.) The NK cells were identified as CD3⁻ CD56+cells. Live / dead aqua staining was used to distinguish live versus dead cells. NK cells alone or with WI38 were used as controls to compare the NK cell phenotypes in the presence of the VHH-Fc polypeptides.Figures 29A-29B. Schematics of exemplary constructs encoding both CAR and a STriKE. Figure 29A) Schematic of an exemplary FAP VHH-based STriKE construct including a nucleotide sequence encoding a CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aFAP VHH-IL-aCD16 VHH. Figure 29B) Schematic of an exemplary’ FAP scFv-based STriKE construct including a nucleotide sequence encoding a CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aFAP scFv-IL-15-aCD16 VHH. T cells were transduced with a lentiviral vector containing aFAP VHH-based STriKE construct or aFAP scFv-based STriKE construct to generate aFAP VHH-IL-aCD16 VHH secreting CAR T cells or aFAP scFv-IL-15-aCD16 VHH secreting CAR T cells, respectively.Figure 30. Schematic of exemplary’ constructs that can be used to generate BCMA-specific CAR T cells that can express and secrete a bispecific SIRPa engager (BiSE). Representative constructs where a first construct can encode a BCMA-specific CAR and a second construct can encode either a aFAP scFv-aSIRPa BISE or a aFAP VHH-aSIRPa BISE are shown in the top panel and the third panel from the top.Representative constructs that can encode both a BCMA-specific CAR and either a aFAP scFv-aSIRPa BISE or a aFAP VHH-aSIRPa BISE are shown in the second and fourth panels from the top.Figure 31. Schematic of exemplary' construct encoding both a CAR and a scFv-based SiNE. A construct including a nucleotide sequence encoding a CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aFAP scFv-IL-15- aCD16 STriKE. T cells were transduced with a lentiviral vector containing the construct to generate aFAP scFv-IL-15- aCD16 scFv secreting CAR T cells.Figures 32A-32C. Schematics of exemplary constructs encoding both a CAR and a VHH-based SiNE. Figure 32A) A construct including a nucleotide sequence encoding a BCMA-specific CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aFAP VHH-aCD16 SiNE. T cells were transduced with a lentiviral vector containing the construct to generate aFAP- aCD16 secreting CAR T cells. Figure 32B) A construct including a nucleotide sequence encoding a BCMA-specific CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aNKG2D-aFAP SiNE. T cells were transduced with a lentiviral vector containing the construct to generate aNKG2D-aFAP secreting CAR T cells. Figure 32C) A construct including a nucleotidesequence encoding a BCMA-specific CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aNKp30-aFAP SiNE. T cells were transduced with a lentiviral vector containing the construct to generate aNKp30-aFAP secreting CAR T cells.Figures 33A-33B. Schematics of exemplary constructs encoding both a CAR and a SiNE including a VVH and a scFv. Figure 33A) A construct including a nucleotide sequence encoding CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aNKG2D-aFAP sc-Fv SiNE. T cells were transduced with a lentiviral vector containing the construct to generate otNKG2D-aFAP secreting CAR T cells. Figure 33 B) A construct including a nucleotide sequence encoding a CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aNKp30-aFAP scFv SiNE. T cells were transduced with a lentiviral vector containing the construct to generate aNKp30-aFAP secreting CAR T cells.Figure 34. Schematic of an exemplary construct encoding both a CAR and a scFv-based SiNE. A construct including a nucleotide sequence encoding a CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding a FAP scFv-CD16 scFv-based SiNE. T cells were transduced with a lentiviral vector containing the construct to generate aFAP scFv-aCD16 scFv secreting CAR T cells.Figures 35A-35B. Monocytes and macrophages highly express SIRPa. Figure 35A) Flow cytometric histograms demonstrating expression of SIRPa on MO macrophages. To generate macrophages, human monocytes were isolated from healthy donor PBMCs and cultured at 1 x 106cell / mL in ultra-low-attachment 96- well U-bottom plates (Thermo Fisher Scientific) for 7-10 days with human recombinant M-CSF(25 ng / mL). After incubation, macrophages were harvested and SIRPa expression was assessed via flow cytometry. Macrophages were identified as CD3⁻ CD80+CD14+cells. Live / dead aqua staining was used to distinguish live versus dead cells. Figure 35B) Flow cytometric histograms demonstrating relatively equal expression of SIRPa on monocytes and macrophages. Monocytes were isolated from the PBMCs of healthy donors and assessed for SIRPa expression on day 1. 7 days later, macrophages (cultured as described in Figure 35A) were harvested and SIRPa expression was assessed via flow cytometry. Macrophages and monocytes were identified as CD3’ CD80+CD14+and CD3’CD14+cells, respectively. Live / dead aqua staining was used to distinguish live versus dead cells.Figures 36A-36B. Monocytes and macrophages and NK cells express CD16. Figure 36A) Flow cytometric histograms demonstrating expression of CD16 on macrophages and monocytes. Monocytes were isolated from the PBMCs of healthy donors and assessed for CD16 expression on day 1. To generate macrophages, human monocytes were isolated from healthy donor PBMCs and cultured at 1 x 106cell / mL in ultra-low-attachment 96-well U-bottom plates (Thermo Fisher Scientific) for 7-10 days with human recombinant M-CSF (25 ng / mL). After incubation, macrophages were harvested and CD16 expression was assessed via flow cytometry. Macrophages and monocytes were identified as CD3‘ CD80+CD14+and CD3" CD14+cells, respectively. Live / dead aqua staining was used to distinguish live versus dead cells. Figure 36B) Flow cytometric histograms demonstrating expression of CD 16 on NK cells. NK cells were isolated from the PBMCs of healthy donors and assessed for CD 16 expression via flow cytometry. NK cells were defined as CD3’ CD56+cells. Live / dead aqua staining was used to distinguish live versus dead cells.Figure 37. NK cells express IL-15 receptor alpha (IL-15ra). Flow cytometric histogram demonstrating expression of IL-15ra on NK cells. NK cells were isolated from the PBMCs of healthy donors and assessed for IL-15ra expression via flow cytometry. NK cells w ere defined as CD3⁻ CD56+cells. Live / dead aqua staining was used to distinguish live versus dead cells.Figure 38. Flow cytometric histogram demonstrating expression of CD47 on tumor cells.Figure 39. Flow cytometric histogram demonstrating expression of FAP on GFP+WI-38 cells and wildtype (untransduced; UTD) cells.Figure 40. Schematic demonstrating the function of StriKE and FAP VHHFc + SIRPa molecules in TME.Figures 41A-41D. Secreted STriKEs successfully bound the target antigens. Figure 41 A) Supernatants of UTD HEK293F cells, or those transduced with BCMA, BCMA P2A IL-15, BCMA P2A VHH-STriKE, BCMA P2A scFv-STriKE, and BCMA P2A mCherry VHH, BCMA P2A CD47 VHH, BCMA P2A SIRPA VHH, BCMA CD3-FAP scFv, BCMA KWAR23 (SIRPa scFv). BCMA CD 16 VHH-FAP scFv, or BCMAVHHFc were collected, purified via Ni-NTA resins, and subjected to SEC on days 0, 3, and 6 post-transduction. Flow cytometric histograms demonstrating secondary His-tag detection of SEC purified VHHFcs, VHH-STriKEs, and CD16-FAP scFvs that were bound to WI38 cells expressing FAP are shown. Figure 4 IB) Flow cytometric histograms demonstrating His-tag detection of SEC purified VHHFcs, CD 16a VHH-FAP scFv, and VHH-STriKEs, and IL-15 that were bound to primary NK cells are shown. Figure 41C) Flow cytometric histograms demonstrating His-tag detection of SEC purified CD47 VHH, CD3-FAP scFvs, IL-15 and, to a tiny degree, VHH-STriKEs, that were bound to T cells are shown, whereas all other molecules did not successfully bind to T cells. Figure 41D) Flow cytometric histograms demonstrating His-tag detection of SEC purified VHHFcs, CD16a VHH-FAP scFv, SIRPa VHH, CD47 VHH, VHH-STriKEs, KWAR23 (SIRPa scFv) that were bound to monocytes are shown.Figures 42A-42B. BCMA-specific CAR T cells with secretion of STriKEs killed the target cancer cells in the presence of CAFs and NK cells. Figure 42A) Luciferasebased cytotoxicity assay was performed for UTD, BCMA, and BCMA-specific CAR T cells secreting NK cell activating proteins (BCMA scFv-STriKE) or IL-15 (BCMA VHH-STriKE), which were co-cultured with luciferase OPM-2 cells for 48 hours. Killing percentage was measured as the percentage luminescence of the target cells. Figure 42B) Luciferase-based cytotoxicity assay was performed for UTD, BCMA, and BCMA-specific CAR T cells secreting NK cell activating proteins (BCMA scFv-STriKE or BCMA VHH-STriKE) or IL-15, which were co-cultured with luciferase OPM-2 cells, NK cells, and CAFs for 48 hours. Killing percentage was measured as the percentage luminescence of the target cells.Figures 43A-43B. BCMA-specific CAR T cells secreting VHH-STriKEs led to increased expression of degranulation markers at low effectortarget (E: T) ratios. NK cells were co-cultured with BCMA-specific CAR T cells secreting polypeptides, and the target cells (WI38 cells) at an effector / target ratio of 1:1:1. Figure 43 A) Cells were stained with FITC-conjugated anti-CD107a (H4A3, BioLegend) at the beginning of a 4-hour incubation. One hour after the addition of anti-CD107a, cells were given golgi stop (1:1,500) and golgi plug (1:1,000; both from BD Biosciences), followed by a3-hour incubation. Cells were then stained with alive / dead fixable aqua staining kit (catalog no.: L-34966, Thermo Fisher Scientific), anti-CD56, and anti-CD3. The cells were fixed in2% paraformaldehyde (Thermo Fisher Scientific) and permeabihzed (eBioscience permeabilization medium). Figure 43B) The permeabilized cells were stained with BV421 -conjugated IFNy (4S. B3, BioLegend), and were evaluated using a flow cytometry using a three-laser CytoFLEX (Beckman Coulter, Chaska, MN, USA). All analyses were performed using FlowJo X10.0.7r2 software (Ashland, OR. USA).Figures 44A-44B. Secreted VHH-STriKEs led to increased NK cell activation in the presence of CAFs, as measured by CD69 expression. Figure 44A) NK cells were incubated with OPM-2 cells and UTD, BCMA-specific CAR T, or BCMA-specific CAR T cells secreting IL- 15 or VHH-STriKEs for 48 hours at a 2: 1: 1 ratio. The expression of NK activation marker CD69 was assessed by flow cytometry. NK cells were identified as CD3⁻ CD56+cells. Live / dead aqua staining was used to distinguish live versus dead cells. Figure 44B) NK cells were incubated with OPM-2 cells, patient-derived CAFs, and UTD, BCMA-specific CAR T. or BCMA-specific CAR T cells secreting IL- 15 or VHH-STriKEs for 48 hours at a 2: 1:0.5: 1 ratio. The expression of NK activation marker CD69+was assessed by flow cytometry. NK cells were identified as CD3" CD56+cells. NK cells alone or with CAFs were used as controls to compare the NK cell phenotypes in the presence of VHH-STriKE or IL-15 polypeptides.Figures 45A-45B. To assess STriKE activation of myeloid cells, a phagocytosis assay was performed. Monocytes / macrophages and CART cells were generated from autologous healthy donor PBMCs. On day 7 of monocytes / macrophages and CART cell production, GFP+WI-38 target cells were added to ultra-low attachment 96-well U-bottom plates containing macrophages / monocytes (50,000 cells / well).Monocytes / macrophages alone served as a control. Figure 45 A) Concentrated supernatants from BCMA-CART, BCMA-CART VHH-STriKEs, BCMA CART P2A IL-15 were added to the monocyte and WI-38 cell co-cultures for 30-45 minutes. Serum-free RPMI was added as a negative control in lieu of supernatants. After a 3 hour incubation, cells were washed, and an Fc-block was performed by incubating cells in a diluted Human TruStain FcX solution for 10 minutes before staining with BD Horizon™ Viability Stain Zombie R718 and anti-CDl lb antibodies. Cells were then analyzed by flow cytometry. Phagocytosis was assessed as the number of CDllb+and GFP+macrophages, normalized to the control conditions. Figure 45 B) Concentrated supernatants from BCMA-CART, BCMA-CART VHHFc, BCMA CART P2A SIRPaVHH, or BCMA CART P2A VHHFc P2A SIRPa VHH were added to macrophage and WI-38 cell co-cultures for 30-45 minutes. Serum-free RPMI was added as a negative control in lieu of supernatants. After a 3 hour incubation, cells were washed, and an Fc-block was performed by incubating cells in a diluted Human TruStain FcX solution for 10 minutes before staining with BD Horizon™ Viability Stain Zombie R718 and anti-CD1 lb antibodies. Cells were then analyzed by flow cytometry. Phagocytosis was assessed as the number of CD1 lb+and GFP+macrophages, normalized to the control conditions.Figures 46A-46B. BCMA-specific CAR T cells with secretion of STriKEs killed the target cancer cells in the presence of CAFs and NK cells. Figure 46A) Luciferasebased cytotoxicity assay was performed for UTD, BCMA, and BCMA-specific CAR T cells secreting phagocytosis inducing proteins (BCMA VHHFc, BCMA SIRPa VHH, BCMA FAP VHHFc + SIRPA VHH) or controls (BCMA or UTD), which were cocultured with luciferase+OPM-2 cells for 48 hours. Killing percentage was measured as the percentage luminescence of the target cells. Figure 46B) Luciferase-based cytotoxicity assay was performed for secreting phagocytosis inducing proteins (BCMA VHHFc, BCMA SIRPa VHH, BCMA FAP VHHFc + SIRPA VHH) or controls (BCMA or UTD). which were co-cultured with luciferase4OPM-2 cells. M2-polarized tumor associated macrophages (TAMs), and CAFs for 48 hours. Killing percentage was measured as the percentage luminescence of the target cells.Figures 47A-47C. Representative histograms demonstrating the expression of CD163, CD206, and CD80 on macrophages. Figure 47A) CD163 expression on macrophages after a 3-day co-culture with BCMA-specific CAR T cells secreting phagocytosis inducing proteins (BCMA VHHFc, BCMA SIRPa VHH, BCMA FAP VHHFc + SIRPA VHH) or controls (BCMA or UTD), OPM-2 cells, and patient-derived CAFs. Figure 47B) CD206 expression on macrophages after a 3-day co-culture with BCMA-specific CAR T cells secreting phagocytosis inducing proteins (BCMA VHHFc, BCMA SIRPa VHH, BCMA FAP VHHFc + SIRPA VHH) or controls (BCMA or UTD), OPM-2 cells, and patient-derived CAFs. Figure 47C) CD80 expression on macrophages after a 3-day co-culture with BCMA-specific CAR T cells secreting phagocytosis inducing proteins (BCMA VHHFc, BCMA SIRPa VHH, BCMA FAP VHHFc + SIRPA VHH) or controls (BCMA or UTD), OPM-2 cells, and patient-derived CAFs.Figures 48A-48K. After demonstrating a robust in-vitro activity, BCMA-CART -STriKE efficacy was tested in vivo. Figure 48A) Schematic of in vivo experiment: First, NSG mice received 7.5xl06patient-derived bone marrow-CAFs (BM-CAFs) and IxlO6luciferase+ 0PM2 cells via intravenous (IV) injection. After confirming and randomizing by tumor engraftment, the mice were intravenously treated with IxlO6BCMA VHHFc, BCMA SIRPa VHH, BCMA FAP VHHFc + SIRPA VHH, BCMA-CART, BCMA-CART VHH-STriKEs, BCMA CART P2A IL-15 or controls (BCMA mCherry VHH or UTD) and 7.5xl05donor-matched CD 16+ innate immune cells. Figures 48B and 48F) Tumor growth curve (Figure 48B) and representative images (Figure 48F) were measured by bioluminescence imaging. BCMA-CART-STriKE and BCMA FAP VHHFc + SIRPA VHH treated mice achieved total tumor clearance and long-term survival compared to the control groups (p<0.001) as shown in bioluminescence imaging for day 0 - 90. Figure 48C) Mouse weight over time showed that treatment with BCMA-CART cells secreting IL- 15 led to lethal weight loss associated with explosive T cell expansion. Figure 48D) CD3+ T cells detected in mouse blood harvested on Day 10. Figure 48E) CD3- CD56+ NK cells detected in mouse blood harvested on Day 10. Figure 48G) CD 14+ myeloid cells detected in mouse blood harvested on Day 10. Figure 48H) CD3+ T cells detected in mouse spleens (harvested at end-point). Figure 481) CD14+ myeloid cells detected in mouse spleens (harvested at end-point). Figure 48J) Survival curve post CART injection. Figure 48K) H& E stained images of mouse bone marrows.Figures 49A-49M. The efficacy of BCMA-CART-STriKE was tested in immunocompetent in vivo models. Figure 49A) Murine BALBc A20 lymphoma cell lines were transduced to express human BCMA. Flow cytometry confirmed 100%human BCMA expression in the cells. Figure 49B) Mouse CART cells were generated from splenocytes by manual digestion of spleens from male or female BALBc mice.Enrichment of T cells was performed by Easy Sep mouse T cell isolation kit per manufacturer's protocol (StemCell Technologies). Single or dual transduction with hBCMA-CAR and / or secreted proteins fusions, and subsequent expansion were performed. CAR expression and secreted protein expression were confirmed on day 6 of CAR expansion. CAR expression was measured via tEGFR expression and secreted protein was measured viatNGFR expression. Figure 49C) Luciferase-based cytotoxicity assay as performed for UTD. BCMA, and BCMA VHHFc, BCMA CD47 VHH, BCMAFAP VHHFc + CD47 VHH. which were co-cultured with luciferase+human-BCMA+ A20 cells for 48 hours. Killing percentage was measured as the percentage luminescence of the target cells. For proliferation assays, human-BCMA+ A20 cells were co-cultured with UTD, BCMA, and BCMA VHHFc, BCMA CD47 VHH, BCMA FAP VHHFc + CD47 VHH at 1: 1 ratios. Cells were co-cultured for 3 or 5 days, and then were harvested and stained. Figure 49D) CART cells were measured as the number of tEGFR+ cells. Figure 49E) CART cells with secretion were measured as tNGFR+cells. Figure 49F) A20 tumor cells were measured via muCD19+expression. Figure 49G) Schematic of in vivo experiment: BALBc mice received intraperitoneal (I. P.) injections of cyclophosphamide (150 mg / kg.) One day later, mice received 300,000 human-BCMA+ luciferase+ A20 cells via IV injection. After confirming and randomizing by tumor engraftment, the mice were intravenously treatment with 7.5xl06UTD, BCMA, and BCMA VHHFc, BCMA CD47 VHH, BCMA FAP VHHFc + CD47 VHH. Figure 49H) Representative tumor burden images are shown. Figure 491) Bioluminescence imaging was used to measure tumor growth curve. Figure 49 J) CART cells (tEGFR+ CD3+ T cells) were detected in mouse blood harvested on day 10. Figure 49K) CART cells secretion proteins (tNGFR+ CD3+ T cells) were detected in mouse blood harvested on day 10. Figure 49L) CD47+ cells were detected in mouse blood harvested on day 10. Figure 49M) CDllb+ myeloid cells were detected in mouse blood harvested on day 10.Figures 50A-50K. The efficacy of BCMA-CART-STriKE was assessed in C57BL / 6 immunocompetent in vivo models. Figure 50A) Murine C57BL / 6 B16 melanoma cell lines were transduced to express human BCMA. Flow cytometry confirmed 100%human BCMA expression in the cells. Figure 50B) Mouse CART cells were generated from splenocytes by manual digestion of spleens from male or female BALBc mice. Enrichment of T cells was performed by Easy Sep mouse T cell isolation kit per manufacturer’s protocol (StemCell Technologies). Single or dual transduction with hBCMA-CAR and / or secreted proteins fusions, and subsequent expansion were performed. CAR expression and secreted protein expression were confirmed on day 6 of CAR expansion. CAR expression was measured via tEGFR expression and secreted protein via tNGFR expression. Figure 50C) Luciferase-based cytotoxicity assay was performed for UTD, BCMA. and BCMA VHHFc. BCMA CD47 VHH. BCMA FAP VHHFc + CD47 VHH, which were co-cultured with luciferase+human-BCMA+ B16cells for 48 hours. Killing percentage was measured as the percentage luminescence of the target cells. For proliferation assays, human-BCMA+ Bl 6 cells were co-cultured with UTD, BCMA, and BCMA VHHFc, BCMA CD47 VHH, BCMA FAP VHHFc + CD47 VHH at 1: 1 ratios. Cells were co-cultured for 3 or 5 days, and then were harvested and stained. Figure 50D) CART cells were measured as the number of tEGFR+ cells. Figure 50E) CART cells with secretion were measured as tNGFR+cells. Figure 50F) Bl 6 tumor cells were measured via muCD19+expression. Figure 50G) Schematic of in-vivo experiment: First, C57BL / 6 mice received I. P. injections of cyclophosphamide (150 mg / kg.) One day later, mice received 500,000 human-BCMA+ luciferase+ B16 cells via subcutaneous (SQ) injection. After confirming and randomizing by tumor engraftment, mice received IV treatment with 7.5xl06UTD, BCMA, and BCMA VHHFc, BCMA CD47 VHH, BCMA FAP VHHFc + CD47 VHH. Figure 50H) Representative graph showing tumor burden growth measured by caliper. Figure 501) CART cells secretion proteins (tEGFR+ tNGFR+ CDC3+ T cells) were detected in mouse blood harvested on day 10. Figure 50J) CART cells (tEGFR+ CD3+ T cells) were detected in mouse blood harvested on day 10. Figure 50K) CD47+ cells were detected in mouse blood harvested on day 10.Figures 51A-51J. Assessing the potential toxi cities of BCMA-CART-StriKEs in humanized mice. Figure 51 A) Schematic of experiment: Mice were intravenously injected with OPM-2 cells either with or without patient-derived BM-CAFs (IxlO6each). Subsequent bioluminescence imaging and blood sampling were used to monitor tumor growth in mice wi th or without patient-derived CAFs. Figures 51B-15C) Tumor growth was measured in the presence or absence of patient-derived BM-CAFs as shown in radiance plots (Figure 51B) and bioluminescence images (Figure 51C). Figure 51D) Humanized mice engrafted with OPM-2 and patient BM-CAFs exhibited lower NK cell counts in the peripheral blood compared to OPM-2 alone. CD3- CD56- NK cells were detected in mouse blood harvested on weeks 2, 4, and 6. Figure 51E) Humanized mice engrafted with OPM-2 and patient BM-CAFs exhibited lower T cell counts in the peripheral blood compared to OPM-2 alone. CD3+ T cells were detected in mouse blood harvested on weeks 2, 4, and 6. Figure 51F) Humanized mice engrafted with OPM-2 and patient BM-CAFs exhibited fibroblast-specific protein 1 (FSP-1) and FAP+ CAFs in their harvested bone marrows. CD45- CD3- CD 138- FSP-1+ or FAP+ CAFs were detected inmouse bone marrows harvested on week 6. Figure 51G) Schematic of experiment: Mice were intravenously injected with OPM-2 cells and patient-derived BM-CAFs (IxlO6each). After confirming engraftment and randomizing, mice were intravenously administered IxlO6BCMA-CART-VHH-StriKEs or BCMA-CART-FAP VHHFc-SIRPa VHH (or controls, BCMA or UTD). Figures 51H-51J) BCMA-CART-VHH-STriKE or BCMA-CART-FAP VHHFc-SIRPa VHH treated mice exhibited greater tumor clearance as shown via bioluminescence values (Figure 51H), enduring survival (p<0.05) (Figure 51I), and higher T cell expansion compared to UTD, p<0.001, or BCMA CART cells, p<0.01 (Figure 51J).Figures 52A-52F. C57BL / 6 CART cell secretion and killing of BCMA+ human OPM-2 cells were tested. Figures 52A-52B) Mouse CART cells were generated from splenocytes by manual digestion of spleens from male or female BALBc mice.Enrichment of T cells was performed by Easy Sep mouse T cell isolation kit per manufacturer's protocol (StemCell Technologies). Single or dual transduction with hBCMA-CAR and / or secreted proteins fusions, and subsequent expansion were performed. CAR expression and secreted protein expression were confirmed on day 6 of CAR expansion. CAR expression was measured via tEGFR expression (Figure 52 A), and secreted protein via tNGFR expression (Figure 52B). Figure 52C) Enzyme Linked Immunosorbent Assay (ELISA) was performed on supernatants from murine UTD, BCMA, and BCMA VHHFc, BCMA CD47 VHH, BCMA FAP VHHFc + CD47 VHH cells that were harvested on day 0, 3 and 7 post-transduction. Figure 52D) Western blot detected His-tagged secreted proteins in supernatants from murine UTD, BCMA. and BCMA VHHFc, BCMA CD47 VHH, BCMA FAP VHHFc + CD47 VHH cells that were harvested on day 7. Figure 52E) Luciferase-based cytotoxicity assay was performed for UTD, BCMA, and BCMA VHHFc, BCMA CD47 VHH, BCMA FAP VHHFc + CD47 VHH, which were co-cultured with luciferase OPM-2 cells for 48 hoursFigure Killing percentage was measured as the percentage luminescence of the target cells. 52F) Proliferation assay of human-BCMA+ OPM-2 cells that were co-cultured with UTD, BCMA, and BCMA VHHFc, BCMA CD47 VHH, BCMA FAP VHHFc + CD47 VHH at 1:1 ratios. Cells were co-cultured for 3 or 5 days, and then were harvested and stained. CART cells were measured as the number of tEGFR+ cells.Figures 53A-53E. Confirmation of target expression on BM samples from multiple myeloma (MM) patients. Figure 53A) Using scRNA-seq of public data sets, it was found that macrophages and monocytes w ithin the MM TME of untreated patients exhibited high expression of CD16a. also known as FcyRIII. Figure 53B) High expression of CD47 was found on myeloid cancer cells in untreated MM patients compared to the healthy controls and MM precursor patients (Monoclonal Gammopathy of Undetermined Significance (MGUS)). Figures 53C-53E) Next the levels of FAP, CD16a, and SIRPa expressions were assessed in BM cells derived from MM patient. Figure 53C) Flow cytometry analysis of FAP expression showed that BM-CAFs from MM patients expressed high levels of FAP (more so than MGUS patients). Figures 53D-53E) MM-patient BM-derived myeloid cells expressed high levels of CD16 (Figure 53D) and SIRPa (Figure 53E) as assessed by flow cytometry.Figures 54A-54E. BM-CAFs from BCMA-CART cell therapy non-responders were more immunosuppressive and had more extensive communication among the BM-CAF cells. Figure 54A) Bone marrow samples from MM patients treated with BCMA-CART cell therapy (n = 3 responders who had complete durable (>6 months) response, n = 4 non-responders who had progressive disease at month 3 of follow up) were isolated and sent for scRNA-seq. BM-CAFs from BCMA-CART non-responders exhibited increased crosstalk between immunosuppressive BM-CAF populations and M2-like macrophages compared to responders. It was found that BM-CAFs from non-responders proliferated significantly more than BM-CAFs from the responders. Figures 54B-54C) Non-responder BM-CAFs also showed significantly higher levels of immunosuppressive cells in the makeup of the BM tumor microenvironments as shown in the bar graph display of different cell types (Figure 54B) and in UMAP plots (Figure 54C). Figures 54D-54E) The non responders (left) had higher expression of both SIPRa (Figure 54D) and CD47 (Figure 54E) expression compared to the responders (right).Figures 55A-55E. NSG models of BCMA-CART cells secreting STriKEs or phagocytosis inducing proteins combined with macrophages. Figure 55A) Schematic of in-vivo experiment: First, NSG mice were intravenously injected with 7.5xl06patient-derived BM-CAFs and IxlO6luciferase+ 0PM2 cells. After confirming and randomizing by tumor engraftment, mice were intravenously treated with IxlO6BCMA VHHFc, BCMA SIRPa VHH. BCMA FAP VHHFc + SIRPA VHH. BCMA-CART. BCMA-CART VHH-STriKEs. BCMA CART P2A IL-15 or controls (BCMA mCherry VHH or UTD) and 7.5xl05donor-matched macrophages. Figures 55B-55C) Representative images of tumor grow th (Figure 55B) as measured by bioluminescence imaging and graphed tumor growth curves (Figure 55C.) BCMA-CART-STriKE and BCMA FAP VHHFc + SIRPA VHH treated mice achieved total tumor clearance and long-term survival compared to the controls (p<0.001) as shown in bioluminescence imaging for day 0 - 90. Figure 55D) Bone marrows isolated from the control BCMA-CART treated mice (left) showed FSP-1+ CAFs while BCMA-CART-STriKE and BCMA FAP VHHFc + SIRPA VHH treated mice (middle and right, respectively) showed a lack of FSP-1+ CAFs as detected by flow cytometry. Figure 55E) Observable populations of large CAFs in the ungated flow' plots of mice treated with BCMA-CART secreting mCherry VHH controls, SIRPa VHH, and CD47 VHH alone while BCMA-CART-STriKE and BCMA FAP VHHFc + SIRPA VHH treated mice showed an absence of FSP-1+CAFs cells (as indicated by the circle in the plots.)Figures 56A-56E. NSG SQ models of BCMA-CART cells secreting STriKEs or phagocytosis inducing proteins combined with macrophages. BCMA-CART STriKEs yielded superior in vivo antitumor efficacy in combination with CD16+ monocytes. Figure 56A) Schematic illustrating that NSG mice were intravenously engrafted with 1 x 106of each of luciferase+BCMA+OPM-2 MM cells and FAP+WI-38 fibroblasts. When tumor burden reached approximately 108photons / second as assessed by BLI, mice were randomized to intravenous treatment with IxlO6BCMA VHHFc, BCMA SIRPa VHH, BCMA FAP VHHFc + SIRPA VHH, BCMA-CART, BCMA-CART VHH-STriKEs, BCMA CART P2A IL- 15 or controls (BCMA mCherry VHH or UTD) and IxlO6donor-matched CD16+ monocytes. Figure 56B) Mice were weighed overtime. Figure 56C) Representative tumor burden w as measured by a caliper. Figure 56D) CD3+ T cells w ere detected in mouse blood harvested on day 10. Figure 56E) Survival curve post treatment.Figure 57. Schematic of an exemplary FAP VHH-based STriKE construct including a nucleotide sequence encoding a CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aFAP VHH-IL-12-aCD16 VHH. aFAP VHH-IL-12- aCD16 CART cells were generated by transducing T cells with a lentiviral construct containing a BCMA CAR, and an aFAP VHH-IL-12- aCD16 STriKE.Figure 58. Schematic of an exemplary FAP scFv-based STriKE construct including a nucleotide sequence encoding a CAR, followed by a P2A sequence, followed by a nucleotide sequence encoding an aFAP scFv-IL-12-aCD16 VHH. aFAP scFv-IL-12-aCD16 CART cells are generated by transducing T cells with alentivirus construct containing a BCMA CAR and aFAP scFv-IL-12- aCD16 STriKE.Figures 59A-59D. T cells were transduced with a lentiviral vector containing a CAR and FAP VHH-based STriKE construct or aFAP scFv-based STriKE construct to generate aFAP VHH-IL-12aCD16 VHH secreting CAR T cells or aFAP scFv-IL-12-aCD16 VHH secreting CAR T cells, respectively. Figure 59A) Histograms demonstrating CAR expression of the constructs. Figures 59B-59D) Secreted IL-12 STriKE and control protein binding to FAP+ cells (Figure 59B), macrophages (Figure 59C), and NK cells (Figure 59D) were confirmed via flow cytometry.Figures 60A-60B. CAR T cells (with or without secretion of phagocytosis-inducing molecules) killed antigen+ tumor cells. Figure 60A) CART cells secreting IL-12 STriKEs were tested in a luciferase-based killing assay with UTD, CAR-T alone, CAR-T secreting IL-12 or CAR T cells secreting IL-12 STriKEs molecules co-cultured with CAFs, TAMs, and cancer cells. Figure 60B) A luciferase-based cytotoxic assay was performed for UTD, CAR-T alone, CAR-T secreting IL- 12 or CAR T cells secreting IL-12 STriKEs molecules, which were each co-cultured with target cells for 24 hours and 48 hours.Figures 61 A-61B. CAR T cells secreting IL-12 STriKEs were co-cultured with differentiated MO macrophages (Figure 61A) or NK cells (Figure 61B). CAFs, and target cells for 72 hours. CART cell proliferation was assessed via flow cytometry by the number of CD3+ CD138- FSP-1- cells. ** P<0.01; *** P<0.001; and ****p<0.0001.DETAILED DESCRIPTIONThis document provides methods and materials for generating CAR T cells that (1) can express one or more CARs having the ability’ to bind a cancer-specific antigen and (2) can express (e.g., express and secrete) one or more cell engagers each having the ability to bind (i) an immunosuppressive cell of aTME and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. In some cases, a CAR T cell provided herein can be engineered to contain nucleic acid (e.g., exogenous nucleic acid)including (a) a nucleotide sequence encoding one or more CARs having the ability to bind a cancer-specific antigen and (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. For example, a CAR T cell can be engineered to contain nucleic acid (e.g., exogenous nucleic acid) that includes (a) a nucleotide sequence encoding one or more CARs having the abi li ty to bind a cancer-specific antigen and (b) a nucleotide sequence encoding a cell engager having the ability' to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME to generate a T cell that (1) can express one or more CARs having the ability to bind a cancer-specific antigen and (2) can express one or more cell engagers each having the ability to bind (i) an immunosuppressive cell of a TME and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME.The term "exogenous’' as used herein with reference to nucleic acid and a particular cell refers to any nucleic acid that does not originate from that particular cell as found in nature. Thus, all non-naturally-occurring nucleic acid is considered to be exogenous to a cell once introduced into the cell. It is important to note that non-naturally-occurring nucleic acid can contain nucleic acid sequences or fragments of nucleic acid sequences that are found in nature provided the nucleic acid as a whole does not exist in nature. For example, a nucleic acid molecule containing a genomic DNA sequence within an expression vector is non-naturally-occurring nucleic acid, and thus is exogenous to a cell once introduced into the cell, since that nucleic acid molecule as a whole (genomic DNA plus vector DNA) does not exist in nature. Thus, any vector, autonomously replicating plasmid, or virus (e.g., retrovirus, adenovirus, or herpes virus) that as a whole does not exist in nature is considered to be non-naturally -occurring nucleic acid. It follows that genomic DNA fragments produced by PCR or restriction endonuclease treatment as well as cDNAs are considered to be non-naturally-occurring nucleic acid since they exist as separate molecules not found in nature. It also follows that any nucleic acid containing a promoter sequence and polypeptide-encoding sequence (e.g., cDNA or genomic DNA) in an arrangement not found in nature is non-naturally -occurring nucleic acid. For example, a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and(2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can contain a nucleotide sequence encoding a CAR having the ability7to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME that originated from outside of the cell such as a nucleotide sequence from another organism and synthetic nucleotide sequence.A CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can be any appropriate T cell. AT cell can be a naive T cell. Examples of T cells that can be used to generate CAR T cells as described herein include, without limitation, cytotoxic T cells (e.g., CD4+CTLs and / or CD8+CTLs). In some cases, 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 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 CAR cell other than a CAR T cell. For example, the methods and materials provide herein can be used to generate a CAR+immune cell other than a T cell. Examples of cells that can be used to generate a 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 CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can express (e.g., constitutively express) any appropriate CAR having the ability to bind a cancer-specific antigen. A CAR that can be used to make a 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, anantigen-binding fragment (Fab), a variable region of an 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). When an antigen binding domain is a scFv, a VH of the scFv and a VL of the scFv can be directly-connected or can be connected via a linker (e.g.. a peptide linker).A CAR having the ability to bind a cancer-specific antigen and that can be used to make a CAR T cell described herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability- to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME) can bind any appropriate cancer-specific antigen. F or 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, w ithout limitation, B-cell maturation antigen (BCMA), 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, 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 BCMA polypeptide, also referred to as a BCMA-specific CAR. 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 CS1 polypeptide, also referred to as a CSl-specific CAR.In some cases, a BCMA-specific CAR provided herein 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: 107-108 (see, e.g., Example 2).In some cases, a BCMA-specific CAR provided herein can be designed to include a binding molecule (e.g.. an antigen binding domain) that includes at least one set of three CDRs (e g., CDR1, CDR2, and CDR3) of a binding molecule provided herein (e.g., SEQ ID NOs: 1-3 and / or 4-6). For example, a binding molecule of a CAR targeting a BCMA 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 alight chain) of an antigen binding fragment provided herein (e.g., SEQ ID NOs: 1-3 and 4-6). For example, an antigen binding domain of a CAR targeting a BCMA polypeptide can be designed to include a VH domain described herein or a scFv antibody described herein.In some cases, BCMA-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: 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, 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:4, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 5, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 6. In some cases, a CAR having the abi 1 i ty to bind to a BCMA polypeptide (e.g., a human BCMA polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 1 A.Table 1 A. Exemplary CDR sequences for a binding molecule that can bind a BCMA polypeptide.A CDR that can be included in a binding molecule (e.g., an antigen binding domain) of a CAR having the ability to bind to a BCMA polypeptide (e.g., a human BCMA polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs: 1-6 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: 1-6), has zero, one, tw o, three, four, or five amino acid residues preceding the articulated sequence of the sequence identifier (e.g., any one of SEQ ID NOs: 1-6), 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: 1-6), provided that the CAR retains the ability to bind to a BCMA polypeptide (e.g., a human BCMA polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain) of a CAR having the ability- to bind to a BCMA polypeptide (e.g., a human BCMA polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs: 1-3 and / or 4-6 can include an scFv having the sequence set forth in SEQ ID NO:7 or an scFv having the sequence set forth in SEQ ID NO: 8.In some cases, a CSl-specific CAR provided herein 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: 185-186 (see, e.g., Example 2).In some cases, a CSl-specific CAR provided herein can be designed to include a binding molecule (e.g.. an antigen binding domain) that includes at least one set of three CDRs (e.g., CDR1, CDR2, and CDR3) of a binding molecule provided herein (e.g., SEQ ID NOs: 187-189 and / or 190-192). For example, abinding molecule of a CAR targeting a CS1 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:187-189 and 190-192). For example, an antigen bindingdomain of a CAR targeting a CS1 polypeptide can be designed to include a VH domain described herein or a scFv antibody described herein.In some cases, CS 1 -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: 187, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 188, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 189, 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: 190, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 191, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 192. In some cases, a CAR having the ability to bind to 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 IB.Table IB. Exemplary CDR sequences for a binding molecule that can bind a CS1 polypeptide.A CDR that can be included in a binding molecule (e.g., an antigen binding domain) of a CAR having the ability to bind to a CS 1 polypeptide (e.g.. a human CS 1 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs: 187-192 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: 187-192), 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: 187-192), and / or has zero, one, two, three, four, or five amino acid residues following the articulatedsequence of the sequence identifier (e.g., any one of SEQ ID NOs: 187-192), provided that the CAR retains the ability to bind to a CS1 polypeptide (e.g., a human CS1 polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain) of a CAR having the ability to bind to a CS 1 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: 187-189 and / or 190-192 can include an scFv having the sequence set forth in SEQ ID NO: 193 or an scFv having the sequence set forth in SEQ ID NO: 194.In some cases, a CAR having the ability to bind a cancer-specific antigen (e.g., a BCMA-specific CAR or a CS 1 -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 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 / 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 BCMA-specific CAR or a CS1 -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 betw een 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 theplasma membrane. Examples of transmembrane domains that can be used as described herein include, without limitation, CD3L transmembrane domains, CD4 transmembrane domains, CD8 (e.g., a CD8a) 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] ,A CAR having the ability to bind a cancer-specific antigen (e.g., a BCMA-specific CAR or a CS1 -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 as described herein include, without limitation, BBζ signaling domains, 28ζ signaling domains, CD2 signaling domains, CD3ζ signaling domains, CD28 signaling domains, Toll-like receptor (TLR) signaling domains (e.g., TLR3 or TLR4 signaling domains), CD27 intracellular signaling domains, 0X40 (CD 134) intracellular signaling domains, 4-1BB (CD137) intracellular signaling domains, CD278 intracellular signaling domains, DAP 10 intracellular signaling domains, DAP 12 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, andCD40 intracellular signaling domains. In some cases, a CAR for use as described herein can be designed to be a first-generation CAR having a CD3ζ intracellular signaling domain. 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 CD3ζ intracellular signaling domain. In some cases, a CAR for use as described herein can be designed to be a third generation CAR having (a) a CD28 intracellular signaling domain followed by (b) a CD27 intracellular signaling domain, an 0X40 intracellular signaling domains, or a 4-1BB intracellular signaling domain followed by (c) a CD3ζ intracellular 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 a cancer-specific antigen can be as set forth in Table 2.Table 2. Exemplar)’ CARs having the ability to bind to a cancer-specific antigen.A CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability- to bind a cancer-specific antigen and (2) express a cell engager having the ability- to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can express (e.g., express and secrete) any appropriate one or more cell engagers each having the ability- to bind (i) an immunosuppressive cell of a TME and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. A cell engager that can be expressed by a CAR T cell provided herein can have the ability to link (i) an immunosuppressive cell of a TME and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME together. For example, a cell engager that can be expressed by a CAR T cell provided herein can include two or more (e.g., two, three, four or five) binding molecules where at least one binding molecule has the ability- to bind an immunosuppressive cell of a TME and where at least one binding molecule has the ability to bind an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. When such a cell engager links an immunosuppressive cell and an immune cell(e.g., an innate immune cell or an adaptive immune cell), the innate immune cell can be activated to target (e.g., target and destroy) the linked immunosuppressive cell.A cell engager that can be expressed (e.g., expressed and secreted) by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can be any appropriate type of molecule (e.g., a polypeptide). Examples of cell engagers that can be expressed by a CAR T cell provided herein include, without limitation, T cell engagers (e.g.. bi-specific T cells engagers (BiTEs) and tri-specific T cell engagers (tri-specific TCEs)), macrophage engagers (e.g., bispecific macrophage engagers (BiMEs) such as bispecific SIRPa engagers (BiSEs)), and NK cell engagers (e.g., bispecific NK cell engagers (BiKEs) and tri-specific NK engagers (TriKEs)).A cell engager that can be expressed (e.g., expressed and secreted) by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the abi 1 i ty to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can target (e.g., target and bind) any appropriate immunosuppressive cell of a TME. Examples of immunosuppressive cells that can be present in a TME and targeted by an engager include, without limitation, fibroblasts (e.g., cancer-associated fibroblasts), immunosuppressive macrophages, immunosuppressive monocytes, regulatory T cells, and gamma-delta T cells.A cell engager that can be expressed (e.g., expressed and secreted) by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include one or more binding molecules having the ability to bind a polypeptide present on an immunosuppressive cell of a TME. In some cases, a cell engager that can be expressed by a CAR T cell provided herein can include a binding molecule (e.g., an antigen binding domain) having the ability to bind to an antigen expressed by an immunosuppressive cell present in a TME. 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 a binding molecule in a cell engager that can be expressed by a CAR T cell provided herein include, without limitation, fibroblast activation protein (FAP) polypeptides (e.g., FAP-alpha (FAPa) polypeptides), CS1 polypeptides, and mesothelin polypeptides. For example, a cell engager that can be expressed by a CAR T cell provided herein can target a FAP+cell.In some cases, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include any appropriate binding molecule (e.g., any appropriate antigen binding domain) that can bind (e.g., specifically bind) to a FAP polypeptide (e.g., a human FAP polypeptide). A binding molecule that can bind a FAP polypeptide can also be referred to as an anti-FAP binding molecule. For example, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the 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: 109-110 (see, e.g., Example 5).In some cases, a binding molecule (e.g., an antigen binding domain) having the ability to bind a FAP polypeptide 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 binding molecule having the ability to bind a FAP polypeptide can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 3.Table 3. Exemplary CDR sequences for a binding molecule having the ability to bind a FAP poly peptide.A CDR that can be included in a binding molecule (e.g., an antigen binding domain of a cell engager) 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: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-ll), 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 binding molecule (e.g., cell engager) retains the ability to bind to a FAP polypeptide (e.g., a human FAP polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind 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:9-ll can include a heavy chain variable domain having the sequence set forth in SEQ ID NO: 12.In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a FAP polypeptide 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: 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. In some cases, a binding molecule having the ability to bind a FAP polypeptide can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 4.Table 4. Exemplary CDR sequences for a binding molecule having the ability to bind a FAP polypeptide.A CDR that can be included in a binding molecule (e.g., an antigen binding domain of a cell engager) 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: 13-15 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: 13-15), 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: 13-15), 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: 13-15), provided that the binding molecule (e.g., cell engager) retains the abi lity to bind to a FAP polypeptide (e.g., a human FAP polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain) having the ability to bind 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: 13-15 can include a heavy chain variable domain having the sequence set forth in SEQ ID NO: 16.In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) 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: 17, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 18, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO: 19, 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:20, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:21, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:22. When a binding molecule includes both a heavy chain variable domain and a light chain variable domain, the heavy chain variable domain and the light chain variable domain can be directly connected or can be connected via a linker (e.g., a peptide linker). In some cases, a binding molecule 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 5.Table 5. Exemplary CDR sequences for a binding molecule that can bind a FAP polypeptide.A binding molecule (e.g., an antigen binding domain of a cell engager) 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: 17-22 is a binding molecule 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: 17-22), 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: 17-22), 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: 17-22), provided that the binding molecule (e.g., cell engager) retains the ability’ to bind to a FAP polypeptide (e.g., a human FAP polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) 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: 17-19 and / or 20-22 can include, an scFv having the sequence set forth in SEQ ID NO:23 or an scFv having the sequence set forth in SEQ ID NO:24.A cell engager that can be expressed (e.g., expressed and secreted) by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can target (e.g., target and bind) any appropriate immune cell. In some cases, an immune cell can be an innate immune cell. In some cases, an immune cell can be an adaptive immune cell. Examples of immunecells that can be present in a TME and targeted by a cell engager include, without limitation, macrophages, NK cells, and T cells.A cell engager that can be expressed (e.g., expressed and secreted) by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include one or more binding molecules having the ability to bind a polypeptide present on an immunosuppressive cell of a TME. In some cases, a cell engager that can be expressed by a CAR T cell provided herein can include a binding molecule (e.g., a polypeptide) having the ability to bind to a receptor expressed by an immune cell (e.g., an innate immune cell or an adaptive immune cell) present in a TME. In some cases, a cell engager that can be expressed by a CAR T cell provided herein can include a binding molecule (e.g., an antigen binding domain) having the ability to bind to an antigen expressed by an immune cell (e.g., an innate immune cell or an adaptive immune cell) present in a TME. For example, such an antigen can be a cell surface antigen expressed by an immune cell present in a TME. In some cases, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME can target a macrophage present in a TME. In some cases, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can target a NK cell present in a TME. Examples of polypeptides that can be recognized by a binding molecule in a cell engager having the abi 1 ity to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME as described herein include, without limitation, Fc receptors, interleukin 15 (IL-15) receptors, SIRPa polypeptides, CD 16 polypeptides, Nkp30 polypeptides, NKG2D polypeptides, NKG3C polypeptides. nkp64 polypeptides, and siglec-10 polypeptides.In some cases, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include a polypeptide that can be targeted by a receptor (e.g., a surface receptor) present on an immune cell of a TME. A receptor (e.g., a surface receptor) present on an immune cell of a TME can target any appropriatepolypeptide. In some cases, a polypeptide that can be targeted by a receptor present on an immune cell of aTME can be a cytokine. In some cases, a polypeptide that can be targeted by a receptor present on an immune cell of a TME can be a chemokine.Examples of polypeptides that can be targeted by a receptor present on an immune cell of aTME include, without limitation, fragment crystallizable (Fc) region polypeptides, IL-15 polypeptides, IL-7 polypeptides, IL-2 polypeptides, IL-12 polypeptides, IL-18 polypeptides, and IL-21 polypeptides. In some cases, a polypeptide that can be targeted by a receptor present on an immune cell of a TME can be as described elsewhere (see, e.g., U. S. Patent Application Publication No. 2018 / 0282386).In some cases, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include a Fc region polypeptide. A Fc region polypeptide can be any appropriate Fc region polypeptide. For example, a Fc region polypeptide can have the amino acid sequence set forth in the National Center for Biotechnology Information (NCBI) databases at Accession Nos. BAG65283 (residues 242-473), BAC04226.1 (residues 247-478), BAC05014.1 (residues 240-471), CAC20454.1 (residues 99-320), BAC05016.1 (residues 238-469), BAC85350.1 (residues 243-474), BAC85529.1 (residues 244-475), and BAC85429.1 (residues (238-469), or the amino acid sequence set forth in The UniProt Knowledgebase (UniProtKB; see, e.g.. The UniProt Consortium, Nucleic Acids Research, 51(D1): D523-D531 (2023)) at accession nos. P0DOX5, P01859, P01861, P01860, P01857, and P01863. In some cases, a Fc region polypeptide can have the amino acid sequence set forth in SEQ ID NO:25. In some cases, a Fc region polypeptide can comprise, consist essentially of, or consist of the amino acid sequence set forth in SEQ ID NO:25. AFc region polypeptide that consists essentially of the amino acid sequence set forth in SEQ ID NO:25 is a polypeptide with one, two, three, four, five, six, seven, eight, nine, or ten amino acid deletions, additions, substitutions, or combinations thereof, as compared to the articulated sequence of SEQ ID NO:25, provided that the polypeptide retains the ability to bind to a Fc receptor polypeptide (e.g., a human Fc receptor polypeptide).In some cases, a cell engager having the ab i 1 i ty to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include an IL-15 polypeptide. An IL-15polypeptide can be any appropriate an IL-15 polypeptide. For example, an IL-15 polypeptide can have the amino acid sequence set forth in UniProtKB at accession nos. P40933, P40933, and P48346. In some cases, an IL-15 polypeptide can have the amino acid sequence set forth in SEQ ID NO:26. In some cases, an IL-15 polypeptide can be as shown in Example 7. In some cases, a Fc region polypeptide can comprise, consist essentially of, or consist of the amino acid sequence set forth in SEQ ID NO:26. A Fc region polypeptide that consists essentially of the amino acid sequence set forth in SEQ ID NO:26 is a polypeptide with one, two, three, four, five, six, seven, eight, nine, or ten amino acid deletions, additions, substitutions, or combinations thereof, as compared to the articulated sequence of SEQ ID NO:26, provided that the polypeptide (e.g., cell engager) retains the ability’ to bind to an IL- 15 receptor (e.g., a human IL- 15 receptor).In some cases, a cell engager having the ab i 1 i ty to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include any appropriate binding molecule (e.g.. any appropriate antigen binding domain) that can bind (e.g., specifically bind) to a SIRPa polypeptide (e.g., a human SIRPa polypeptide). A binding molecule that can bind a SIRPa polypeptide can also be referred to as an anti-SIRPa binding molecule. For example, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include a binding molecule 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: 111-112 (see, e.g., Example 12).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a SIRPa 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:27, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:28, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:29, 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: 30, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:31, and (iii) a CDR3 that comprises.consists essentially of. or consists of the amino acid sequence set forth in SEQ ID NO:32. In some cases, a binding molecule having the ability to bind a SIRPa polypeptide (e.g., a human SIRPa polypeptide) can include CDRs that comprise, consist essentially of, or consist of the CDR amino acid sequences set forth in Table 6.Table 6. Exemplary CDR sequences for a binding molecule that can bind a SIRPa polypeptide.A binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to a SIRPa polypeptide (e.g., a human SIRPa polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:27-32 is a binding molecule 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:27-32), 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:27-32), 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:27-32), provided that the binding molecule (e.g., cell engager) retains the abil ity to bind to a SIRPa polypeptide (e.g., a human SIRPa polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to a SIRPa polypeptide (e.g., a human SIRPa polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:27-29 and / or 30-32 can include, an scFv having the sequence set forth in SEQ ID NO:33 or an scFv having the sequence set forth in SEQ ID NO:34.In some cases, a cell engager having the ability' to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include any appropriate binding molecule (e.g.,any appropriate antigen binding domain) that can bind (e.g.. specifically bind) to a CD16 polypeptide (e.g., a human CD16 polypeptide). A binding molecule that can bind a CD16 polypeptide can also be referred to as an anti-CD16 binding molecule. For example, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME can include a binding molecule 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:113-115 (see, e.g., Example 15).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a CD 16 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:35, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:36, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:37. In some cases, a binding molecule having the abi lity to bind a CD16 polypeptide (e.g., a human CD16 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 a binding molecule that can bind a CD 16 polypeptide.A binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to a CD 16 polypeptide (e.g., a human CD 16 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:35-37 is a binding molecule 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:35-37), 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:35-37), and / or has zero, one, two, three, four, or five amino acid residues following the articulated sequence of the sequenceidentifier (e.g., any one of SEQ ID NOs:35-37), provided that the binding molecule (e.g., cell engager) retains the ability' to bind to a CD16 polypeptide (e.g., a human CD16 polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to a CD 16 polypeptide (e.g.. a human CD 16 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs: 35-37 can include a heavy chain variable domain having the sequence set forth in SEQ ID NO:38.In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a CD 16 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:39, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:40, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:41, 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:42, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:43, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:44. In some cases, a binding molecule having the ability to bind a CD16 polypeptide (e.g., a human CD16 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 a binding molecule that can bind a CD 16 polypeptide.A binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to a CD 16 polypeptide (e.g., a human CD 16 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:39-44 is a binding molecule 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:39-44), 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:39-44), 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:39-44), provided that the binding molecule (e.g., cell engager) retains the ability to bind to a CD16 polypeptide (e.g., a human CD16 polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to a CD 16 polypeptide (e.g., a human CD 16 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:39-41 and / or 42-44 can include, an scFv having the sequence set forth in SEQ ID NO:45 or an scFv having the sequence set forth in SEQ ID NO:46.In some cases, a cell engager having the ab i 1 i ty to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME can include any appropriate binding molecule (e.g., any appropriate antigen binding domain) that can bind (e.g., specifically bind) to aNkp30 polypeptide (e.g., a human Nkp30 polypeptide). A binding molecule that can bind a Nkp30 polypeptide can also be referred to as an anti-Nkp30 binding molecule. For example, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include a binding molecule 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: 113-115 (see, e.g., Example 15).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a Nkp30 polypeptide 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:47, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:48,and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:49. In some cases, a binding molecule (e.g., a cell engager) having the ability' to bind aNkp30 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 a binding molecule having the ability’ to bind a Nkp30 polypeptide.A CDR that can be included in a binding molecule (e.g.. an antigen binding domain of a cell engager) having the ability to bind to aNkp30 polypeptide (e.g., a human Nkp30 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:47-49 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:47-49), 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:47-49), 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:47-49), provided that the binding molecule (e.g., cell engager) retains the ability to bind to a Nkp30 polypeptide (e.g., a human Nkp30 polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a Nkp30 polypeptide (e.g., a human Nkp30 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:47-49 can include a heavy chain variable domain having the sequence set forth in SEQ ID NO:50.In some cases, a cell engager having the ability' to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include any appropriate binding molecule (e.g.. any appropriate antigen binding domain) that can bind (e.g., specifically bind) to a NKG2D polypeptide (e.g., a human NKG2D polypeptide). A binding molecule that can bind aNKG2D polypeptide can also be referred to as an anti-NKG2D binding molecule.For example, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include a binding molecule 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:113-115 (see, e.g.. Example 15).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a NKG2D polypeptide 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:51, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:52, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:53. In some cases, a binding molecule (e.g., a cell engager) having the ability to bind a NKG2D 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 a binding molecule having the ability to bind a NKG2D polypeptide.A CDR that can be included in a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to aNKG2D polypeptide (e.g., a human NKG2D polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:51-53 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:51-53), 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:51-53), 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:51-53), provided that the binding molecule (e.g., cell engager) retains the ability to bind to a NKG2D polypeptide (e.g., ahumanNKG2D polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engage) having the ability to bind aNKG2D polypeptide (e.g., a human NKG2D polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:51-53 can include aheavy chain variable domain having the sequence set forth in SEQ ID NO: 54.In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a NKG2D polypeptide 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:55, (ii) a CDR2 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:56, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:57. In some cases, a binding molecule (e.g., a cell engager) having the ability to bind a NKG2D poly peptide 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 a binding molecule having the ability to bind a NKG2D polypeptide.A CDR that can be included in a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to aNKG2D polypeptide (e.g., a human NKG2D polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:55-57 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:55-57), 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:55-57), 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:55-57), provided that the binding molecule (e.g., cell engager) retains the ability to bind to a NKG2D polypeptide (e.g., ahumanNKG2D polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a NKG2D polypeptide (e.g., a human NKG2D polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs: 55-57 can include a heavy chain variable domain having the sequence set forth in SEQ ID NO:58.In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME) can include one or more additional components. In some cases, a cell engager that can be expressed by a CAR T cell provided herein can include one or more molecules that can block a cellular anti-phagocytosis signal (e.g., can block CD47-SIRPa interactions). For example, a cell engager that can be expressed by a CAR T cell provided herein can include one or more molecules that can bind CD47. In some cases, a cell engager that can be expressed by a CAR T cell provided herein can include one or more signal peptides. For example, a cell engager that can be expressed by a CAR T cell provided herein can include one or more signal peptides to enhance secretion of the cell engager from the CAR T cell.In some cases, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME also can include a binding molecule (e.g., an antigen binding domain) that can bind (e.g., specifically bind) to a CD47 polypeptide (e.g., a human CD47 polypeptide). For example, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e g., an innate immune cell or an adaptive immune cell) of the TME also can include a binding molecule 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:116-119 (see, e.g., Example 9).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind a CD47 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:59, (ii) a CDR2 that comprises,consists essentially of. or consists of the amino acid sequence set forth in SEQ ID NO:60, and (iii) a CDR3 that comprises, consists essentially of, or consists of the amino acid sequence set forth in SEQ ID NO:61. In some cases, a binding molecule having the ability to bind a CD47 polypeptide (e.g., a human CD47 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 a binding molecule that can bind a CD47 polypeptide.A binding molecule (e.g., an antigen binding domain of a cell engager) having the ability' to bind to a CD47 polypeptide (e.g., a human CD47 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs:59-61 is a binding molecule 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:59-61), 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:59-61), 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:59-61), provided that the binding molecule (e.g., a cell engager) retains the ability' to bind to a CD47 polypeptide (e.g., a human CD47 polypeptide).In some cases, a binding molecule (e.g., an antigen binding domain of a cell engager) having the ability to bind to a CD47 polypeptide (e.g., a human CD47 polypeptide) that consists essentially of a CDR amino acid sequence set forth in any one of SEQ ID NOs: 59-61 can include a heavy chain variable domain having the sequence set forth in SEQ ID NO: 62.In some cases, a cell engager that be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancerspecific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or anadaptive immune cell) of the TME) can include a signal peptide. A signal peptide can be any appropriate signal peptide. Examples of signal peptides that can be included in a cell engager described herein include, without limitation, IgK leader sequences (e.g., murine IgK leader sequences), IL-15 leader sequences, IL-2 leader sequences, IgE leader sequences, and GM-CSF leader sequences. In some cases, a signal peptide can be as described elsewhere (see, e.g., International Patent Application Publication No. WO 2023 / 201288). In some cases, a signal peptide can be as shown in in Table 13. In some cases, a signal peptide can comprise, consist essentially of, or consist of the amino acid sequence set forth in any one of SEQ ID NOs: 195-211. A signal peptide that consists essentially of the amino acid sequence set forth in any one of SEQ ID NOs: 195-211 is a polypeptide with one, two. three, four, five, six, seven, eight, nine, or ten amino acid deletions, additions, substitutions, or combinations thereof, as compared to the articulated sequence (e.g., the sequence of any one of SEQ ID NOs: 195-211), provided that the signal peptide retains the ability to enhance secretion of the cell engager from the CAR T cell.In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL-12, followed by an anti-FAP binding molecule. For example, a cell engager that includes an anti-CD16a binding molecule, followed by an IL-12, followed by an anti-FAP binding molecule can have the amino acid sequence set forth in any one of SEQ ID NOs:247 or 249 (see, e.g., Example 19).In some cases, a cell engager having the ab i 1 i ty to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include an IL-12 polypeptide. An IL-12 polypeptide can be any appropriate an IL-12 polypeptide. For example, an IL-12 polypeptide can have the amino acid sequence set forth in UniProtKB at accession nos. P29459, P29460, or a heterodimer of P29459 and P29460. In some cases, an IL-12 polypeptide can have the amino acid sequence set forth in SEQ ID NO:251, 253, or 255. In some cases, an IL- 12 polypeptide can be as shown in Example 19.Table 13. Exemplary signal peptide sequences.In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include a peptide tag. A peptide tag can be any appropriate peptide tag. Examples of peptide tags that can be included in a cell engager described herein include, without limitation, histidine tags (e.g., polypeptides including 6 copies of a histidine (a 6X his tag), hemagglutinin (HA) tags, myc tags, mCherry tags, and fluorescent polypeptides (e.g., GFP, YFP, and RFP). In cases where a cell engager that can be expressed by a CAR T cell provided herein includes a peptide tag, the peptide tag can be present at the N-terminal end of the cell engager and / or the C-terminal end of the cell engager.In some cases, any two components of a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having theability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can be directly connected. For example, when a cell engager includes a binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME and a binding molecule having the ability to bind an immune cell of the TME. the binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME can be directly connected to the binding molecule having the ability to bind an immune cell of the TME. For example, when a cell engager includes a binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME, a polypeptide that can be targeted by a receptor (e.g., a surface receptor) present on an immune cell of a TME, and a binding molecule having the ability to bind an immune cell of the TME, the binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME can be directly connected to the polypeptide that can be targeted by a receptor present on an immune cell of a TME, and the polypeptide that can be targeted by a receptor present on an immune cell of a TME can be directly connected to the binding molecule having the ability to bind an immune cell of the TME.In some cases, any tw o components of a cell engager that can be expressed by a CAR T cell provided herein (e g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can be connected by a linker. For example, when a cell engager includes a binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME and a binding molecule having the ability to bind an immune cell of the TME, the binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME can be connected to the binding molecule having the ability to bind an immune cell of the TME via a linker. For example, when a cell engager includes a binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME, a polypeptide that can be targeted by a receptor (e.g., a surface receptor) present on an immune cell of a TME, and a binding molecule having the ability to bind an immune cell of the TME, the binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME can be connected to the polypeptide that can betargeted by a receptor present on an immune cell of a TME via linker, and / or the polypeptide that can be targeted by a receptor present on an immune cell of a TME can be connected to the binding molecule having the ability' to bind an immune cell of the TME via a linker. When a cell engager includes a first linker connecting binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME to the polypeptide that can be targeted by a receptor present on an immune cell of a TME and includes a second linker connecting the polypeptide that can be targeted by a receptor present on an immune cell of a TME to a binding molecule having the ability to bind an immune cell of the TME, the first linker and the second linker can be the same or can be different.Any appropriate linker can be used to connect any two components of a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability- to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME). In some cases, a linker can be a peptide linker. In some cases, a linker sequence that can be used to connect a binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME and a binding molecule having the ability to bind an immune cell of the TME can be as described elsewhere (see, e.g.. International Patent Application Publication No. WO 2023 / 201288). In some cases, a linker sequence that can be used to connect a binding molecule having the ability to bind a polypeptide present on an immunosuppressive cell of a TME and a binding molecule having the ability to bind an immune cell of the TME can be as set forth in Table 14.Table 14. Exemplary- signal peptide sequences.In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide. For example, a cell engager that includes an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide can have the sequence set forth in any one of SEQ ID NOs:63-66 (see, e.g., Example 8).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by a an IgK leader sequence, followed by an anti-CD47 binding molecule. For example, a cell engager that includes IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by a an IgK leader sequence, followed by an anti-CD47 binding molecule, can have the sequence set forth in SEQ ID NO:67 or SEQ ID NO:68 (see, e.g., Example 11).In some cases, a cell engager can that be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2Apolypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule. For example, a cell engager that includes an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule can have the sequence set forth in SEQ ID NO:69 or SEQ ID NO:70 (see, e.g., Example 11).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-SIRPa binding molecule. For example, a cell engager that includes an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-SIRPa binding molecule scFv can have the sequence set forth in any one of SEQ ID NOs:71-74 (see, e.g., Example 14).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL- 15, followed by an anti-FAP binding molecule. For example, a cell engager that includes an anti-CD16a binding molecule, followed by an IL-15, followed by an anti-FAP binding molecule can have the sequence set forth in any one of SEQ ID NOs:75-78 (see, e.g.. Example 17).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL-15, followed by an anti-CD16a binding molecule. For example, a cell engager that includes an anti-FAP binding molecule,followed by an IL- 15, followed by an anti-CD16a binding molecule can have the sequence set forth in SEQ ID NO:79 or SEQ ID NO:80 (see, e.g., Example 17).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule. For example, a cell engager that includes an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule can have the sequence set forth in any one of SEQ ID NOs:81-84 (see, e.g., Example 17).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule. For example, a cell engager that includes an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule can have the sequence set forth in any one of SEQ ID NOs:85-88 (see. e.g., Example 17).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an anti-FAP binding molecule. For example, a cell engager that includes an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an anti-FAP binding molecule can have the sequence set forth in any one of SEQ ID NOs:89-92 and 103-106 (see, e.g., Example 18).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-CD16a binding molecule. For example, a cell engager that includes an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-CD16a binding molecule can have the sequence set forth in any one of SEQ ID NOs:93-94 (see, e.g., Example 18).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an anti-FAP binding molecule. For example, a cell engager that includes an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an anti-FAP binding molecule can have the sequence set forth in any one of SEQ ID NOs:95-98 (see, e.g., Example 18).In some cases, a cell engager that can be expressed by a CAR T cell provided herein (e.g., a CAR T cell engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can include an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an anti-FAP binding molecule. For example, a cell engager that includes an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an anti-FAP binding molecule can have the sequence set forth in any one of SEQ ID NOs:99-102 (see, e.g.. Example 18).Also provided herein are nucleic acid sequences (e.g., nucleic acid constructs) that can be used to generate CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability' to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME). For example.nucleic acid sequences that contain (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can be used to a generate CAR T cells provided herein.A nucleic acid sequence provided herein (e.g., a nucleic acid sequence including (a) nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can be any appropriate type of nucleic acid sequence. In some cases, a nucleic acid sequence can be in the form of a construct such as a vector. For example, a nucleic acid construct can be in the form of 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 alentiviral vector or a retroviral vector.In some cases, a nucleic acid construct including (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include one or more regulatory elements operably linked to the nucleotide sequence encoding the CAR and / or the nucleotide sequence encoding the cell engager. For example, a viral vector having a genome (e.g.. a singlestranded or double-stranded DNA genome) including a nucleic acid sequence (e.g.. an engineered DNA sequence) including (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include one or more regulatory elements operably linked to the nucleotide sequence encoding the CAR. For example, a viral vector having a genome (e.g., a single-stranded or double-stranded DNA genome) including a nucleic acid sequence (e.g., an engineered DNA sequence) including (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engagerhaving the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can include one or more regulatory7elements operably linked to the nucleotide sequence encoding the cell engager. Such regulatory elements can include, without limitation, promoter sequences, enhancer sequences, response elements, signal peptides, translation initiation sites (e.g., Kozak sequences), internal ribosome entry sequences, polyadenylation signals, terminators, and inducible elements that modulate expression (e.g., transcription or translation) of a nucleic acid. The choice of regulatory element(s) that can be included in a viral vector provided herein (e.g., a viral vector designed to express (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can depend on several factors, including, without limitation, inducibility. targeting, and the level of expression desired. For example, a promoter can be included in a viral vector provided herein to facilitate transcription of (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. A promoter can be a naturally occurring promoter or a recombinant promoter. A promoter can be ubiquitous or inducible (e.g., in the presence of tetracycline), and can affect the expression of a nucleic acid encoding a polypeptide in a general or tissue-specific manner.The term "operably linked’7as used herein with respect to a regulatory element and (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability' to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME refers to positioning of the regulatory element relative to the nucleotide sequence encoding a CAR and / or the nucleotide sequence encoding the cell engager in such a way as to permit or facilitate expression of the CAR and / or the cell engager. For example, a viral vector provided herein (e.g., a viral vector designed to express (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engagerhaving the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can contain a promoter and a nucleotide sequence encoding a CAR having the ability' to bind a cancerspecific antigen. In this case, the promoter can be operably linked to the nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen such that it drives expression of the CAR in cells. Examples of promoters that can be used to drive expression of (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability’ to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME include, without limitation, EFla promoters and CMV promoters.In some cases, (a) a nucleotide sequence encoding a CAR having the ability' to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can be present one separate nucleic acid constructs (e.g., on separate viral vectors). For example, a first viral vector can have a genome (e.g., a single-stranded or double-stranded DNA genome) including a nucleotide sequence encoding a CAR having the ability to bind a cancerspecific antigen that is operably linked to a promoter, and a second viral vector can have a genome (e.g., a single-stranded or double-stranded DNA genome) including a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME that is operably linked to a promoter.In some cases, (a) a nucleotide sequence encoding a CAR having the ability' to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME can be present on the same nucleic acid construct (e.g., on the same viral vector). For example, a single viral vector can have a genome (e.g., a single-stranded or double-stranded DNA genome) including a nucleic acid sequence including a promoter operably linked to (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) animmunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME where the nucleotide sequence encoding the CAR polypeptide and the nucleotide sequence encoding the cell engager are separated by one or more features that allow for translation of two or more polypeptides from a single nucleic acid sequence (e.g., from a single messenger RNA (mRNA) transcript). Examples of features that allowing for translation of two or more polypeptides from a single nucleic acid sequence (e.g., from a single mRNA transcript) include, without limitation, nucleotide sequences encoding a 2A polypeptide (e.g., P2A polypeptides, T2A polypeptides. E2A polypeptides, and F2A polypeptides), internal ribosome entry sites (IRESs), and polypeptide cleavage sites (e.g., furin cleavage sites). In some cases, a single nucleic acid sequence can be used to translate two polypeptides. For example, a single nucleic acid sequence can include a nucleotide sequence encoding a first polypeptide and a nucleotide sequence encoding a second polypeptide, and the nucleotide sequence encoding the first polypeptide and the nucleotide sequence encoding the second polypeptide can be separated by a nucleotide sequence encoding a 2A polypeptide. In some cases, a single nucleic acid sequence can be used to translate three polypeptides. For example, a single nucleic acid sequence can include a nucleotide sequence encoding a first polypeptide, a nucleotide sequence encoding a second polypeptide, and a nucleotide sequence encoding a third polypeptide, where the nucleotide sequence encoding the first polypeptide and the nucleotide sequence encoding the second polypeptide can be separated by a first nucleotide sequence encoding a 2A polypeptide, and the nucleotide sequence encoding the second polypeptide and the nucleotide sequence encoding the third polypeptide can be separated by a second nucleotide sequence encoding a 2A polypeptide. In such cases, the first nucleotide sequence encoding a 2A polypeptide and the second nucleotide sequence encoding a 2A polypeptide can encode the same 2A polypeptide or different 2A polypeptides.In some cases, a single viral vector can have a genome (e.g., a single-stranded or double-stranded DNA genome) including a nucleic acid sequence including (a) a first promoter operably linked to a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and (b) a second promoter operably linked to a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or anadaptive immune cell) of the TME. In such cases, the first promoter and the second promoter can be the same promoter or can be different promoters. A promoter used to drive expression can be a constitutive promotor or a regulatable promotor. Examples of regulatable promoters that can be used as described herein include, without limitation, inducible promotors, repressible promotors, and tissue-specific promoters. Examples of viral promotors that can be used as described herein include, without limitation, EFla promoters and CMV promoters.In some cases, a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of a TME can be an inducible cell engager. In some cases, an inducible cell engager can be an expression-inducible cell engager. For example, a cell can include a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of s TME that is operably linked to a regulatable promotor (e.g.. an activation-dependent promoter, an inducible promotor, or a tissue-specific promoters) such that the cell engager is only expressed in the cell when the regulatable promoter is activated.In some cases, an inducible cell engager can be an activation-inducible cell engager. For example, a cell that can express a BCMA-specific CAR, can express a cell engager, and can express one or more response elements such that the cell engager is only expressed by the cell when the CAR(s) intracellular signaling domain(s) are activated (e.g., by binding to a BCMA polypeptide). For example, a cell that can express a CS1-specific CAR, can express a cell engager, and can express one or more response elements such that the cell engager is only expressed in the cell when the CAR(s) intracellular signaling domain(s) are activated (e.g., by binding to a CS1 polypeptide).Examples of systems that can be used to induce a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of a TME upon activation of a CAR include, without limitation, synthetic Notch (synNotch) receptors, TET-on systems, NFAT inducible systems, and GAL4 I upstream activation sequence (UAS) systems.Any appropriate method can be used to introduce (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) anucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME into a T cell to generate a CAR T cell provided herein. For example, a nucleic acid sequence provided herein (e.g., a nucleic acid sequence including (a) a nucleotide sequence encoding a CAR having the ability to bind a cancerspecific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) can be introduced into one or more T cells. Nucleic acid can be introduced in a T cell using any appropriate method. In some cases, nucleic acid can be 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 including a nucleic acid sequence containing (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. In cases where T cells are engineered ex vivo to contain (a) a nucleotide sequence encoding a CAR having the ability’ to bind a cancer-specific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME, 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, nucleic acid designed to produce and release a viral vector (e.g., a lentiviral vector or a retroviral vector) in vivo that contains (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME, that can infect T cells in vivo, that can be replicationdefective within infected T cells, and that can drive expression of the CAR and the cell engager within infected T cells can be introduced into a T cell to generate a CAR T cell provided herein within a mammal (e.g., a human). For example, viral vectors (e.g..modified lentiviral vectors, modified adeno-associated virus vectors, or measles virus vectors) can be designed to produce and release a viral vector (e.g., a lentiviral vector or a retroviral vector) that contains (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e g., an innate immune cell or an adaptive immune cell) of the TME in vivo, and can be used to generate a CAR T cell provided herein within a mammal (e.g., a human). For example, lipid nanoparticles (LNPs) can be designed to produce and release a viral vector (e.g., a lentiviral vector or a retroviral vector) that contains (a) a nucleotide sequence encoding a CAR having the ability to bind a cancer-specific antigen and (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME in vivo, and can be used to generate a CAR T cell provided herein within a mammal (e.g., a human).In some cases, a CAR T cell provided herein (e g., a CAR T cell engineered to (1) express a CAR having the ability' to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME) can be stimulated. In some cases, a T cell can be stimulated at the same time as being engineered to include (a) a nucleotide sequence encoding a CAR having the ability to bind a cancerspecific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability’ to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. 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 nucleotide sequence encoding a CAR having the ability to bind a cancerspecific antigen and / or (b) a nucleotide sequence encoding a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME second, or vice versa. AT 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, polypeptides that can bind a CD3 polypeptide (e.g., anti-CD3 antibodies), polypeptides that can bind a CD28 polypeptide(e.g., anti-CD28 antibodies), polypeptides that can bind a41BB polypeptide (e.g., anti-41BB antibodies), polypeptides that can bind aCD27 polypeptide (e.g., anti-CD27 antibodies), polypeptides that can bind a CD2 polypeptide (e.g., anti-CD2 antibodies), and ICOS polypeptides.This document also provides methods and materials for treating cancer. For example, CART cells provided herein (e g., CART cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) 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, CAR T cells provided herein can be used in an adoptive cell therapy to treat a mammal (e.g., a human) having cancer. For example, nucleic acid designed to generate CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) in vivo can be administered to a mammal (e.g., a human) having cancer to treat the mammal.In some cases, CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the abi 1 i ty to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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 CAR T cells provided herein (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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 CAR T cells provided herein (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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, CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the abi 1 i ty to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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 CAR T cells provided herein (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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 CAR T cells provided herein (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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 CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) 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. For example, from about 100,000 to about 10,000.000,000 CAR T cells provided herein (e.g., from about 100,000 to about 1,000,000.000. from about 100,000 to about 500,000.000, from about 100,000 to about 100,000,000, from about 100,000 to about 500,000, from about 100,000 to about 250,000, from about 250,000 to about 10,000,000,000, from about 500,000 to about 10,000,000,000, from about 1,000,000 to about 10,000,000,000, from about 100,000,000 to about 10,000,000,000. from about 100,000 to about 500,000,000.from about 250,000 to about 1,000,000,000, from about 500,000 to about 500,000,000, from about 1,000,000 to about 100,000,000, from about 250,000 to about 1,000,000, from about 500,000 to about 10,000,000, from about 1,000,000 to about 500,000,000, or from about 10,000,000 to about 1,000,000,000 CAR T cells provided herein) can be administered to a mammal having cancer to treat the mammal.Any appropriate amount of nucleic acid designed to generate CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) in vivo can be administered 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 CAR T cells provided herein (e.g., T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME) in, for example, an adoptive T cell therapy such as a CAR T cell therapy using the methods and materials described herein. For example, a human having a cancer can be treated with nucleic acid designed to generate CAR T cells provided herein in vivo 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, multiple myelomas, pancreatic cancers, breast cancers, and leukemias. For example, cancer including one or more BCMA+cancer cells can be treated as described herein. For example, cancer including one or more FAP+cells in the cancer TME can be treated as described herein.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, CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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 CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e g., an innate immune cell or an adaptive immune cell) of the TME) and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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 CAR T cells provided herein (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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-Ll 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.In cases where CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability’ to bind a cancer-specific antigen and (2) express a cell engager having the ability to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME) and / or nucleic acid designed to generate CAR T cells provided herein in vivo 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 CAR T cells provided herein (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) and containing the one or more additional agents) or independently. For example, a composition including 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 CAR T cells provided herein (e.g., CAR T cells engineered to (1) express a CAR having the ability to bind a cancerspecific antigen and (2) express a cell engager having the ability' to bind both (i) an immunosuppressive cell and (ii) an immune cell (e.g.. an innate immune cell or an adaptive immune cell) of the TME) and / or nucleic acid designed to generate CAR T cells provided herein in vivo, 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 CAR T cells provided herein (and / or nucleic acid designed to generate CAR T cells provided herein in vivo) 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 CAR T cells provided herein. For example, CAR T cells providedherein 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.EXAMPLESExample 1: CAR T cells engineered to target cells in a tumor microenvironment This Example describes the design and generation of CAR T cells that can secrete one or more cell engagers having the ability to bind (i) an immunosuppressive cell of a TME and (ii) an immune cell (e.g., an innate immune cell or an adaptive immune cell) of the TME. The cell engager(s) can activate innate immune cells and / or adaptive immune cells (e g., macrophages or natural killer cells) to kill immunosuppressive cells (e.g., cancer-associated fibroblasts) within the TME. For example, cell engagers can be phagocytosis -inducing molecules that can activate innate immune cells and / or adaptive immune cells (e.g., macrophages or natural killer cells) to kill immunosuppressive cells (e.g., cancer associated fibroblasts (CAFs)) in the TME.METHODSCell linesMultiple myeloma (MM) cell line MMES and fibroblast cell line WI38 were purchased from ATCC, Manassas, VA, USA. MM cell line OPM-2 was purchased from DSMZ, (Braunschweig, Germany.) Where indicated, these cell lines were transduced with a luciferase-ZsGreen lentivirus (Addgene, Cambridge, MA, USA), and sorted to 100% purity. WI38 cells were cultured in DIO medium made with Dulbecco’s Modified Eagle Medium (DMEM) (Gibco, Gaithersburg, MD, USA), 10% fetal bovine serum (FBS, Sigma, St. Louis, MO, USA), and 1% penicillin-streptomycin-glutamine (Gibco, Gaithersburg, MD, USA). MM cell lines OPM-2 and MM1. S were cultured in RIO medium made with Roswell Park Memorial Institute (RPMI) 1640 (Gibco, Gaithersburg. MD, USA), 10% fetal bovine serum (FBS, Sigma, St. Louis, MO, USA), and 1% penicillin-streptomycin-glutamine (Gibco, Gaithersburg, MD, USA). HEK293F cells were cultured in HyCell™ TransFx media supplemented with 2.5 mL 100X penicillin-streptomycin, 20 mL glutamine (200 mM stock), and 7 mL Pluronic F-68 (10%) added to a 1 -liter bottle.Flow cytometric analysis of B-cell maturation antigen (BCMA) expression on MM1. S and OPM-2 cells showed similar patterns. All the cell lines used regularly tested negative for mycoplasma contamination throughout the whole duration of this study.Generation of CAR constructsTransgenes for all constructs (CAR constructs and secreted polypeptide constructs) were designed in SnapGene (Version 7.1). After synthesizing, the constructs were cloned into a lentiviral plasmid backbone regulated by a human EF-1 a promoter (Genscript). Each CAR construct contained a CD8 hinge domain, a CD8 transmembrane domain, a 41BB or a CD28 co-stimulatory domain, and an intracellular CD3^ signaling domain. Secreted polypeptide sequences were designed with an IgK leader, an scFv (single-chain variable fragment) or a VHH (variable heavy heavy) against either FAP, CS1, or mesothelin, followed (optionally) by a wildtype TL-15 molecule, and lastly a CD16 VHH linked to a His-tag. The scFvs and VHHs against human / murine FAP were generated using phage display (Biomolecular Discovery.)CAR T-cell productionPeripheral blood mononuclear cells (PBMC) were isolated from de-identified normal donor blood apheresis cones obtained using SepMate tubes (STEMCELL Technologies, Vancouver, Canada). T cells were separated by negative selection magnetic beads using the EasySepTM Human T Cell Isolation Kit (STEMCELL Technologies). T cells isolated from the normal donors were stimulated using cell therapy systems dynabeads CD3 / CD28 (Life Technologies, Oslo, Norway) at a 1:3 ratio (cells: beads). The cells were transduced for 24 hours after stimulation with lentivirus particles at a multiplicity of infection (MOI) of 3.0. Magnetic bead removal and the evaluation of CAR expression on the T cells were performed by flow cytometry on day 6. CAR T cells were harvested and cryopreserved on day 8 for future experiments. CAR T cells were thawed and rested in the T cell culture medium 6-12 hours prior to use, as specified in each experiment.Protein PurificationHEK293F cells were transduced with the respective CAR constructs and cultured in HyCell™ TransFx media supplemented with 2.5 mL 100X penicillin-streptomycin, 20 mL glutamine (200 mM stock), and 7 mL pluronic F-68 (10%) (added to a IL bottle) until there were 5 million cells / mL. Supernatants were collected and incubated with HisPur Ni-NTA Resin (Thermo Fisher Scientific) for 2 hours at 4 °C under gentle agitation. The supernatant-resin mixture was then washed with Ni-NTA wash buffer (50 mM Tris pH 8.0, 500 mM NaCl, 5% glycerol, and 25 mM imidazole). His-tag polypeptides were eluted in Ni-NTA elution buffer (50 mM Tris pH 8.0, 500 mM NaCl, 5% glycerol, and 250 mM imidazole). The eluted polypeptides were further purified with size exclusion chromatography on a SuperDex 75 column run in PBS. Endotoxin removal was performed by extensive washing of the column-bound materials with endotoxin-free PBS and 0.1% TritonXl 14. The polypeptides were further concentrated using Amicon Ultra- 15 Centrifugal Filter Units (EMD Millipore).Western BlottingThe polypeptide samples from CAR T cell supernatant or HEK293F cells were separated by SDS-PAGE in Mini-PROTEAN TGX Precast Protein Gels at 4-20% (BioRad). The polypeptides were transferred to nitrocellulose membranes (ThermoFisher Scientific) and blocked in a blocking buffer composed of 1: 10 10x Tris-buffered saline and 1: 1,000 Tw een 20 (Bio-Rad) with 5% bovine serum albumin (Sigma- Aldrich). The membranes were probed with an anti-His-tag antibody (1:2,500, Clone 3D5, Invitrogen) overnight at 4 °C. Following overnight incubation with primary antibody, membranes were washed with Tris-buffered saline Tw een 20 (TBST) three times for 10 minutes and incubated with horseradish peroxi dase-conjugated goat anti-mouse IgG antibody (1:2,000, Cell Signaling Technology) for 1 hour at room temperature. Bands were detected with Pierce ECL Western Blotting Substrate on an iBright CL1000 Imaging System (ThermoFisher Scientific). Band intensities were quantified using Invitrogen iBright Analysis Software.Protein Binding AssaysTo test whether secreted polypeptides bind to their target cells, 2pg of purified polypeptides were incubated with target cells (WI38 cells, macrophages, monocytes, NK cells, or T cells) expressing appropriate antigens for 30 minutes at room temperature. The cells were then washed and stained with APC-conjugated His-tag antibodies and live / dead fixable aqua dead cell stain kit (Invitrogen, Carlsbad, CA). Cells with or without bound proteins were analyzed by flow cytometry.Flow CytometryAnti-human antibodies were purchased from Biolegend. R& D Systems. eBioscience, or BD Biosciences (San Diego, CA, USA). Sample preparation for flow cytometry was performed as described elsewhere (see, e.g., PCT Publication No:WO / 2023 / 107898). CountBright™ beads (Invitrogen, Carlsbad, CA, USA) were used for cell number quantitation, as described elsewhere (see, e g., PCT Publication No:WO / 2023 / 107898). Human BCMA / TNFRSF17 polypeptides conjugated to FITC (BCA-HF254-25UG, ACRO Biosysytems, Newark, DE) were used to detect the expression of BCMA-specific CARs. The following antibodies were also used: CD3 (clone UCHT1) APC (cat# 17-0038-42, eBiosciences, San Diego, CA, USA), and CD3 (clone OKT3) Brilliant Violet 650 (cat# 317324, BioLegend. San Diego. CA, USA), CD107a (clone H4A3) FITC (cat# 555800, BD Pharmingen, San Diego, CA, USA), BCMA (clone 19F2) PE-Cy7 (cat# 357507, BioLegend, San Diego, CA, USA), and BCMA (clone 19F2) PE (cat# 357504, BioLegend, San Diego, CA, USA), FAP (clone 427819) PE (cat# FAB3715P-025, R& D Systems, Minneapolis, MN, USA) and FAP (Clone 427819) AF700 (cat# FAB3715N-100UG, R& D Systems, Eugene. OR, USA), CD69 (clone FN50) Brilliant Violet 785 (cat# 310932, BioLegend, San Diego, CA, USA), CD25 (clone BC96) Brilliant Violet 605 (cat# 302631, BioLegend, San Diego, CA, USA), IFN-y (clone 4S. B3) Brilliant Violet 421 (cat# 502532, BioLegend, San Diego, CA, USA), CD56 (clone HCD56) PE (cat# 318306, BioLegend. San Diego, CA, USA), CD8 (clone SKI) Alexa Fluor" 700 (cat# 344724, BioLegend, San Diego, CA, USA), His tag (Clone # ADI.1.10) APC (Catalog #: IC050A, R& D Systems, Eugene, OR, USA), anti-HA. ll epitope tag (clone 16B12) Brilliant Violet 421 (cat# 682405, BioLegend, San Diego, CA, USA), CD206 (clone 15-2) Alexa Fluor® 700 (cat# 321132. BioLegend, San Diego, CA, USA), CD163 (clone GH1 / 63) APC / Cyanine7 (cat# 333622, BioLegend, San Diego, CA,USA), CD14 (clone 63D3) FITC (cat# 367116, BioLegend. San Diego. CA, USA), and CD86 (clone BU63) PE (cat# 374206, BioLegend, San Diego, CA, USA).Flow cytometry was performed on a three-laser CytoFLEX (Beckman Coulter, Chaska, MN, USA). All analyses were performed using FlowJo X10.0.7r2 software (Ashland, OR, USA).Luciferase killing assayCAR T cells or UTD were co-incubated with the innate immune cells (NK, macrophage, or monocyte) and target cells that express click beetle green (CBG) luciferase at varying effectortarget (E: T) ratios. For killing assays, the FAP+WI38 luciferase cell line or the BCMA+luciferase+MM cell line OPM-2 or MM1. S cell lines were used.Luciferase+control target cells were incubated at the indicated ratios with effector T cells for 24, 48, or 72 hours as indicated in the specific experiment. Killing was measured by bioluminescence imaging (BLI) on aXenogen TVIS-200 Spectrum camera (PerkinElmer, Hopkinton, MA) as a measure of residual live cells. For killing experiments, samples were treated with 1 pL of d-luciferin (30 pg / mL) per 100 pL sample volume (Gold Biotechnology’, St. Louis, MO) for 10 minutes before imaging.Proliferation assaysFor proliferation assays, innate immune cells (NK cells, monocytes, or macrophages) were labeled with carboxyfluorescein diacetate succinimidyl ester (Life Technologies) and were co-cultured with CAR T cells and the target cells (WI38 cells. OPM-2 cells, or MM1. S cells) at the indicated ratios. Cells were co-cultured for 3 or 5 days, and then were harvested and stained.For NK cell experiments, cells were stained with CD3 (clone UCHT1) APC (eBiosciences, San Diego, CA, USA), CD56 (clone HCD56) PE (BioLegend. San Diego, CA, USA), CD8 (clone SKI) Alexa Fluor* 700 (cat# 344724, BioLegend, San Diego, CA, USA), and live / dead fixable aqua dead cell stain kit (Invitrogen, Carlsbad, CA). IL-15 or phorbol myristate acetate, and ionomycin (MilliporeSigma, Burlington, MA) were used as positive nonspecific stimulants of T cells and NK cells at different concentrations, as indicated in the specific experiments. NK alone or co-culture conditions without CART cells were used as negative controls to demonstrate the innate immune cell activity without stimulation. CAR T cells cultured in medium were used as a negative control to measure non-specific CAR T activation. NK cells and T cells were identified as LiveDead CD56 CD3 and LiveDead CD56 CD3 cells, respectively.For monocyte and macrophage proliferation assays, cells were stained with CD3 (clone UCHT1) APC (eBiosciences, San Diego, CA, USA), CD163 (clone GHI / 63) APC / Cyanine7 (BioLegend, San Diego, CA, USA), and CD14 (clone 63D3) FITC (BioLegend, San Diego, CA, USA). T cells were identified as LiveDead CD 163’CD 14‘ CD3; monocytes and macrophages were identified as LiveDead CDI4 CD3 cells and LiveDead CD I4 CD 163 CD3' cells, respectively. Lipopolysaccharide (LPS) (MilliporeSigma, Burlington, MA) was used as a positive nonspecific stimulant of monocytes and macrophages and phorbol myristate acetate and ionomycin (MilliporeSigma. Burlington, MA) were used as positive nonspecific stimulants of T cells at different concentrations as indicated in the specific experiments.Activation and polarization assaysInnate immune cells (NK cells, monocytes, or macrophages) were labeled with carboxy fluorescein diacetate succinimidyl ester (Life Technologies) and cocultured with CAR T cells and target cells (WI38 cells, OPM-2 cells, or MM1. S cells) at the indicated ratios for 3 and 5 days.NK cell co-cultures w ere stained with CD3 (clone UCHT1) APC (eBiosciences, San Diego, CA, USA), CD56 (clone HCD56) PE (BioLegend, San Diego, CA, USA), CD69 (clone FN50) Brilliant Violet 785 (BioLegend, San Diego, CA, USA), and CD25 (clone BC96) Brilliant Violet 605 (BioLegend, San Diego, CA, USA). Live / dead fixable aqua dead cell staining kit (Invitrogen, Carlsbad, CA) was used to evaluate the expression of T cell and NK-cell activation marker using flow' cytometry.Monocyte or macrophage cell co-cultures were stained with CD3 (clone UCHT1) APC (eBiosciences, San Diego, CA, USA), CD206 (clone 15-2) Alexa Fluor" 700 (cat# 321132, BioLegend, San Diego, CA, USA), CD163 (clone GHI / 63) APC / Cyanme7 (BioLegend, San Diego, CA, USA), CD14 (clone 63D3) FITC (BioLegend, San Diego, CA, USA), and CD86 (clone BU63) PE (BioLegend, San Diego, CA. USA). Live / deadfixable aqua dead cell staining kit (In vitrogen. Carlsbad, CA) was used to evaluate the polarization states of the macrophages and the monocytes.Degranulation AssaysNK cells were co-cultured with CAR T cells secreting polypeptides or with purified polypeptides alone (no CAR T cells) and target cells (WI38 cells, OPM-2 cells, or MM 1. S cells) at an effector / target ratio of 2: 1: 1 (without CAR T or MM cell lines) and 2: 1:1:1 (with MM cell lines and CAR T cells). Cells were stained with FITC-conjugated anti-CD107a (H4A3. BioLegend) at the beginning of a 4-hour incubation. One hour after the addition of anti-CD107a, cells were incubated with golgi stop (1:1,500) and golgi plug (1: 1,000; both from BD Biosciences) for 3 hours. Cells were then stained with the live / dead fixable aqua staining kit (catalog no.: L-34966, Thermo Fisher Scientific), anti-CD56, and anti-CD3. The cells were fixed in 2% paraformaldehyde (Thermo Fisher Scientific) and permeabilized (eBioscience permeabilization medium). The permeabilized cells were stained with BV421 -conjugated IFNy (4S. B3, BioLegend) and evaluated using a flow cytometry7on a three-laser CytoFLEX (Beckman Coulter, Chaska, MN, USA). All analyses were performed using FlowJo X10.0.7r2 software (Ashland, OR, USA).RESULTSMolecules targeting immunosuppressive TME cells that bind Fc receptors and induce phagocytosisCAR-T cells capable of secreting CAF-targeting, innate immune cell activating molecules were generated. These secreted proteins included a VHHFc, a VHHFc and CD47 or SIRPa VHH, or a bispecific macrophage / monocyte engager (BiME) composed of a VHH linked to an scFv. VHHs are single-domain antibody fragments (variable heavy domain of heavy chain antibodies (VHH)) and VHHFcs are fusion proteins comprised of an antibody Fc domains connected to a VHH (Figures 1, 2A, and 2B.) In the design, the VHH portion of the secreted proteins targeted fibroblast activation protein (FAP), which is highly expressed on cancer associated fibroblasts, hereafter referred to as CAFs (Figures 2A and 4A). The Fc portions of VHHFcs bound to Fc-receptors on innate immune cells including monocytes, macrophages, NK cells (Figures 2B, 4A, 4B, and 4D). VHHFcs w ere also engineered to be co-secreted with VHH molecules targetingeither CD47 or SIRPa (Figures 4B-4D). CD47 is an antigen that is highly expressed by cancer cells and is known to inhibit phagocytosis in the TME (Figure 4B.) SIRPa is a ligand of CD47 that is expressed on myeloid cells in the TME. Binding of SIRPa and CD47 results in inhibition of macrophage phagocytosis (Figure 4A). In the BiME molecules, the VHH portion targeted FAP and the scFv portion targeted SIRPa (Figure 4C). VHH domains against mCherry served as a negative control (Figures 18, 19B, and 19C).Lentiviral vectors used for the generation of CART cells were comprised of a CDS signal sequence followed by a CAR scFv connected to a hinge and a transmembrane domain linked to a 4-1BB and CD3 intracellular signaling domains (Figures 5, 6, and 16). For secreting CART cells, aP2A, IRES, or separate cytomegalovirus (CMV) construct followed the CD3^ activation domain, and these were linked to a secretory signal sequence (e.g., IgK) to drive secretion of the VHHFc, VHHFc + VHH, or BiMEs. All secreted proteins contained a polyhistidine-tag (His-tag) or HA tag at the C termini to allow for subsequent detection and purification of secreted proteins (Figure 6). The entire multicistronic transgene, including sequences encoding the secreted proteins, was placed under the control of an EFlalpha promoter (Figure 6). Control CART cells lacking secreted proteins consisted of the same backbone as well as the same CAR architecture. To induce CAR expression and protein secretion, primary human T cells were transduced with lentiviral vectors encoding the multicistronic transgene. Efficient transduction of lentiviral vectors into primary human T cells was determined using How cytometric detection of CARs (Figure 9).Supernatants from cells secreting or not secreting proteins were collected and incubated with HisPur Ni-NTA resins (Thermo Fisher Scientific). The supernatant-resin mixture w as then washed with Ni-NTA wash buffer (10 mM imidazole in PBS). His-tag proteins were then eluted in Ni-NTA elution buffer (350 mM NaCl, 350 mM imidazole in PBS). Eluted proteins were further purified with size exclusion chromatography on a SuperDex 75 or 200 column run in PBS (Figures 7A-7C). The quantity of VHHFc, VHH, or BiME produced was approximated using A260 / A280 values on a nanodrop post-SEC purification (Figure 8A).Next, expression of FAP on wildtype (UTD) and GFP+WI-38 cells was confirmed (Figure 39), SIRPa and FcyRIll (CD16) expression on monocytes andmacrophages (Figures 35 and 36A), and CD47 on tumor cells (Figure 38). Secreted VHHFcs, VHHs, and BiMEs from transduced primary human T cells bound specifically to cells expressing the appropriate cognate antigen or target (Figure 8B and 8C).The ability of CAR-T cells secreting proteins to lyse target cancer cells compared to non-secreting control CAR-T cells was then evaluated. CAR-T cells secreting proteins showed equal cell-lysis capacity compared to their non-secreting counterparts, which confirmed that addition of a secreted protein into the lentiviral construct did not impair CAR function (Figures 10A and 10B). The capacity of the secreted proteins to induce innate immune cell activation and parallel killing of CAFs alongside CAR-T cell killing of tumor cells was also assessed. Following coculture of tumor cells, CAR-T cells, M2-like macrophages and FAP+WI-38 cells, it was found that CAR-T cells secreting proteins induced greater macrophage expansion compared to non-secreting CAR-T cells or UTD T cells (Figure 12). CAR-T cells secreting proteins also demonstrated a reduction of M2-like macrophage markers CD163 and CD206 (Figure 13) and an increase in the Ml-like macrophage markers, CD86 (Figure 14.) CAR-T cells secreting both VHHFcs and anti-CD47 VHH molecules exhibited the greatest reduction of macrophages bearing M2-like markers (Figure 13) while BiME or VHHFc secreting CAR-T cells showed the greatest increase in CD86 expression (Figure 14). It was also shown that secreted VHHFcs induced increased NK cell activation, as measured by CD25 and CD69 expression (Figure 28).Molecules targeting immunosuppressive TME cells that bind CD16a and activating cytokine / chemokine receptorsCAR-T cells capable of secreting CAF-targeting, innate immune cell activating molecules were generated. These secreted proteins included STriKEs with either an anti-FAP scFv or VHH, BiSEs, and SiNEs. In this design, one VHH or scFv portion of the secreted proteins target fibroblast activation protein (FAP), which is highly expressed on cancer associated fibroblasts, hereafter referred to as CAFs (Figure 15B). The anti-CD16a VHH, anti-NKG2D, anti-NKP30, anti-NKP33, and / or IL-15 (interchangeable with other activating cytokines) portions of these molecules bind to activating receptors and cytokine receptors on innate immune cells including monocytes, macrophages, and NK cells (Figures 15A, 15B, and 16). Secreted wildtype IL-15 and secreted VHH domains against mCherry served as controls (Figures 16, 18, 19B, and 19C).Lentiviral vectors used for the generation of CART cells were comprised of a CD8 signal sequence followed by a CAR scFv connected to a hinge and a transmembrane domain linked to a 4-1BB and CD3^ intracellular signaling domains (Figure 16). For secreting CART cells, a P2A, IRES, or separate cytomegalovirus (CMV) construct followed the CD3^ activation domain, and these were linked to an secretory signal sequence (e.g., IgK) to drive secretion of the STriKEs, BiSEs, or SiNEs. All secreted proteins contained a His-tag or HA tag at the C termini to allow for subsequent detection and purification of secreted proteins (Figure 16. The entire multicistronic transgene, including sequences encoding the secreted proteins, was placed under the control of an EFl alpha promoter (Figure 16). Control CART cells lacking secreted proteins consisted of the same backbone as well as the same CAR architecture (Figure 16). To induce CAR expression and protein secretion, primary human T cells were transduced with lentiviral vectors encoding the multicistronic transgene. Efficient transduction of lentiviral vectors into primary human T cells was determined using flow cytometric detection of CARs (Figures 18 and 27).Supernatants from cells secreting or not secreting proteins were collected and incubated with HisPur Ni-NTA resins (Thermo Fisher Scientific). The supernatant-resin mixture was then washed with Ni-NTA wash buffer (10 mM imidazole in PBS). His-tag proteins were then eluted in Ni-NTA elution buffer (350 mM NaCL 350 mM imidazole in PBS). Eluted proteins were further purified with size exclusion chromatography on a SuperDex 75 or 200 column run in PBS (Figures 17A and 17B). The quantity of STriKEs, BiSEs, or SiNEs produced was approximated using A260 / A280 values on a nanodrop post-SEC purification (Figure 19A.)Next, expression of FAP on wildtype (UTD) and GFP+WI-38 cells (Figure 39) and expression of IL-15 receptors and FcyRIII (CD16a) on NK cells, monocytes, and macrophages (Figures 36 and 37) was confirmed. Secreted STriKEs, BiSEs, or SiNEs from transduced primary human T cells bound specifically to cells expressing the appropriate cognate antigen or target (Figures 19B and 19C).The ability of CAR-T cells secreting proteins to lyse target cancer cells compared to non-secreting control CAR-T cells was then evaluated. CAR-T cells secreting proteins showed equal cell-lysis capacity compared to their non-secreting counterparts, which confirmed that addition of a secreted protein into the lentiviral construct does not notablyimpair CAR function (Figures 20A and 20B). The capacity of the secreted proteins to induce innate immune cell activation and parallel killing of CAFs alongside CAR-T cell killing of tumor cells was also assessed. Following coculture of CAR-T cells, luciferase FAP+WI-38 cells, and NK it was found that CAR-T cells secreting STriKEs, BiSEs, or SiNEs induced killing of FAP+WI-38 cells (Figure 20C). This killing was abrogated when either NK cells or secreted proteins were absent, suggesting that the killing of FAP+targets was dependent on NK cell exposure to secreted proteins (Figure 20C). Following coculture of CAR-T cells, NK and FAP+WI-38 cells, it was found that CAR-T cells secreting STriKEs. BiSEs, or SiNEs induced greater NK cell expansion compared to nonsecreting CAR-T cells, CAR-T cells secreting IL-15 alone, or UTD T cells (Figure 21). CAR-T cells secreting STriKEs, BiSEs, or SiNEs also appeared to induce greater NK cell activation, as observed by the increased expression of NK activation markers CD25+and CD69+markers (Figures 21, 22A, and 22B). Finally, an increase in the degranulation of NK cells when combined with CAR-T cells secreting STriKEs. BiSEs, or SiNEs and FAP+WI-38 cells was also observed. Degranulation was measured via expression of CD107a and IFNy (Figure 21).Example 2 Exemplary Cancer -Specific AntigensThis Example provides amino acid sequences of exemplary7polypeptides that can be targeted by a CAR having the ability to bind a cancer-specific antigen.Exemplary BCMA PolypeptideAn exemplary7human BCMA polypeptide (SEQ ID NO: 107). The |boxed| amino acid sequence of this human BCMA polypeptide depicts the BCMA extracellular domain (SEQ ID NO: 108).IMLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTN^ ILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTG DEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCK SLPAALSATEIEKSISAR (SEQ ID NO: 107)Exemplary CS1 PolypeptideAn exemplary' human CS1 polypeptide (SEQ ID NO: 185). The |boxed| amino acid sequence of this human CS1 polypeptide depicts the BCMA extracellular domain (SEQ ID NO: 186)MAGSPTCLTLIYILWQLTGSAA|SGPVKELVGSVGGAVTFPLKSKVKQVDSIVWTF NTTPLVTIQPEGGTIIVTQNRNRERVDFPDGGYSLKLSKLKKNDSGIYYVGIYSSSL QQPSTQEYVLHVYEHLSKPKVTMGLQSNKNGTCVTNLTCCMEHGEEDVIYTWK ALGQAANESHNGSILPISWRWGESDMTFICVARNPVSRNFSSPILARKLCEGAAD DPDSSM|VLLCLLLVPLLLSLFVLGLFLWFLKRERQEEYIEEKKRVDICRETPNICP HSGENTEYDTIPHTNRTILKEDPANTVYSTVEIPKKMENPHSLLTMPDTPRLFAYE NVI (SEQ ID NO: 185)Example 3: Exemplary Binding Molecules Having the Ability to Bind a Cancer-Specific AntigenThis Example provides structures of exemplary scFvs having the ability7to bind a cancer-specific antigen. The and framework sequences of each variable domain areprovided and delineated.The CDRs indicated herein are based on a Kabat numbering scheme. It will be understood that alternative CDRs may be derived from the provided sequences using alterative numbering schemes such as Chothia numbering.Exemplary anti-BCMA scFv (anti-BCMA clone #1)VH domain + Linker + VL domain:Q[QLVQSGPELKKPGETVK[SCKASGYTFT|DYSIN]WVKRAPGKGLKWMG|WI ITE TREPAYAYDFRG|RFAFSLETSASTAYLQINNLKYEDTATYFCAL|DYSYAMDY|W GQGTSVTVSSGSrS'GSG G GEGS'T^GDIVLTQSPPSLAMSLGKRATISC^ASESV TILGSHLIH|WYQQKPGQPPTLLIQ|LASNVQT]GVPARFSGSGSRTDFTLTIDPVEED DVAVYYC|LQSRTIPRT|FGGGTKLEIK (SEQ ID NO:7)Nucleotide sequence encoding an anti-BCMA scFv set forth in SEQ ID NO: 7 CAAATCCAACTCGTCCAATCTGGTCCGGAACTGAAGAAGCCGGGTGAGACAG TCAAGATTTCCTGTAAAGCCTCTGGTTATACGTTTACCGATTACTCAATAAAC TGGGTTAAACGAGCGCCAGGTAAGGGTCTTAAGTGGATGGGTTGGATAAATA CTGAGACGAGAGAGCCGGCGTATGCGTATGACTTTCGCGGTAGGTTCGCTTTT TCCCTCGAGACTAGTGCATCAACCGCTTACCTGCAGATCAACAACCTCAAATA TGAAGACACGGCAACCTACTTTTGCGCGCTCGACTACTCATATGCGATGGACT ACTGGGGTCAGGGAACCAGCGTTACAGTTTCTTCTGGCAGCACCTCAGGATC CGGGAAACCAGGCAGTGGTGAGGGATCTACGAAAGGCGATATAGTCCTTACA CAGTCACCTCCCAGCCTCGCGATGTCTCTCGGCAAGCGGGCCACTATATCTTG TCGCGCCAGCGAGTCTGTCACTATTCTCGGTAGCCACTTGATCCACTGGTATC AACAGAAGCCGGGGCAACCGCCAACCCTTCTGATCCAGCTTGCGTCTAACGT CCAAACCGGTGTGCCGGCTCGGTTTAGCGGCTCCGGTAGTCGCACGGACTTTA CACTTACGATCGACCCCGTCGAGGAAGACGACGTGGCGGTCTATTATTGTTTG CAGAGTCGCACAATCCCACGCACGTTTGGAGGAGGCACAAAGCTGGAGATTA AA (SEQ ID NO: 120)Exemplary anti-BCMA scFv (anti-BCMA clone #2)VL domain + Linker + VH domain:Nucleotide sequence encoding an anti-BCMA scFv set forth in SEQ ID NO:8 GATATAGTCCTTACACAGTCACCTCCCAGCCTCGCGATGTCTCTCGGCAAGCG GGCCACTATATCTTGTCGCGCCAGCGAGTCTGTCACTATTCTCGGTAGCCACT TGATCCACTGGTATCAACAGAAGCCGGGGCAACCGCCAACCCTTCTGATCCA GCTTGCGTCTAACGTCCAAACCGGTGTGCCGGCTCGGTTTAGCGGCTCCGGTA GTCGCACGGACTTTACACTTACGATCGACCCCGTCGAGGAAGACGACGTGGC GGTCTATTATTGTTTGCAGAGTCGCACAATCCCACGCACGTTTGGAGGAGGCAGTGAGGGATCTACGAAAGGCCAAATCCAACTCGTCCAATCTGGTCCGGAACT GAAGAAGCCGGGTGAGACAGTCAAGATTTCCTGTAAAGCCTCTGGTTATACG TTTACCGATTACTCAATAAACTGGGTTAAACGAGCGCCAGGTAAGGGTCTTA AGTGGATGGGTTGGATAAATACTGAGACGAGAGAGCCGGCGTATGCGTATGA CTTTCGCGGTAGGTTCGCTTTTTCCCTCGAGACTAGTGCATCAACCGCTTACCT GCAGATCAACAACCTCAAATATGAAGACACGGCAACCTACTTTTGCGCGCTC GACTACTCATATGCGATGGACTACTGGGGTCAGGGAACCAGCGTTACAGTTT CTTCT (SEQ ID NO: 121)Exemplary anti-CSl scFv (clone #1)VH domain + Linker + VL domain:QVQLQQPGAELVRPGASVKLSCKASGYSFTTYWMNWVKQRPGQGLEWIGMIHP SDSETRLNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCARSTMIATRAM DYWGQGTSVTVSGGGGS'GGGGS'GGGGSDIVMTQSQKSMSTSVGDRVSITCKAS QDVITGVAWYQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTDFTFTISNVQAE DLAVYYCQQHYSTPLTFGAGTKLELK (SEQ ID NO: 193)Nucleotide sequence encoding an anti-CSl scFv set forth in SEQ ID NO:193 CAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTGAGGCCTGGAGCTTCAG TGAAGCTGTCCTGCAAGGCTTCGGGGTACTCCTTCACCACCTACTGGATGAAC TGGGTGAAGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGCATGATTCATC CTTCCGATAGTGAAACTAGGTTAAATCAGAAGTTCAAGGACAAGGCCACATT GACTGTAGACAAATCCTCCAGCACAGCCTACATGCAACTCAGCAGCCCGACA TCTGAGGACTCTGCGGTCTATTACTGTGCAAGATCTACTATGATTGCGACGAG GGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCGGCGGTGGC GGTTCTGGTGGCGGTGGCTCCGGCGGTGGCGGTTCTGACATTGTGATGACCCA GTCTCAGAAATCCATGTCCACATCAGTAGGAGACAGGGTCAGCATCACCTGC AAGGCCAGTCAGGATGTTATTACTGGTGTAGCCTGGTATCAACAGAAACCAG GGCAATCTCCTAAATTACTGATTTACTCGGCATCCTACCGGTACACTGGAGTC CCTGATCGCTTCACTGGCAGTGGATCTGGGACGGATTTCACTTTCACCATCAG CAATGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAACATTATAGTA CTCCTCTCACTTTCGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO:212)Exemplary anti-CSl scFv (clone #2)VL domain + Linker + VH domain:DIVMTQSQKSMSTSVGDRVSITCKASQDVITGVAWYQQKPGQSPKLLIYSASYRY TGVPDRFTGSGSGTDFTFTISNVQAEDLAVYYCQQHYSTPLTFGAGTKLELKGGGG5GGGGSGGGG QVQLQQPGAELVRPGASVKLSCKASGYSFTTYWMNWVKQRP GQGLEWIGMIHPSDSETRLNQKFKDKATLTVDKSS STAYMQLS SPTSEDS AVYYC ARSTMIATRAMDYWGQGTSVTVS (SEQ ID NO: 194)Nucleotide sequence encoding an anti-SLAMF7 scFv set forth in SEQ ID NO:194 GACATTGTGATGACCCAGTCTCAGAAATCCATGTCCACATCAGTAGGAGACA GGGTCAGCATCACCTGCAAGGCCAGTCAGGATGTTATTACTGGTGTAGCCTG GTATCAACAGAAACCAGGGCAATCTCCTAAATTACTGATTTACTCGGCATCCT ACCGGTACACTGGAGTCCCTGATCGCTTCACTGGCAGTGGATCTGGGACGGA TTTCACTTTCACCATCAGCAATGTGCAGGCTGAAGACCTGGCAGTTTATTACT GTCAGCAACATTATAGTACTCCTCTCACTTTCGGTGCTGGGACCAAGCTGGAG CTGAAAGGCGGTGGCGGTTCTGGTGGCGGTGGCTCCGGCGGTGGCGGTTCTC AGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTGAGGCCTGGAGCTTCAGT GAAGCTGTCCTGCAAGGCTTCGGGGTACTCCTTCACCACCTACTGGATGAACT GGGTGAAGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGCATGATTCATCC TTCCGATAGTGAAACTAGGTTAAATCAGAAGTTCAAGGACAAGGCCACATTG ACTGTAGACAAATCCTCCAGCACAGCCTACATGCAACTCAGCAGCCCGACAT CTGAGGACTCTGCGGTCTATTACTGTGCAAGATCTACTATGATTGCGACGAGG GCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCC (SEQ ID NO:213)Example 4: Exemplary CARs Having the Ability’ to Bind a Cancer -Specific Antigen This Example provides amino acid sequences of CARs designed to bind a cancerspecific antigen and nucleotide sequences encoding such CARs. The various components of each CAR (e.g., domains and linkers) are provided and delineated.CAR designed using CDRs of anti-BCMA clone #1 (as shown in Example 3):|CD8a Leader Sequence) + anti-BCMA scFv + |CD8ot + CD8a TransmembraneDomain + 4- IBB Intracellular Signaling Domain + CD3^ Intracellular Signaling Domain|MALPVTALLLPLALLLHAARP|QIQLVQSGPELKKPGETVKISCKASGYTFTDYSIN WVKRAPGKGLKWMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKY EDTATYFCALDYSYAMDYWGQGTSVTVSSGSTSGSGKPGSGEGSTKGDIVLTQS PPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQPPTLLIQLASNVQTGVP ARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK|TTTPAPRPP| TPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD|IYIWAPLAGTCGVLLLSLVI TLYC|KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL|RVKFSRSAD APAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNEL QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 122)Nucleotide sequence encoding a CAR set forth in SEQ ID NO: 122 ATGGCGCTGCCAGTAACCGCACTCCTTCTCCCGCTGGCTCTCCTCCTCCACGC GGCACGCCCGGATATAGTTCTGACACAGTCTCCTCCGAGCCTTGCAATGTCAC TGGGCAAGCGAGCTACGATCAGCTGCCGGGCCAGTGAATCCGTGACTATACT GGGAAGCCACCTGATTCACTGGTATCAGCAAAAACCCGGTCAACCGCCGACA CTCTTGATACAGCTTGCAAGTAACGTGCAGACAGGAGTCCCTGCCCGGTTTAG CGGAAGCGGTTCAAGAACAGATTTTACACTGACCATAGACCCGGTAGAAGAA GACGATGTGGCAGTCTACTATTGCCTCCAGTCTCGCACTATTCCAAGAACTTT TGGGGGAGGGACTAAATTGGAAATTAAAGGATCCACTTCCGGGTCCGGGAAG CCAGGGTCTGGTGAAGGATCCACGAAGGGCCAGATACAACTCGTTCAATCCG GCCCAGAGTTGAAGAAGCCAGGCGAAACAGTAAAAATAAGTTGCAAAGCAA GTGGATATACGTTTACCGACTATTCCATTAATTGGGTGAAACGCGCGCCCGGA AAAGGGCTCAAATGGATGGGTTGGATAAACACAGAAACACGCGAACCGGCT TACGCGTACGACTTCCGAGGTCGATTTGCATTCTCTCTCGAGACTTCAGCTTC AACCGCCTACCTGCAGATCAATAACCTTAAGTATGAGGACACTGCCACTTACT TTTGTGCCCTCGATTATTCATACGCCATGGACTATTGGGGGCAAGGTACGTCA GTAACGGTGAGTTCTACCACAACGCCTGCCCCAAGGCCGCCTACTCCGGCGCCCACAATCGCTTCTCAACCGCTTAGTTTGCGGCCGGAAGCGTGCAGGCCGGCT GCAGGAGGTGCCGTACACACGAGAGGGTTGGATTTCGCCTGTGACATTTATA TTTGGGCTCCTCTCGCCGGCACTTGTGGGGTGTTGCTGCTCAGCCTTGTGATC ACTCTTTATTGCAAGCGGGGAAGAAAGAAACTCTTGTATATTTTCAAGCAACC ATTTATGCGGCCCGTACAAACAACACAAGAGGAGGACGGTTGTAGCTGTCGG TTTCCGGAGGAAGAAGAAGGCGGGTGCGAGCTGAGAGTTAAGTTCAGTAGG AGCGCCGATGCTCCCGCTTACAAACAAGGTCAAAACCAGTTGTACAATGAAT TGAACCTCGGCCGCAGAGAGGAGTATGACGTGCTCGACAAGAGGAGGGGGC GGGATCCCGAGATGGGGGGAAAACCCCGACGGAAGAACCCACAAGAGGGGT TGTATAATGAGCTCCAGAAGGATAAGATGGCGGAGGCATATTCCGAGATTGG CATGAAAGGTGAACGGAGAAGGGGTAAGGGGCATGATGGTCTCTACCAGGG ACTCTCAACAGCCACGAAAGACACCTATGACGCTCTCCACATGCAGGCTCTC CCCCCACGA (SEQ ID NO: 123)CAR designed using CDRs of anti-BCMA clone #2 (as shown in Example 3):CD8a Leader Sequence, + anti-BCMA scFv + Hinge, + CD8a TransmembraneDomain + 4- IBB Intracellular Signaling Domain + CD3(^ Intracellular Signaling DomainMALPVTALLLPLALLLHAARP|DIVLTQSPPSLAMSLGKRATISCRASESVTILGSH LIHWYQQKPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVY YCLQSRTIPRTFGGGTKLEIKGSTSGSGKPGSGEGSTKGQIQLVQSGPELKKPGET VKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAYAYDFRGRFAFS LETS ASTAYLQINNLKYEDTATYFCALDYSY AMD YWGQGTSVTVSSffffPAPRP PTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD|IYIWAPLAGTCGVLLLSLV ITLYC|KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL|RVKFSRSA DAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO: 124)Nucleotide sequence encoding a CAR set forth in SEQ ID NO: 124 ATGGCGCTGCCAGTAACCGCACTCCTTCTCCCGCTGGCTCTCCTCCTCCACGC GGCACGCCCGGATATAGTTCTGACACAGTCTCCTCCGAGCCTTGCAATGTCACTGGGCAAGCGAGCTACGATCAGCTGCCGGGCCAGTGAATCCGTGACTATACT GGGAAGCCACCTGATTCACTGGTATCAGCAAAAACCCGGTCAACCGCCGACA CTCTTGATACAGCTTGCAAGTAACGTGCAGACAGGAGTCCCTGCCCGGTTTAG CGGAAGCGGTTCAAGAACAGATTTTACACTGACCATAGACCCGGTAGAAGAA GACGATGTGGCAGTCTACTATTGCCTCCAGTCTCGCACTATTCCAAGAACTTT TGGGGGAGGGACTAAATTGGAAATTAAAGGATCCACTTCCGGGTCCGGGAAG CCAGGGTCTGGTGAAGGATCCACGAAGGGCCAGATACAACTCGTTCAATCCG GCCCAGAGTTGAAGAAGCCAGGCGAAACAGTAAAAATAAGTTGCAAAGCAA GTGGATATACGTTTACCGACTATTCCATTAATTGGGTGAAACGCGCGCCCGGA AAAGGGCTCAAATGGATGGGTTGGATAAACACAGAAACACGCGAACCGGCT TACGCGTACGACTTCCGAGGTCGATTTGCATTCTCTCTCGAGACTTCAGCTTC AACCGCCTACCTGCAGATCAATAACCTTAAGTATGAGGACACTGCCACTTACT TTTGTGCCCTCGATTATTCATACGCCATGGACTATTGGGGGCAAGGTACGTCA GTAACGGTGAGTTCTACCACAACGCCTGCCCCAAGGCCGCCTACTCCGGCGC CCACAATCGCTTCTCAACCGCTTAGTTTGCGGCCGGAAGCGTGCAGGCCGGCT GCAGGAGGTGCCGTACACACGAGAGGGTTGGATTTCGCCTGTGACATTTATA TTTGGGCTCCTCTCGCCGGCACTTGTGGGGTGTTGCTGCTCAGCCTTGTGATC ACTCTTTATTGCAAGCGGGGAAGAAAGAAACTCTTGTATATTTTCAAGCAACC ATTTATGCGGCCCGTACAAACAACACAAGAGGAGGACGGTTGTAGCTGTCGG TTTCCGGAGGAAGAAGAAGGCGGGTGCGAGCTGAGAGTTAAGTTCAGTAGG AGCGCCGATGCTCCCGCTTACAAACAAGGTCAAAACCAGTTGTACAATGAAT TGAACCTCGGCCGCAGAGAGGAGTATGACGTGCTCGACAAGAGGAGGGGGC GGGATCCCGAGATGGGGGGAAAACCCCGACGGAAGAACCCACAAGAGGGGT TGTATAATGAGCTCCAGAAGGATAAGATGGCGGAGGCATATTCCGAGATTGG CATGAAAGGTGAACGGAGAAGGGGTAAGGGGCATGATGGTCTCTACCAGGG ACTCTCAACAGCCACGAAAGACACCTATGACGCTCTCCACATGCAGGCTCTC CCCCCACGA (SEQ ID NO: 125)CAR designed using CDRs of anti-CSl clone #1 (as shown in Example 3):Leader Sequence) + anti-SLAMF7 scFv + |lgG Hingej + CD28 Transmembrane Domain + CD28 Intracellular Signaling Domain + CD3^ Intracellular Signaling Domain|MALPVTALLLPLALLLHAARP|QVQLQQPGAELVRPGASVKLSCKASGYSFTTY WMNWVKQRPGQGLEWIGMIHPSDSETRLNQKFKDKATLTVDKSSSTAYMQLSS PTSEDSAVYYCARSTMIATRAMDYWGQGTSVTVSGGGGSGGGGSGGGGSDIVM TQSQKSMSTSVGDRVSITCKASQDVITGVAWYQQKPGQSPKLLIYSASYRYTGVP DRFTGSGSGTDFTFTISNVQAEDLAVYYCQQHYSTPLTFGAGTKLELKISCDKTHI TCPPCPDPK|FWVLVVVGGVLACYSLLVTVAFIIFWV|RSKRSRLLHSDYMNMT PRRPGPTRKHYQPYAPPRDFAAYRS|RVKFSRSADAPAYKQGQNQLYNELNLG RREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGER RRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:214)Nucleotide sequence encoding a CAR set forth in SEQ ID NO: 214 ATGGCGCTGCCGGTGACCGCGCTGCTGCTGCCGCTGGCGCTGCTGCTGCATGC GGCGCGCCCGCAGGTGCAGCTGCAGCAGCCGGGCGCGGAACTGGTGCGCCCG GGCGCGAGCGTGAAACTGAGCTGCAAAGCGAGCGGCTATAGCTTTACCACCT ATTGGATGAACTGGGTGAAACAGCGCCCGGGCCAGGGCCTGGAATGGATTGG CATGATTCATCCGAGCGATAGCGAAACCCGCCTGAACCAGAAATTTAAAGAT AAAGCGACCCTGACCGTGGATAAAAGCAGCAGCACCGCGTATATGCAGCTGA GCAGCCCGACCAGCGAAGATAGCGCGGTGTATTATTGCGCGCGCAGCACCAT GATTGCGACCCGCGCGATGGATTATTGGGGCCAGGGCACCAGCGTGACCGTG AGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGAT ATTGTGATGACCCAGAGCCAGAAAAGCATGAGCACCAGCGTGGGCGATCGCG TGAGCATTACCTGCAAAGCGAGCCAGGATGTGATTACCGGCGTGGCGTGGTA TCAGCAGAAACCGGGCCAGAGCCCGAAACTGCTGATTTATAGCGCGAGCTAT CGCTATACCGGCGTGCCGGATCGCTTTACCGGCAGCGGCAGCGGCACCGATT TTACCTTTACCATTAGCAACGTGCAGGCGGAAGATCTGGCGGTGTATTATTGC CAGCAGCATTATAGCACCCCGCTGACCTTTGGCGCGGGCACCAAACTGGAAC TGAAAAGCTGCGATAAAACCCATACCTGCCCGCCGTGCCCGGATCCGAAATT TTGGGTGCTGGTGGTGGTGGGCGGCGTGCTGGCGTGCTATAGCCTGCTGGTGACCGTGGCGTTTATTATTTTTTGGGTGCGCAGCAAACGCAGCCGCCTGCTGCA TAGCGATTATATGAACATGACCCCGCGCCGCCCGGGCCCGACCCGCAAACAT TATCAGCCGTATGCGCCGCCGCGCGATTTTGCGGCGTATCGCAGCCGCGTGA AATTTAGCCGCAGCGCGGATGCGCCGGCGTATAAACAGGGCCAGAACCAGCT GTATAACGAACTGAACCTGGGCCGCCGCGAAGAATATGATGTGCTGGATAAA CGCCGCGGCCGCGATCCGGAAATGGGCGGCAAACCGCGCCGCAAAAACCCG CAGGAAGGCCTGTATAACGAACTGCAGAAAGATAAAATGCGGAAGCGTATA GCGAAATTGGCATGAAAGGCGAACGCCGCCGCGGCAAAGGCCATGATGGCC TGTATCAGGGCCTGAGCACCGCGACCAAAGATACCTATGATGCGCTGCATAT GCAGGCGCTGCCGCCGCGC (SEQ ID NO:215)Example 5: Exemplary FAP PolypeptidesThis Example provides an amino acid sequence of a human FAP polypeptide (SEQ ID NO: 109). The amino acid sequence of this human FAP polypeptidedepicts the FAP extracellular domain (SEQ ID NO: 110).MKTWVKIVFGVATSAVLALLVMCIV|LRPSRVHNSEENTMRALTLKDILNGTFSY KTFFPNWISGQEYLHQSADNNIVLYNIETGQSYTILSNRTMKSVNASNYGLSPDR|QFVYLESDYSKLWRYSYTATYYIYDLSNGEFVRGNELPRPIQYLCWSPVGSKLA| fVYQNNIYLKQRPGDPPFQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPN| GKFLAYAEFNDTDIPVIAYSYYGDEQYPRTINIPYPKAGAKNPVVRIFIIDTTYPAY|VGPQEVPVPAMIASSDYYFSWLTWVTDERVCLQWLKRVQNVSVLSICDFREDW| QTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYDAISYYKIFSDKDGYKHIHYIKD|TVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEYPGRRNIYRISIGSYPPSKKCVT| |CHLRKERCQYYTASFSDYAKYYALVCYGPGIPISTLHDGRTDQEIKILEENKELEN| ALKNIQLPKEEIKKLEVDEITLWYKMILPPQFDRSKKYPLLIQVYGGPCSQSVRSV|FAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQITAVR| KFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVY|TERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQI| AKALVNAQVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSDl (SEQ ID NO: 109)Example 6: Exemplary Binding Molecules Having the Ability to Bind a EAP Polypeptide This Example provides structures of exemplary VHHs and scFvs having the ability to bind a FAP polypeptide. The |CDRs| and framework sequences of each variable domain are provided and delineated.The CDRs indicated herein are based on a Kabat numbering scheme. It will be understood that alternative CDRs may be derived from the provided sequences using alterative numbering schemes such as Chothia numbering.Exemplary anti-FAP VHH (anti-FAP clone #1)> QVQLQESGGGLVQAGGSLRLSCWSGSFDSR^AM^WYRQALGKERVWV^Gns] DGSTNYADAVKG|RFTISRDNDKNTVYLQMNSLKPEDTAVYYCNA|WPPRIGLGS WGQGTQVTVSS (SEQ ID NO: 12)Nucleotide sequence encoding an anti-FAP VHH set forth in SEQ ID NO:12 CAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTGTGCAAGCCGGCGGTTCTCT TAGACTTTCATGTTGGAGCGGTAGCTTCGACTCCCGAAACGCCATGGCCTGGT ACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGGTCGCCGGCATAATTAGCGA CGGCAGCACAAACTACGCAGATGCAGTGAAAGGCCGCTTTACTATTTCTAGA GATAACGATAAGAACACAGTCTATCTTCAGATGAATTCCCTCAAGCCGGAAG ACACCGCCGTATATTATTGCAACGCATGGCCTCCTAGGATAGGGCTTGGTAGT TGGGGGCAGGGTACTCAGGTTACAGTCAGCTCA (SEQ ID NO: 126)Exemplary anti-FAP VHH (anti-FAP clone #2) QVQLQESGGGLVQTGGSLRLSCAASGSIFV|GNAMG|WYRQALGNQRELVA|GITS DGITYYPD VKG|RFTISRDNDKNTIYLQMNSLKPEDTAVYYCNL|WPPRIGFA |W GQGTQVTVSS (SEQ ID NO: 16)Nucleotide sequence encoding an anti-FAP VHH set forth in SEQ ID NO:16 CAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTGGTGCAGACCGGCGGCAGC CTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTTTTGTGGGCAACGCGATGG GCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGAACTGGTGGCGGGCATTAC CAGCGATGGCATTACCTATTATCCGGATAGCGTGAAAGGCCGCTTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGCAGATGAACAGCCTGAAACC GGAAGATACCGCGGTGTATTATTGCAACCTGTGGCCGCCGCGCATTGGCTTTG CGAGCTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGC (SEQ ID NO: 127)Exemplary anti-FAP scFv (anti-FAP clone #3)VH domain + Linker + VL domain:QVQLQQSGAELARPGASVNLSCK S|GYTFTNN|GINWLKQRTGQGLEWIGEI|YPR |STN|TLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCAR|TLTAPFAF^VG QGTLVTVSAGS7NGSG yGS'G£’GS7XGQIVLTQSPAIMSASPGEKVTMTC|SA||G GVPARFSGSGSGTSYSLTISSMEAEDAATYYClQQWSFNPP^FGGGTKLEIKR (SEQ ID NO:23)Nucleotide sequence encoding an anti-FAP scFv set forth in SEQ ID NO:23 CAGGTGCAGCTCCAGCAGAGTGGCGCAGAGCTCGCTCGCCCAGGCGCTTCTG TGAATCTGAGTTGTAAGGCCTCCGGATATACTTTTACGAACAACGGCATCAAC TGGCTGAAGCAGCGGACCGGCCAGGGCCTGGAGTGGATCGGCGAAATATACC CCCGGTCCACAAACACTCTCTATAACGAGAAGTTTAAGGGCAAAGCAACTCT GACCGCGGACAGGTCCTCTAACACAGCCTATATGGAGCTGAGAAGCTTGACG AGTGAGGACTCCGCTGTCTATTTTTGCGCCCGAACTCTGACCGCTCCTTTTGCT TTTTGGGGCCAGGGCACGCTCGTGACCGTAAGTGCGGGCTCCACTAGCGGTT CCGGCAAACCTGGCAGCGGAGAAGGCAGCACCAAAGGGCAGATCGTCCTGA CGCAGTCTCCAGCCATCATGAGCGCCTCACCCGGCGAAAAGGTGACCATGAC CTGCTCAGCCTCTTCTGGTGTGAATTTCATGCACTGGTACCAGCAAAAAAGTG GGACCTCCCCTAAAAGGTGGATCTTCGATACCAGCAAACTGGCTTCTGGCGTT CCCGCAAGGTTTAGCGGCTCTGGTTCCGGCACATCATACAGCCTGACGATCA GCAGCATGGAGGCAGAAGACGCAGCTACCTATTACTGCCAGCAATGGAGCTT TAACCCACCTACTTTCGGAGGAGGAACAAAGCTGGAAATAAAAAGA (SEQ ID NO: 128)Exemplary anti-FAP scFv (anti-FAP clone #4)VL domain + Linker + VH domain:Nucleotide sequence encoding an anti-FAP scFv set forth in SEQ ID NO:24 CAGATCGTCCTGACGCAGTCTCCAGCCATCATGAGCGCCTCACCCGGCGAAA AGGTGACCATGACCTGCTCAGCCTCTTCTGGTGTGAATTTCATGCACTGGTAC CAGCAAAAAAGTGGGACCTCCCCTAAAAGGTGGATCTTCGATACCAGCAAAC TGGCTTCTGGCGTTCCCGCAAGGTTTAGCGGCTCTGGTTCCGGCACATCATAC AGCCTGACGATCAGCAGCATGGAGGCAGAAGACGCAGCTACCTATTACTGCC AGCAATGGAGCTTTAACCCACCTACTTTCGGAGGAGGAACAAAGCTGGAAAT AAAAAGAGGCTCCACTAGCGGTTCCGGCAAACCTGGCAGCGGAGAAGGCAG CACCAAAGGGCAGGTGCAGCTCCAGCAGAGTGGCGCAGAGCTCGCTCGCCCA GGCGCTTCTGTGAATCTGAGTTGTAAGGCCTCCGGATATACTTTTACGAACAA CGGCATCAACTGGCTGAAGCAGCGGACCGGCCAGGGCCTGGAGTGGATCGGC GAAATATACCCCCGGTCCACAAACACTCTCTATAACGAGAAGTTTAAGGGCA AAGCAACTCTGACCGCGGACAGGTCCTCTAACACAGCCTATATGGAGCTGAG AAGCTTGACGAGTGAGGACTCCGCTGTCTATTTTTGCGCCCGAACTCTGACCG CTCCTTTTGCTTTTTGGGGCCAGGGCACGCTCGTGACCGTAAGTGCG (SEQ ID NO: 129)Example 7: Exemplary Polypeptides Targeted by a Receptor Present on an Immune Cell This Example provides sequence of an exemplary polypeptides that can be targeted by a receptor present on an immune cell.Human Fc polypeptide:THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP VPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGPFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK (SEQ ID NO:25)Nucleotide sequence encoding an FC region polypeptide set forth in SEQ ID NO:25 ACGCATACCTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATCCGT GTTCCTCTTTCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTCCTG AAGTGACATGCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAAATT TAATTGGTACGTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCACGG GAGGAACAATATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCTTGC ACCAGGACTGGCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAAAG CTCTGCCGGTGCCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCCCG GGAACCTCAGGTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAGAA TCAGGTCTCTCTCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGCCGT CGAATGGGAGTCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCCCCA GTATTGGACTCAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGATAA ATCTAGGTGGCAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAGCA TTGCACAATCACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAG (SEQ ID NO: 130)Human IL- 15 Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGD ASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 26)Nucleotide sequence encoding an IL-15 polypeptide set forth in SEQ ID NO:26 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGCTGGAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO: 131)Human IL-15N72D Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGD ASIHDTVENLIILANDSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 216)Nucleotide sequence encoding an IL-15N72D polypeptide set forth in SEQ ID: 216 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGCTGGAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACGATAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:217)Human IL-15N72A Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGD ASIHDTVENLIILANASLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 218)Nucleotide sequence encoding an IL-15N72A polypeptide set forth in SEQ ID:218 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGCTGGAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACGCGAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:219)Human IL- 15E46K Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLKLQVISLESG DAS1HDTVENL11LANNSLSSNGNVTESGCKECEELEEKN1KEFLQSFVH1VQMF1N TS (SEQ ID NO: 220)Nucleotide sequence encoding an 1L-15E46K polypeptide set forth in SEQ 1D:22O AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGCTGAAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:221)Human IL-15L45E, E46K Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLEKLQVISLESG DASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFIN TS (SEQ ID NO:222)Nucleotide sequence encoding a human IL-15L45E, E46K Polypeptide set forth in SEQ ID:222 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGGAAAAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:223)Human IL-15L45E Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLEELQVISLESGD ASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 224)Nucleotide sequence encoding a human IL-15L45E Polypeptide set forth in SEQ ID:224 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGACAAAGTGACCGCGATGAAATGCTTTCTGGAAGAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:225)Human IL-15N72E Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLEELQVISLESGD ASIHDTVENLTILANESLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS(SEQ ID NO:226)Nucleotide sequence encoding a human IL-15N72E Polypeptide set forth in SEQ ID:226 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGGAAGAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACGAAAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:227)Human IL-15V49D Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLEELQDISLESGD ASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 228)Nucleotide sequence encoding a human IL-15V49D Polypeptide set forth in SEQ 1D:228 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGGAAGAACTGCAGGATATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:229)Human IL-15I50D Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLEELQVDSLESG DASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFIN TS (SEQ ID NO:230)Nucleotide sequence encoding a human IL-15I50D Polypeptide set forth in SEQ ID:230 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGGAAGAACTGCAGGTGGATAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:231)Human IL-15E93Q Polypeptide:NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLEELQVISLESGD ASIHDTVENLIILANESLSSNGNVTESGCKECEELEQKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 232)Nucleotide sequence encoding a human IL-15E93Q Polypeptide set forth in SEQ ID:232 AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGGAAGAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACGAAAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAG AATGCGAAGAACTGGAACAGAAAAACATTAAAGAATTTCTGCAGAGCTTTGT GCATATTGTGCAGATGTTTATTAACACCAGC (SEQ ID NO:233)Example 8: Exemplary VHH-Ecs Having the Ability to Bind a BAP Polypeptide This Example provides amino acid sequences of VHH-Fcs designed to bind a FAP polypeptide and nucleotide sequences encoding such VHH-Fcs. The various components of each VHH-Fc (e.g., domains and linkers) are provided and delineated.VHH-Fc designed using CDRs of anti-FAP clone #1 (as shown in Example 6):|lgK Leader Sequence, + anti-FAP VHH + |Fc region of human IgGl| + 6x His TagMETDTLLLWVLLLWVPGSTGD|QVQLQESGGGLVQAGGSLRLSCWSGSFDSRNA MAWYRQALGKERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLK PEDTAVYYCNAWPPRIGLGSWGQGTQVTVSS rHTCPPCPAPELLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST|YRVVSVLTVLHQDWLNGKEYKCKVSNKA. LPVPIEKTISKAKGQPREPQVYTLPP| SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLYS|KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK^HHHHH (SEQ ID NO:63)Nucleotide sequence encoding a VHH-Fc set forth in SEQ ID NO:63 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTGTGCAAGCC GGCGGTTCTCTTAGACTTTCATGTTGGAGCGGTAGCTTCGACTCCCGAAACGC CATGGCCTGGTACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGGTCGCCGGC ATAATTAGCGACGGCAGCACAAACTACGCAGATGCAGTGAAAGGCCGCTTTA CTATTTCTAGAGATAACGATAAGAACACAGTCTATCTTCAGATGAATTCCCTC AAGCCGGAAGACACCGCCGTATATTATTGCAACGCATGGCCTCCTAGGATAG GGCTTGGTAGTTGGGGGCAGGGTACTCAGGTTACAGTCAGCTCAACGCATAC CTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATCCGTGTTCCTCTT TCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTCCTGAAGTGACAT GCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAAATTTAATTGGTAC GTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCACGGGAGGAACAA TATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCTTGCACCAGGACTG GCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAAAGCTCTGCCGGTGCCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCCCGGGAACCTCAG GTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAGAATCAGGTCTCTC TCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGCCGTCGAATGGGAG TCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCCCCAGTATTGGACT CAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGATAAATCTAGGTGG CAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAGCATTGCACAATC ACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAGCACCACCACCATCAC CA (SEQ ID NO: 132)VHH-Fc designed using CDRs of anti-FAP clone #1 (as shown in Example 6):Leader Sequence) + anti-FAP VHH + |Fc region of human IgGl with longer+ 6x His TagMETDTLLLWVLLLWVPGSTGD|QVQLQESGGGLVQAGGSLRLSCWSGSFDSRNA MAWYRQALGKERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLK PEDTAVYYCNAWPPRIGLGSWGQGTQVTVSS^KTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN|STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPVPIEKTISKAKGQPREPQVYTL| |PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFL| YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK|HHHHHH (SEQ ID NO:64)Nucleotide sequence encoding a VHH-Fc set forth in SEQ ID NO:64 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTGTGCAAGCC GGCGGTTCTCTTAGACTTTCATGTTGGAGCGGTAGCTTCGACTCCCGAAACGC CATGGCCTGGTACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGGTCGCCGGC ATAATTAGCGACGGCAGCACAAACTACGCAGATGCAGTGAAAGGCCGCTTTA CTATTTCTAGAGATAACGATAAGAACACAGTCTATCTTCAGATGAATTCCCTC AAGCCGGAAGACACCGCCGTATATTATTGCAACGCATGGCCTCCTAGGATAG GGCTTGGTAGTTGGGGGCAGGGTACTCAGGTTACAGTCAGCTCAGATAAGAC GCATACCTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATCCGTGTTCCTCTTTCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTCCTGAA GTGACATGCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAAATTTA ATTGGTACGTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCACGGGA GGAACAATATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCTTGCAC CAGGACTGGCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAAAGCTC TGCCGGTGCCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCCCGGGA ACCTCAGGTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAGAATCAG GTCTCTCTCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGCCGTCGA ATGGGAGTCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCCCCAGTA TTGGACTCAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGATAAATCT AGGTGGCAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAGCATTGC ACAATCACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAGCACCACCAC CATCACCA (SEQ ID NO: 133)VHH-Fc designed using CDRs of anti-FAP clone #2 (as shown in Example 6):IgK Leader Sequence, + anti-FAP VHH + |Fc region of human IgGl| + 6x His TagQVQLQESGGGLVQTGGSLRLSCAASGSIFVGNA MGWYRQALGNQRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKP EDTAVYYCNLWPPRIGFASWGQGTQVTVSSffHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPVPIEKTISKAKGQPREPQVYTLPPS|REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLYSK| LWDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK|HHHHHH (SEQ ID NO:65)Nucleotide sequence encoding a VHH-Fc set forth in SEQ ID NO:65 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTGGTGCAGACC GGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTTTTGTGGGCA ACGCGATGGGCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGAACTGGTGGC GGGCATTACCAGCGATGGCATTACCTATTATCCGGATAGCGTGAAAGGCCGCTTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGCAGATGAACA GCCTGAAACCGGAAGATACCGCGGTGTATTATTGCAACCTGTGGCCGCCGCG CATTGGCTTTGCGAGCTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCACG CATACCTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATCCGTGTT CCTCTTTCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTCCTGAAG TGACATGCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAAATTTAAT TGGTACGTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCACGGGAGG AACAATATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCTTGCACCA GGACTGGCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAAAGCTCTG CCGGTGCCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCCCGGGAA CCTCAGGTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAGAATCAGG TCTCTCTCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGCCGTCGAAT GGGAGTCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCCCCAGTATT GGACTCAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGATAAATCTA GGTGGCAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAGCATTGCA CAATCACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAGCACCACCACC ATCACCA (SEQ ID NO: 134)VHH-Fc designed using CDRs of anti-FAP clone #2 (as shown in Example 6):Leader Sequence, + anti-FAP VHH + |Fc region of human IgGl with longer hinge, + 6x His TagMETDTLLLWVLLLWVPGSTGD|QVQLQESGGGLVQTGGSLRLSCAASGSIFVGNA MGWYRQALGNQRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKP EDTAVYYCNLWPPRIGFASWGQGTQVTVSS^KTHTCPPCPAPELLGGPSVFLFPP |KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS| TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPVPTEKTISKAKGQPREPQVYTLP PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLY|SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK^HHHHH (SEQ ID NO:66)Nucleotide sequence encoding a VHH-Fc set forth in SEQ ID NO:66 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTGGTGCAGACC GGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTTTTGTGGGCA ACGCGATGGGCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGAACTGGTGGC GGGCATTACCAGCGATGGCATTACCTATTATCCGGATAGCGTGAAAGGCCGC TTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGCAGATGAACA GCCTGAAACCGGAAGATACCGCGGTGTATTATTGCAACCTGTGGCCGCCGCG CATTGGCTTTGCGAGCTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCGAT AAGACGCATACCTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATC CGTGTTCCTCTTTCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTC CTGAAGTGACATGCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAA ATTTAATTGGTACGTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCA CGGGAGGAACAATATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCT TGCACCAGGACTGGCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAA AGCTCTGCCGGTGCCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCC CGGGAACCTCAGGTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAG AATCAGGTCTCTCTCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGC CGTCGAATGGGAGTCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCC CCAGTATTGGACTCAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGAT AAATCTAGGTGGCAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAG CATTGCACAATCACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAGCAC CACCACCATCACCA (SEQ ID NO: 135)Example 9: Exemplary CD47 PolypeptidesThis Example provides an amino acid sequence of a human CD47 polypeptide (SEQ ID NO:116). The boxed amino acid sequences of this human CD47 polypeptide depicts the CD47 extracellular domains (in order from N-terminal to C-terminal: SEQ ID NO: 117, SEQ ID NO: 118, and SEQ ID NO: 119).|MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEV| YVKWKFKGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELTREGETIIELKYRVVSWFSPNE|NILIVIFPIFAILLFWGQFGIKTLK YRSGGMDEKTIALLVAGLVITVIVIVGAILF|VPGEYSLKNA|TGLGLIVTSTGILILL HYYVFSTAIGLTSFVIAILVIQVIAYILAVVGL|SLCIAACIPMHG|PLLISGLSILALAQ LLGLVYMKFVASNQKTTQPPRKAVEEPLNAFKESKGMMNDE (SEQ ID NOT 16)Example 10: Exemplary Binding Molecules Having the Ability to Bind a CD47 PolypeptideThis Example provides structures of exemplary VHHs and scF’s having the ability to bind a CD47 polypeptide. The and framework sequences of each variabledomain are provided and delineated.The CDRs indicated herein are based on a Kabat numbering scheme. It will be understood that alternative CDRs may be derived from the provided sequences using alterative numbering schemes such as Chothia numbering.Exemplary anti-CD47 VHH (anti-CD47 clone #1)Nucleotide sequence encoding an anti-CD47 VHH set forth in SEQ ID NO:62 CAAGTGCAATTGGTCGAATCTGGAGGGGGCTTGGTCGAACCGGGCGGATCAC TTAGGTTGAGCTGTGCGGCTTCAGGAATAATTTTTAAAATTAACGACATGGGG TGGTATAGACAGGCGCCAGGTAAACGAAGGGAGTGGGTGGCGGCCAGCACG GGCGGAGATGAAGCCATTTACAGAGATAGTGTTAAGGATAGGTTCACCATTA GTCGGGATGCAAAGAACTCCGTGTTTCTGCAGATGAATTCACTCAAACCAGA GGATACGGCAGTGTACTACTGCACGGCAGTGATATCCACGGATCGGGATGGT ACTGAGTGGCGCAGGTACTGGGGCCAGGGGACACAGGTGACCGTCAGCTCC(SEQ ID NO: 136)Example 11: Exemplary Binding Molecules Having the Ability to Bind a EAP Polypeptide and Having the Ability to Bind a CD47 polypeptideThis Example provides amino acid sequences of VHH-Fcs designed to bind a FAP polypeptide and to bind a CD47 polypeptide and nucleotide sequences encoding such VHH-Fcs. The various components of each VHH-Fc (e.g., domains and linkers) are provided and delineated.CD47enh VHH-Fc 1.1 designed using CDRs of anti-FAP clone #1 (as shown in Example 6) and using CDRs of anti-CD47 clone #1 (as shown in Example 10):IgK Leader Sequence! + anti-FAP VHH + pc region of human IgGl with the longer hinge + 6x His Tag + P2A Sequence + |lgK Leader Sequence! + anti-CD47 VHH + |Linker| + HA TagQVQLQESGGGLVQAGGSLRLSCWSGSFDSRNA MAWYRQALGKERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLK PEDTAVYYCNAWPPRIGLGSWGQGTQVTVSSfDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN|STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPVPIEKTISKAKGQPREPQVYTL| PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK]HHHHHHG'YG,A7 V FA / YA(MG7)EE£Y / t7^METDTLLLWVLLLWVPGSTGD|QVQLVESGGGLVEPGG SLRLSCAASGIIFKINDMGWYRQAPGKRREWVAASTGGDEAIYRDSVKDRFTISR DAKN VFLQMNSI. KPEDTAVYYCTAVISTDRDGTEWRRYWGQGTQVTVSS[AAA| YPYDVPDYA (SEQ ID NO:67)Nucleotide sequence encoding a CD47enhVHH-Fcl.l set forth in SEQ ID NO:67 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTGTGCAAGCC GGCGGTTCTCTTAGACTTTCATGTTGGAGCGGTAGCTTCGACTCCCGAAACGC CATGGCCTGGTACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGGTCGCCGGC ATAATTAGCGACGGCAGCACAAACTACGCAGATGCAGTGAAAGGCCGCTTTA CTATTTCTAGAGATAACGATAAGAACACAGTCTATCTTCAGATGAATTCCCTCAAGCCGGAAGACACCGCCGTATATTATTGCAACGCATGGCCTCCTAGGATAG GGCTTGGTAGTTGGGGGCAGGGTACTCAGGTTACAGTCAGCTCAGATAAGAC GCATACCTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATCCGTGT TCCTCTTTCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTCCTGAA GTGACATGCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAAATTTA ATTGGTACGTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCACGGGA GGAACAATATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCTTGCAC CAGGACTGGCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAAAGCTC TGCCGGTGCCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCCCGGGA ACCTCAGGTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAGAATCAG GTCTCTCTCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGCCGTCGA ATGGGAGTCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCCCCAGTA TTGGACTCAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGATAAATCT AGGTGGCAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAGCATTGC ACAATCACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAGCACCACCAC CATCACCAGGTTCCGGGGCCACTAACTTTTCTCTGTTGAAGCAGGCTGGGGAT GTCGAGGAAAACCCAGGCCCCATGGAAACAGACACCCTCCTGCTGTGGGTTC TGTTGCTTTGGGTCCCAGGCAGTACAGGTGATCAAGTGCAATTGGTCGAATCT GGAGGGGGCTTGGTCGAACCGGGCGGATCACTTAGGTTGAGCTGTGCGGCTT CAGGAATAATTTTTAAAATTAACGACATGGGGTGGTATAGACAGGCGCCAGG TAAACGAAGGGAGTGGGTGGCGGCCAGCACGGGCGGAGATGAAGCCATTTA CAGAGATAGTGTTAAGGATAGGTTCACCATTAGTCGGGATGCAAAGAACTCC GTGTTTCTGCAGATGAATTCACTCAAACCAGAGGATACGGCAGTGTACTACT GCACGGCAGTGATATCCACGGATCGGGATGGTACTGAGTGGCGCAGGTACTG GGGCCAGGGGACACAGGTGACCGTCAGCTCCGCAGCCGCGTATCCCTACGAT GTCCCTGACTACGGGTCT (SEQ ID NO: 137)CD47enhVHH-Fcl.2 designed using CDRs of anti-FAP clone #1 (as shown in Example 6) and using CDRs of anti-CD47 clone #1 (as shown in Example 10):IgK Leader Sequence! + anti-FAP VHH + |Fc region of human lgGl| + 6x His Tag + P2A Sequence + |lgK Leader Sequence] + anti-CD47 VHH + + HA TagMETDTLLLWVLLLWVPGSTGDlQVQLQESGGGLVQAGGSLRLSCWSGSFDSRNA MAWYRQALGKERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLK PEDTAVYYCNAWPPRIGLGSWGQGTQVTVSSfrHTCPPCPAPELLGGPSVFLFPPK |PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST| YRVVSVLTVLHQDWLNGKEYKCKVSNKALPVPIEKTISKAKGQPREPQVYTLPP|SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLYS| |KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK|HHHHHHGYGA7 VFY Z£F2AG,Z> FF AF>G'F[METDTLLLWVLLLWVPGSTGD|QVQLVESGGGLVEPGGSL RLSCAASGIIFKINDMGWYRQAPGKRREWVAASTGGDEAIYRDSVKDRFTISRDA KNSVFLQMNSLKPEDTAVYYCTAVISTDRDGTEWRRYWGQGTQVTVSS[AAA]YP YDVPDYA (SEQ ID NO: 68)Nucleotide sequence encoding a CD47enhVHH-Fcl.2 set forth in SEQ ID NO:68 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTGTGCAAGCC GGCGGTTCTCTTAGACTTTCATGTTGGAGCGGTAGCTTCGACTCCCGAAACGC CATGGCCTGGTACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGGTCGCCGGC ATAATTAGCGACGGCAGCACAAACTACGCAGATGCAGTGAAAGGCCGCTTTA CTATTTCTAGAGATAACGATAAGAACACAGTCTATCTTCAGATGAATTCCCTC AAGCCGGAAGACACCGCCGTATATTATTGCAACGCATGGCCTCCTAGGATAG GGCTTGGTAGTTGGGGGCAGGGTACTCAGGTTACAGTCAGCTCAACGCATAC CTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATCCGTGTTCCTCTT TCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTCCTGAAGTGACAT GCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAAATTTAATTGGTAC GTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCACGGGAGGAACAA TATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCTTGCACCAGGACTG GCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAAAGCTCTGCCGGTG CCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCCCGGGAACCTCAG GTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAGAATCAGGTCTCTC TCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGCCGTCGAATGGGAG TCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCCCCAGTATTGGACT CAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGATAAATCTAGGTGGCAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAGCATTGCACAATC ACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAGCACCACCACCATCAC CAGGTTCCGGGGCCACTAACTTTTCTCTGTTGAAGCAGGCTGGGGATGTCGAG GAAAACCCAGGCCCCATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGC TTTGGGTCCCAGGCAGTACAGGTGATCAAGTGCAATTGGTCGAATCTGGAGG GGGCTTGGTCGAACCGGGCGGATCACTTAGGTTGAGCTGTGCGGCTTCAGGA ATAATTTTTAAAATTAACGACATGGGGTGGTATAGACAGGCGCCAGGTAAAC GAAGGGAGTGGGTGGCGGCCAGCACGGGCGGAGATGAAGCCATTTACAGAG ATAGTGTTAAGGATAGGTTCACCATTAGTCGGGATGCAAAGAACTCCGTGTTT CTGCAGATGAATTCACTCAAACCAGAGGATACGGCAGTGTACTACTGCACGG CAGTGATATCCACGGATCGGGATGGTACTGAGTGGCGCAGGTACTGGGGCCA GGGGACACAGGTGACCGTCAGCTCCGCAGCCGCGTATCCCTACGATGTCCCT GACTACGGGTCT (SEQ ID NO: 138)CD47enhVHH-Fc2.1 designed using CDRs of anti-FAP clone #2 (as shown in Example 6) and using CDRs of anti-CD47 clone #1 (as shown in Example 10):IgK Leader Sequence, + anti-FAP VHH + |Fc region of human IgGl with the longer hinge + 6x His Tag + P2A Sequence + [IgK Leader Sequence, + anti-CD47 VHH + |Linkei, + HA TagQVQLQESGGGLVQTGGSLRLSCAASGSIFVGNA MGWYRQALGNQRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKP EDTAVYYCNLWPPRIGFASWGQGTQVTVSS^KTHTCPPCPAPELLGGPSVFLFPP, |KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS| TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPVPIEKTISKAKGQPREPQVYTLP|PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLY| SKLTVDKS WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK|HHHHHHG: S'G / 17; VF ALLA'CMGDEE£'Y / JG7 dETDTLLLWVLLLWVPGSTGD|QVQLVESGGGLVEPGGS LRLS C AAS GIIFKINDMGWYRQ APGKRREWV AASTGGDEAIYRDS VKDRFTIS RD AKNSVFLQMNSLKPEDTAVYYCTAVISTDRDGTEWRRYWGQGTQVTVSS|AAA|Y PYDVPDYA (SEQ ID NO:69)Nucleotide sequence encoding a CD47enhVHH-Fc2.1 set forth in SEQ ID NO:69 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTGGTGCAGACC GGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTTTTGTGGGCA ACGCGATGGGCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGAACTGGTGGC GGGCATTACCAGCGATGGCATTACCTATTATCCGGATAGCGTGAAAGGCCGC TTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGCAGATGAACA GCCTGAAACCGGAAGATACCGCGGTGTATTATTGCAACCTGTGGCCGCCGCG CATTGGCTTTGCGAGCTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCGAT AAGACGCATACCTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATC CGTGTTCCTCTTTCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTC CTGAAGTGACATGCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAA ATTTAATTGGTACGTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCA CGGGAGGAACAATATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCT TGCACCAGGACTGGCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAA AGCTCTGCCGGTGCCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCC CGGGAACCTCAGGTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAG AATCAGGTCTCTCTCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGC CGTCGAATGGGAGTCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCC CCAGTATTGGACTCAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGAT AAATCTAGGTGGCAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAG CATTGCACAATCACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAGCAC CACCACCATCACCAGGTTCCGGGGCCACTAACTTTTCTCTGTTGAAGCAGGCT GGGGATGTCGAGGAAAACCCAGGCCCCATGGAAACAGACACCCTCCTGCTGT GGGTTCTGTTGCTTTGGGTCCCAGGCAGTACAGGTGATCAAGTGCAATTGGTC GAATCTGGAGGGGGCTTGGTCGAACCGGGCGGATCACTTAGGTTGAGCTGTG CGGCTTCAGGAATAATTTTTAAAATTAACGACATGGGGTGGTATAGACAGGC GCCAGGTAAACGAAGGGAGTGGGTGGCGGCCAGCACGGGCGGAGATGAAGC CATTTACAGAGATAGTGTTAAGGATAGGTTCACCATTAGTCGGGATGCAAAG AACTCCGTGTTTCTGCAGATGAATTCACTCAAACCAGAGGATACGGCAGTGT ACTACTGCACGGCAGTGATATCCACGGATCGGGATGGTACTGAGTGGCGCAGGTACTGGGGCCAGGGGACACAGGTGACCGTCAGCTCCGCAGCCGCGTATCCC TACGATGTCCCTGACTACGGGTCT (SEQ ID NO: 139)CD47enhVHH-Fc2.2 designed using CDRs of anti-FAP clone #2 (as shown in Example 6) and using CDRs of anti-CD47 clone #1 (as shown in Example 10):IgK Leader Sequence + anti-FAP VHH + Fc region of human IgGl + 6x His Tag + P2A Sequence + |lgK Leader Sequence] + anti-CD47 VHH + + HA TagMETDTLLLWVLLLWVPGSTGDlQVQLQESGGGLVQTGGSLRLSCAASGSIFVGNA MGWYRQALGNQRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKP EDTAVYYCNLWPPRIGFASWGQGTQVTVSSffHTCPPCPAPELLGGPSVFLFPPKP| KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPVPIEKTISKAKGQPREPQVYTLPPS|REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLYSK| LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK|HHHHHHGS,4 TNFSL LAYM GO EEENPGEIMETDTLLLW V L LL W VPGSTG^Q V QLVESGGGLVEPGGSLR LSCAASGIIFKINDMGWYRQAPGKRREWVAASTGGDEAIYRDSVKDRFTISRDA KNSVFLQMNSLKPEDTAVYYCTAVISTDRDGTEWRRYWGQGTQVTVSS|AA^YP YDVPDYA (SEQ ID NO: 70)Nucleotide sequence encoding a CD47enhVHH-Fc2.2 set forth in SEQ ID NO:70 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTGGTGCAGACC GGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTTTTGTGGGCA ACGCGATGGGCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGAACTGGTGGC GGGCATTACCAGCGATGGCATTACCTATTATCCGGATAGCGTGAAAGGCCGC TTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGCAGATGAACA GCCTGAAACCGGAAGATACCGCGGTGTATTATTGCAACCTGTGGCCGCCGCG CATTGGCTTTGCGAGCTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCACG CATACCTGCCCACCTTGCCCTGCTCCCGAGTTGTTGGGCGGCCCATCCGTGTT CCTCTTTCCACCCAAACCTAAGGACACACTGATGATTTCTCGAACTCCTGAAG TGACATGCGTTGTTGTTGACGTTAGCCACGAAGACCCTGAAGTGAAATTTAATTGGTACGTTGATGGCGTGGAGGTACACAATGCGAAAACTAAACCACGGGAGG AACAATATAATAGCACATATCGCGTGGTCAGCGTGCTCACCGTCTTGCACCA GGACTGGCTCAACGGCAAGGAATACAAGTGTAAGGTTAGCAACAAAGCTCTG CCGGTGCCGATTGAAAAAACCATATCAAAAGCGAAAGGTCAGCCCCGGGAA CCTCAGGTATATACGCTGCCACCAAGCCGAGAGGAAATGACGAAGAATCAGG TCTCTCTCACGTGTCTCGTCAAAGGATTCTATCCTTCTGACATCGCCGTCGAAT GGGAGTCTAACGGCCAGCCAGAAAATAATTACAAGACCACTCCCCCAGTATT GGACTCAGATGGTCCTTTTTTCTTGTATTCCAAATTGACGGTCGATAAATCTA GGTGGCAGCAGGGCAACGTATTTTCATGCTCCGTCATGCACGAAGCATTGCA CAATCACTATACCCAAAAATCTCTCTCTCTTTCCCCGGGTAAGCACCACCACC ATCACCAGGTTCCGGGGCCACTAACTTTTCTCTGTTGAAGCAGGCTGGGGATG TCGAGGAAAACCCAGGCCCCATGGAAACAGACACCCTCCTGCTGTGGGTTCT GTTGCTTTGGGTCCCAGGCAGTACAGGTGATCAAGTGCAATTGGTCGAATCTG GAGGGGGCTTGGTCGAACCGGGCGGATCACTTAGGTTGAGCTGTGCGGCTTC AGGAATAATTTTTAAAATTAACGACATGGGGTGGTATAGACAGGCGCCAGGT AAACGAAGGGAGTGGGTGGCGGCCAGCACGGGCGGAGATGAAGCCATTTAC AGAGATAGTGTTAAGGATAGGTTCACCATTAGTCGGGATGCAAAGAACTCCG TGTTTCTGCAGATGAATTCACTCAAACCAGAGGATACGGCAGTGTACTACTGC ACGGCAGTGATATCCACGGATCGGGATGGTACTGAGTGGCGCAGGTACTGGG GCCAGGGGACACAGGTGACCGTCAGCTCCGCAGCCGCGTATCCCTACGATGT CCCTGACTACGGGTCT (SEQ ID NO: 140)Example 12: Exemplary Polypeptides Present on MacrophagesThis Example provides an amino acid sequence of a human SIRPa polypeptide (SEQ ID NO: 111). The boxed amino acid sequence of this human SIRPa polypeptide depicts the SIRPa extracellular domain (SEQ ID NO: 112).MEPAGPAPGRLGPLLCLLLAASCAWSGVAGEEELQVIQPDKSVLVAAGETATLR CTATSLIPVGPIQWFRGAGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRIGN ITPADAGTYYCVKFRKGSPDDVEFKSGAGTELSVRAKPSAPVVSGPAARATPQH TVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYSIHSTAKVVLTRE|DVHSQVICEVAHVTLQGDPLRGTANLSETIRVPPTLEVTQQPVRAENQVNVTCQ|VRKFYPQRLQLTWLENGNVSRTETASTVTENKDGTYNWMSWLLVNVSAHRDD IVVGVVC TLLV ALLMA ALYLVRIRQKKAQGSTSSTRLHEPEKNAREITQDTNDITYADLNLP KGKKPAPQAAEPNNHTEYASIQTSPQPASEDTLTYADLDMVHLNRTPKQPAPKP EPSFSEYASVQVPRK (SEQ ID NO: 111)Example 13: Exemplary Binding Molecules Having the Ability to Bind a Macrophage This Example provides structures of exemplary scFvs having the abil i ty to bind a SIRPa polypeptide. The CDRs and framework sequences of each variable domain are provided and delineated.The CDRs indicated herein are based on a Kabat numbering scheme. It will be understood that alternative CDRs may be derived from the provided sequences using alterative numbering schemes such as Chothia numbering.Exemplary anti-SIRPa scFv (anti-SIRPa clone #1)VH domain + Linker + VL domain:Nucleotide sequence encoding an anti-SIRPa scFv set forth in SEQ ID NO:33 GAAGTCCAATTGCAGCAATCCGGAGCTGAATTGGTTAAGCCGGGTGCGAGTG TCAAACTTAGTTGCACAGCTTCAGGCTTCAACATCAAAGACTATTATATCCAC TGGGTCCAGCAAAGAACGGAGCAAGGCCTCGAGTGGATTGGTCGAATAGATC CCGAGGATGGAGAGACTAAATACGCTCCGAAGTTTCAGGACAAAGCCACTAT AACTGCAGACACTAGTAGTAATACCGCGTATCTTCATCTCTCTAGTCTTACAT CAGAAGATACGGCGGTCTATTATTGTGCGAGATGGGGCGCCTACTGGGGCCA GGGCACCTTGGTGACTGTAAGCTCAGGAGGCGGAGGATCAGGTGGAGGTGGC TCTGGCGGTGGTGGCTCTCAAATAGTATTGACCCAATCTCCGGCCATCATGTCCAAGCTCCTACTTGTATTGGTATCAGCAGAAACCGGGCTCTAGCCCTAAGCTT TGGATTTATAGCACCTCAAACCTTGCTTCCGGGGTTCCTGCAAGGTTCTCCGG CAGTGGGAGCGGTACCAGCTATTCACTCACCATTAGTTCCATGGAAGCGGAA GATGCGGCAAGTTATTTTTGTCACCAATGGTCATCATACCCTCGAACCTTCGG GGCAGGTACAAAGTTGGAGTTGAAGGGAGGCGGAGGATCAGGTGGAGGTGG CTCTGGCGGTGGTGGCTCTCAAATAGTATTGACCCAATCTCCGGCCATCATGT CAGCATCACCAGGTGAAAAAGTGACCCTTACATGTTCCGCCTCATCCAGCGTT TCAAGCTCCTACTTGTATTGGTATCAGCAGAAACCGGGCTCTAGCCCTAAGCT TTGGATTTATAGCACCTCAAACCTTGCTTCCGGGGTTCCTGCAAGGTTCTCCG GCAGTGGGAGCGGTACCAGCTATTCACTCACCATTAGTTCCATGGAAGCGGA AGATGCGGCAAGTTATTTTTGTCACCAATGGTCATCATACCCTCGAACCTTCG GGGCAGGTACAAAGTTGGAGTTGAAG (SEQ ID NO: 141)Exemplary anti-SIRPa scFv (anti-SIRPa clone #2)VL domain + Linker + VH domain:Nucleotide sequence encoding an anti-SIRPa scFv set forth in SEQ ID NO:34 CAAATAGTATTGACCCAATCTCCGGCCATCATGTCAGCATCACCAGGTGAAA AAGTGACCCTTACATGTTCCGCCTCATCCAGCGTTTCAAGCTCCTACTTGTATT GGTATCAGCAGAAACCGGGCTCTAGCCCTAAGCTTTGGATTTATAGCACCTCA AACCTTGCTTCCGGGGTTCCTGCAAGGTTCTCCGGCAGTGGGAGCGGTACCA GCTATTCACTCACCATTAGTTCCATGGAAGCGGAAGATGCGGCAAGTTATTTT TGTCACCAATGGTCATCATACCCTCGAACCTTCGGGGCAGGTACAAAGTTGG AGTTGAAGGGAGGCGGAGGATCAGGTGGAGGTGGCTCTGGCGGTGGTGGCTC TGAAGTCCAATTGCAGCAATCCGGAGCTGAATTGGTTAAGCCGGGTGCGAGT GTCAAACTTAGTTGCACAGCTTCAGGCTTCAACATCAAAGACTATTATATCCA CTGGGTCCAGCAAAGAACGGAGCAAGGCCTCGAGTGGATTGGTCGAATAGATTAACTGCAGACACTAGTAGTAATACCGCGTATCTTCATCTCTCTAGTCTTACA TCAGAAGATACGGCGGTCTATTATTGTGCGAGATGGGGCGCCTACTGGGGCC AGGGCACCTTGGTGACTGTAAGCTCAGGAGGCGGAGGATCAGGTGGAGGTG GCTCTGGCGGTGGTGGCTCTCAAATAGTATTGACCCAATCTCCGGCCATCATG TCAGCATCACCAGGTGAAAAAGTGACCCTTACATGTTCCGCCTCATCCAGCGT TTCAAGCTCCTACTTGTATTGGTATCAGCAGAAACCGGGCTCTAGCCCTAAGC TTTGGATTTATAGCACCTCAAACCTTGCTTCCGGGGTTCCTGCAAGGTTCTCC GGCAGTGGGAGCGGTACCAGCTATTCACTCACCATTAGTTCCATGGAAGCGG AAGATGCGGCAAGTTATTTTTGTCACCAATGGTCATCATACCCTCGAACCTTC GGGGCAGGTACAAAGTTGGAGTTGAAGCACCACCACCATCACCA (SEQ ID NO: 142)Example 14: Exemplary Binding Molecules Having the Ability to Bind a FAP Polypeptide and Having the Ability to Bind a SIRPa polypeptideThis Example provides amino acid sequences of BISEs designed to bind a FAP polypeptide and to bind a SIRPa polypeptide and nucleotide sequences encoding such BISEs. The various components of each BISE (e.g., domains and linkers) are provided and delineated.BISE 1.1 VHH-HL designed using CDRs of anti-FAP clone #1 (as shown in Example 6) and using CDRs of anti-SIRPa clone #1 (as shown in Example 11):|METDTLLLWVLLLWVPGSTGD|QVQLQESGGGLVQAGGSLRLSCWSGSFDSRNA MAWYRQALGKERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLK PEDTAVYYCNAWPPRIGLGSWGQGTQVTVSS^GGSGGGS|EVQLQQSGAELVKP GASVKLSCTASGFNIKDYYIHWVQQRTEQGLEWIGRIDPEDGETKYAPKFQDKA TITADTSSNTAYLHLSSLTSEDTAVYYCARWGAYWGQGTLVTVSGGGGSGGGG SGGGGSQIVLTQSPAIMSASPGEKVTLTCSASSSVSSSYLYWYQQKPGSSPKLWIY STSNLASGVPARFSGSGSGTSYSLTISSMEAEDAASYFCHQWSSYPRTFGAGTKLE LK|HHHHHH| (SEQ ID NO: 71)Nucleotide sequence encoding a BISE 1.1 VHH-HL set forth in SEQ ID NO:71 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTGTGCAAGCC GGCGGTTCTCTTAGACTTTCATGTTGGAGCGGTAGCTTCGACTCCCGAAACGC CATGGCCTGGTACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGGTCGCCGGC ATAATTAGCGACGGCAGCACAAACTACGCAGATGCAGTGAAAGGCCGCTTTA CTATTTCTAGAGATAACGATAAGAACACAGTCTATCTTCAGATGAATTCCCTC AAGCCGGAAGACACCGCCGTATATTATTGCAACGCATGGCCTCCTAGGATAG GGCTTGGTAGTTGGGGGCAGGGTACTCAGGTTACAGTCAGCTCAGGGGGCGG AGGGTCAGGGGGCGGTGGTTCTGAAGTCCAATTGCAGCAATCCGGAGCTGAA TTGGTTAAGCCGGGTGCGAGTGTCAAACTTAGTTGCACAGCTTCAGGCTTCAA CATCAAAGACTATTATATCCACTGGGTCCAGCAAAGAACGGAGCAAGGCCTC GAGTGGATTGGTCGAATAGATCCCGAGGATGGAGAGACTAAATACGCTCCGA AGTTTCAGGACAAAGCCACTATAACTGCAGACACTAGTAGTAATACCGCGTA TCTTCATCTCTCTAGTCTTACATCAGAAGATACGGCGGTCTATTATTGTGCGA GATGGGGCGCCTACTGGGGCCAGGGCACCTTGGTGACTGTAAGCTCAGGAGG CGGAGGATCAGGTGGAGGTGGCTCTGGCGGTGGTGGCTCTCAAATAGTATTG ACCCAATCTCCGGCCATCATGTCAGCATCACCAGGTGAAAAAGTGACCCTTA CATGTTCCGCCTCATCCAGCGTTTCAAGCTCCTACTTGTATTGGTATCAGCAG AAACCGGGCTCTAGCCCTAAGCTTTGGATTTATAGCACCTCAAACCTTGCTTC CGGGGTTCCTGCAAGGTTCTCCGGCAGTGGGAGCGGTACCAGCTATTCACTC ACCATTAGTTCCATGGAAGCGGAAGATGCGGCAAGTTATTTTTGTCACCAATG GTCATCATACCCTCGAACCTTCGGGGCAGGTACAAAGTTGGAGTTGAAGGGA GGCGGAGGATCAGGTGGAGGTGGCTCTGGCGGTGGTGGCTCTCAAATAGTAT TGACCCAATCTCCGGCCATCATGTCAGCATCACCAGGTGAAAAAGTGACCCT TACATGTTCCGCCTCATCCAGCGTTTCAAGCTCCTACTTGTATTGGTATCAGC AGAAACCGGGCTCTAGCCCTAAGCTTTGGATTTATAGCACCTCAAACCTTGCT TCCGGGGTTCCTGCAAGGTTCTCCGGCAGTGGGAGCGGTACCAGCTATTCACT CACCATTAGTTCCATGGAAGCGGAAGATGCGGCAAGTTATTTTTGTCACCAAT GGTCATCATACCCTCGAACCTTCGGGGCAGGTACAAAGTTGGAGTTGAAGCA CCACCACCATCACCA (SEQ ID NO: 143)BISE 1.2 VHH-LH designed using CDRs of anti-FAP clone #1 (as shown in Example 6) and using CDRs of anti-SIRPa clone #2 (as shown in Example 11):IgK Leader+ anti-FAP anti-SIRPa scFv + 6x HisMETDTLLLWVLLLWVPGSTGGLVQAGGSLRLSCWSGSFDSRNA MAWYRQALGKERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLKGEKVTLTCSASSSVSSSYLYWYQQKPGSSPKLWIYSTSNLASGVPARFSGSGSGTS YSLTISSMEAEDAASYFCHQWSSYPRTFGAGTKLELKGGGGSGGGGSGGGGSEV QLQQSGAELVKPGASVKLSCTASGFNIKDYYIHWVQQRTEQGLEWIGRIDPEDGE TKYAPKFQDKATITADTSSNTAYLHLSSLTSEDTAVYYCARWGAYWGQGTLVT VS|HHHHHH (SEQ ID NO: 72)Nucleotide sequence encoding a BISE 1.2 VHH-HL set forth in SEQ ID NO:72 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTGTGCAAGCC GGCGGTTCTCTTAGACTTTCATGTTGGAGCGGTAGCTTCGACTCCCGAAACGC CATGGCCTGGTACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGGTCGCCGGC ATAATTAGCGACGGCAGCACAAACTACGCAGATGCAGTGAAAGGCCGCTTTA CTATTTCTAGAGATAACGATAAGAACACAGTCTATCTTCAGATGAATTCCCTC AAGCCGGAAGACACCGCCGTATATTATTGCAACGCATGGCCTCCTAGGATAG GGCTTGGTAGTTGGGGGCAGGGTACTCAGGTTACAGTCAGCTCAGGGGGCGG AGGGTCAGGGGGCGGTGGTTCTCAAATAGTATTGACCCAATCTCCGGCCATC ATGTCAGCATCACCAGGTGAAAAAGTGACCCTTACATGTTCCGCCTCATCCAG CGTTTCAAGCTCCTACTTGTATTGGTATCAGCAGAAACCGGGCTCTAGCCCTA AGCTTTGGATTTATAGCACCTCAAACCTTGCTTCCGGGGTTCCTGCAAGGTTC TCCGGCAGTGGGAGCGGTACCAGCTATTCACTCACCATTAGTTCCATGGAAG CGGAAGATGCGGCAAGTTATTTTTGTCACCAATGGTCATCATACCCTCGAACC TTCGGGGCAGGTACAAAGTTGGAGTTGAAGGGAGGCGGAGGATCAGGTGGA GGTGGCTCTGGCGGTGGTGGCTCTGAAGTCCAATTGCAGCAATCCGGAGCTG AATTGGTTAAGCCGGGTGCGAGTGTCAAACTTAGTTGCACAGCTTCAGGCTTC AACATCAAAGACTATTATATCCACTGGGTCCAGCAAAGAACGGAGCAAGGCC TCGAGTGGATTGGTCGAATAGATCCCGAGGATGGAGAGACTAAATACGCTCCGAAGTTTCAGGACAAAGCCACTATAACTGCAGACACTAGTAGTAATACCGCG TATCTTCATCTCTCTAGTCTTACATCAGAAGATACGGCGGTCTATTATTGTGC GAGATGGGGCGCCTACTGGGGCCAGGGCACCTTGGTGACTGTAAGCTCAGGA GGCGGAGGATCAGGTGGAGGTGGCTCTGGCGGTGGTGGCTCTCAAATAGTAT TGACCCAATCTCCGGCCATCATGTCAGCATCACCAGGTGAAAAAGTGACCCT TACATGTTCCGCCTCATCCAGCGTTTCAAGCTCCTACTTGTATTGGTATCAGC AGAAACCGGGCTCTAGCCCTAAGCTTTGGATTTATAGCACCTCAAACCTTGCT TCCGGGGTTCCTGCAAGGTTCTCCGGCAGTGGGAGCGGTACCAGCTATTCACT CACCATTAGTTCCATGGAAGCGGAAGATGCGGCAAGTTATTTTTGTCACCAAT GGTCATCATACCCTCGAACCTTCGGGGCAGGTACAAAGTTGGAGTTGAAGCA CCACCACCATCACCA (SEQ ID NO: 144)BISE 2.1 VHH-HL designed using CDRs of anti-FAP clone #2 (as shown in Example 6) and using CDRs of anti-SIRPa clone #1 (as shown in Example 11):QVQLQESGGGLVQTGGSLRLSCAASGSIFVGNA MGWYRQALGNQRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKP EDTAVYYCNLWPPRIGFASWGQGTQVTVSS^GGSGGGS|EVQLQQSGAELVKPG ASVKLSCTASGFNIKDYYIHWVQQRTEQGLEWIGRIDPEDGETKYAPKFQDKATI TADTSSNTAYLHLSSLTSEDTAVYYCARWGAYWGQGTLVTVSGGGGSGGGGSG GGGSAYWGQGTLVTVSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTLTC SASSSVSSSYLYWYQQKPGSSPKLWIYSTSNLASGVPARFSGSGSGTSYSLTISSM EAEDAASYFCHQWSSYPRTFGAGTKLELK)HHHHHH| (SEQ ID NO:73)Nucleotide sequence encoding a BISE 2.1 VHH-HL set forth in SEQ ID NO:73 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTGGTGCAGACC GGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTTTTGTGGGCA ACGCGATGGGCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGAACTGGTGGC GGGCATTACCAGCGATGGCATTACCTATTATCCGGATAGCGTGAAAGGCCGC TTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGCAGATGAACACATTGGCTTTGCGAGCTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCGGG GGCGGAGGGTCAGGGGGCGGTGGTTCTGAAGTCCAATTGCAGCAATCCGGAG CTGAATTGGTTAAGCCGGGTGCGAGTGTCAAACTTAGTTGCACAGCTTCAGG CTTCAACATCAAAGACTATTATATCCACTGGGTCCAGCAAAGAACGGAGCAA GGCCTCGAGTGGATTGGTCGAATAGATCCCGAGGATGGAGAGACTAAATACG CTCCGAAGTTTCAGGACAAAGCCACTATAACTGCAGACACTAGTAGTAATAC CGCGTATCTTCATCTCTCTAGTCTTACATCAGAAGATACGGCGGTCTATTATT GTGCGAGATGGGGCGCCTACTGGGGCCAGGGCACCTTGGTGACTGTAAGCTC AGGAGGCGGAGGATCAGGTGGAGGTGGCTCTGGCGGTGGTGGCTCTCAAATA GTATTGACCCAATCTCCGGCCATCATGTCAGCATCACCAGGTGAAAAAGTGA CCCTTACATGTTCCGCCTCATCCAGCGTTTCAAGCTCCTACTTGTATTGGTATC AGCAGAAACCGGGCTCTAGCCCTAAGCTTTGGATTTATAGCACCTCAAACCTT GCTTCCGGGGTTCCTGCAAGGTTCTCCGGCAGTGGGAGCGGTACCAGCTATTC ACTCACCATTAGTTCCATGGAAGCGGAAGATGCGGCAAGTTATTTTTGTCACC AATGGTCATCATACCCTCGAACCTTCGGGGCAGGTACAAAGTTGGAGTTGAA GGGAGGCGGAGGATCAGGTGGAGGTGGCTCTGGCGGTGGTGGCTCTCAAATA GTATTGACCCAATCTCCGGCCATCATGTCAGCATCACCAGGTGAAAAAGTGA CCCTTACATGTTCCGCCTCATCCAGCGTTTCAAGCTCCTACTTGTATTGGTATC AGCAGAAACCGGGCTCTAGCCCTAAGCTTTGGATTTATAGCACCTCAAACCTT GCTTCCGGGGTTCCTGCAAGGTTCTCCGGCAGTGGGAGCGGTACCAGCTATTC ACTCACCATTAGTTCCATGGAAGCGGAAGATGCGGCAAGTTATTTTTGTCACC AATGGTCATCATACCCTCGAACCTTCGGGGCAGGTACAAAGTTGGAGTTGAA GCACCACCACCATCACCA (SEQ ID NO: 145)BISE 2.2 VHH-LH designed using CDRs of anti-FAP clone #2 (as shown in Example 6) and using CDRs of anti-SIRPa clone #2 (as shown in Example 11):|METDTLLLWVLLLWVPGSTGD|QVQLQESGGGLVQTGGSLRLSCAASGSIFVGNA MGWYRQALGNQRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKP EDTAVYYCNLWPPRIGFASWGQGTQVTVSS^GGSGGGS|AYWGQGTLVTVSGG GGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTLTCSASSSVSSSYLYWYQQKPGSSPKLWIYSTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAASYFCHQWSSYPRT FGAGTKLELKGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKLSCTASGFNI KDYYIHWVQQRTEQGLEWIGRIDPEDGETKYAPKFQDKATITADTSSNTAYLHLS SLTSEDTAVYYCARWGAYWGQGTLVTVS[HHHHHH| (SEQ ID NO:74)Nucleotide sequence encoding a BISE 2.2 VHH-HL set forth in SEQ ID NO:74 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTGGTGCAGACC GGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTTTTGTGGGCA ACGCGATGGGCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGAACTGGTGGC GGGCATTACCAGCGATGGCATTACCTATTATCCGGATAGCGTGAAAGGCCGC TTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGCAGATGAACA GCCTGAAACCGGAAGATACCGCGGTGTATTATTGCAACCTGTGGCCGCCGCG CATTGGCTTTGCGAGCTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCGGG GGCGGAGGGTCAGGGGGCGGTGGTTCTCAAATAGTATTGACCCAATCTCCGG CCATCATGTCAGCATCACCAGGTGAAAAAGTGACCCTTACATGTTCCGCCTCA TCCAGCGTTTCAAGCTCCTACTTGTATTGGTATCAGCAGAAACCGGGCTCTAG CCCTAAGCTTTGGATTTATAGCACCTCAAACCTTGCTTCCGGGGTTCCTGCAA GGTTCTCCGGCAGTGGGAGCGGTACCAGCTATTCACTCACCATTAGTTCCATG GAAGCGGAAGATGCGGCAAGTTATTTTTGTCACCAATGGTCATCATACCCTCG AACCTTCGGGGCAGGTACAAAGTTGGAGTTGAAGGGAGGCGGAGGATCAGG TGGAGGTGGCTCTGGCGGTGGTGGCTCTGAAGTCCAATTGCAGCAATCCGGA GCTGAATTGGTTAAGCCGGGTGCGAGTGTCAAACTTAGTTGCACAGCTTCAG GCTTCAACATCAAAGACTATTATATCCACTGGGTCCAGCAAAGAACGGAGCA AGGCCTCGAGTGGATTGGTCGAATAGATCCCGAGGATGGAGAGACTAAATAC GCTCCGAAGTTTCAGGACAAAGCCACTATAACTGCAGACACTAGTAGTAATA CCGCGTATCTTCATCTCTCTAGTCTTACATCAGAAGATACGGCGGTCTATTAT TGTGCGAGATGGGGCGCCTACTGGGGCCAGGGCACCTTGGTGACTGTAAGCT CAGGAGGCGGAGGATCAGGTGGAGGTGGCTCTGGCGGTGGTGGCTCTCAAAT AGTATTGACCCAATCTCCGGCCATCATGTCAGCATCACCAGGTGAAAAAGTG ACCCTTACATGTTCCGCCTCATCCAGCGTTTCAAGCTCCTACTTGTATTGGTAT CAGCAGAAACCGGGCTCTAGCCCTAAGCTTTGGATTTATAGCACCTCAAACCTCACTCACCATTAGTTCCATGGAAGCGGAAGATGCGGCAAGTTATTTTTGTCAC CAATGGTCATCATACCCTCGAACCTTCGGGGCAGGTACAAAGTTGGAGTTGA AGCACCACCACCATCACCA (SEQ ID NO: 146)Example 15: Exemplary Polypeptides Present on NK CellsThis Example provides an amino acid sequence of a human polypeptides present on NK cells.Exemplary human CD16a polypeptide MWQLLLPTALLLLVSAGMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSP EDNSTQWFHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGW LLLQAPRWVFKEEDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKA TLKDSGSYFCRGLFGSKNVSSETVNITITQGLAVSTISSFFPPGYQVSFCLVMVLLF AVDTGLYFSVKTNIRSSTRDWKDHKFKWRKDPQDK (SEQ ID NO: 113)Exemplary human Nkp30 polypeptide MAWMLLLILIMVHPGSCALWVSQPPE1RTLEGSSAFLPCSFNASQGRLAIGSVTW FRDEVVPGKEVRNGTPEFRGRLAPLASSRFLHDHQAELHIRDVRGHDASIYVCRV EVLGLGVGTGNGTRLVVEKEHPQLGAGTVLLLRAGFYAVSFLSVAVGSTVYYQ GKCLTWKGPRRQLPAVVPAPLPPPCGSSAHLLPPVPGG (SEQ ID NO: 114)Exemplary human NKG2D polypeptide MGWIRGRRSRHSWEMSEFHNYNLDLKKSDFSTRWQKQRCPVVKSKCRENASPF FFCCFIAVAMGIRFIIMVTIWSAVFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNC YQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTN GSWQWEDGSILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV(SEQ ID NO: 115)Example 16: Exemplary Binding Molecules Having the Ability to Bind a NK Cell This Example provides structures of exemplary VHHs and scFvs having the ability' to bind aNK cell (e.g., having the ability to bind a polypeptide expressed on the surface of a NK cell). The and framework sequences of each variable domain areprovided and delineated.The CDRs indicated herein are based on a Kabat numbering scheme. It will be understood that alternative CDRs may be derived from the provided sequences using alterative numbering schemes such as Chothia numbering.Exemplary anti-CD16a VHH (anti-CD16a clone #1)Nucleotide sequence encoding an anti-CD16a VHH set forth in SEQ ID NO:38 CAGGTGCAACTTGTTGAGTCAGGTGGCGGACTTGTGCAGCCAGGAGGCTCTC TCCGCTTGTCATGTGCGGCGTCCGGTCTCACCTTCTCATCCTACAATATGGGTT GGTTTAGACAAGCACCCGGGCAGGGACTGGAAGCGGTCGCATCTATCACTTG GAGTGGACGGGACACCTTTTATGCCGATTCAGTCAAGGGGCGGTTCACGATT AGCAGGGATAACTCTAAGAATACATTGTATCTGCAGATGAATTCTCTTCGGGC GGAAGACACGGCGGTTTACTATTGTGCGGCAAACCCTTGGCCGGTTGCTGCTC CGCGATCAGGAACCTATTGGGGACAAGGTACGCTGGTAACGGTCTCCTCA(SEQ ID NO: 147)Exemplary anti-CD16a scFv (anti-CD16a clone #2)VH domain + Linker + VL domain:TTAGCCGCGATAACGCGAAAAACAGCCTGTATCTGCAGATGAACAGCCTGCG CGCGGAAGATACCGCGGTGTATTATTGCGCGCGCGGCCGCAGCCTGCTGTTT GATTATTGGGGCCAGGGCACCCTGGTGACCGTGAGCCGCGGCGGCGGCGGCA GCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCAGCGAACTGACCCAGGATC CGGCGGTGAGCGTGGCGCTGGGCCAGACCGTGCGCATTACCTGCCAGGGCGA TAGCCTGCGCAGCTATTATGCGAGCTGGTATCAGCAGAAACCGGGCCAGGCG CCGGTGCTGGTGATTTATGGCAAAAACAACCGCCCGAGCGGCATTCCGGATC GCTTTAGCGGCAGCAGCAGCGGCAACACCGCGAGCCTGACCATTACCGGCGC GCAGGCGGAAGATGAAGCGGATTATTATTGCAACAGCCGCGATAGCAGCGGC AACCATGTGGTGTTTGGCGGCGGCACCAAACTGACCGTGCTG (SEQ ID NO: 148)Exemplary anti-CD16a scFv (anti-CD16a clone #3)VL domain + Linker + VH domain:Nucleotide sequence encoding an anti-CD16a scFv set forth in SEQ ID NO:46 AGCGAACTGACCCAGGATCCGGCGGTGAGCGTGGCGCTGGGCCAGACCGTGC GCATTACCTGCCAGGGCGATAGCCTGCGCAGCTATTATGCGAGCTGGTATCA GCAGAAACCGGGCCAGGCGCCGGTGCTGGTGATTTATGGCAAAAACAACCGC CCGAGCGGCATTCCGGATCGCTTTAGCGGCAGCAGCAGCGGCAACACCGCGA GCCTGACCATTACCGGCGCGCAGGCGGAAGATGAAGCGGATTATTATTGCAA CAGCCGCGATAGCAGCGGCAACCATGTGGTGTTTGGCGGCGGCACCAAACTG ACCGTGCTGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGC AGCGAAGTGCAGCTGGTGGAAAGCGGCGGCGGCGTGGTGCGCCCGGGCGGC AGCCTGCGCCTGAGCTGCGCGGCGAGCGGCTTTACCTTTGATGATTATGGCAT GAGCTGGGTGCGCCAGGCGCCGGGCAAAGGCCTGGAATGGGTGAGCGGCAT TAACTGGAACGGCGGCAGCACCGGCTATGCGGATAGCGTGAAAGGCCGCTTTTGCGCGCGGAAGATACCGCGGTGTATTATTGCGCGCGCGGCCGCAGCCTGCT GTTTGATTATTGGGGCCAGGGCACCCTGGTGACCGTGAGCCGC (SEQ ID NO: 149)Exemplary anti-Nkp30 VHH (anti-Nkp30 clone #1)Nucleotide sequence encoding an anti-Nkp30 VHH set forth in SEQ ID NO:50 GAAGTGCAGCTGGTGGAAAGCGGCGGCGGCGTGGTGCAGCCGGGCGGCAGC CTGCGCCTGAGCTGCGCGACCAGCGGCTTTACCCTGGATGATTATACCATTGG CTGGGTGCGCCAGGCGCCGGGCAAAGAACATGAAGGCGTGAGCTGCTTTAGC CCGAGCGATGGCACCACCTATTATGCGGATAGCGTGAAAGGCCGCTTTACCT TTAGCCGCGATAACGCGAAAAACACCGTGTATCTGCAGATGAACAGCCTGCG CGCGGAAGATACCGCGGTGTATTATTGCGCGGCGAGCTTTGCGGATGGCAGC AGCTGGTGCTATGATTATTGGGGCCAGGGCACCCTGGTGACCGTGAGCAGC(SEQ ID NO: 150)Exemplary anti-NKG2D VHH (anti-NKG2D clone #1) QVQLVQSGGGLVQAGGSLRLSCAAS|GLTISNYA|MAWFRQAPGKEREFVAL|INW| ISGNKIYYADSVKGRFTIARDNAKNTVDLQMNSLKPEDTAVYYCIAARFHSYAASII YYSASTYKF|WGQGTQVTVSS (SEQ ID NO:54)Nucleotide sequence encoding an anti-NKG2D VHH set forth in SEQ ID NO:54 CAGGTGCAGCTGGTGCAGAGCGGCGGCGGCCTGGTGCAGGCGGGCGGCAGC CTGCGCCTGAGCTGCGCGGCGAGCGGCCTGACCATTAGCAACTATGCGATGG CGTGGTTTCGCCAGGCGCCGGGCAAAGAACGCGAATTTGTGGCGCTGATTAA CTGGAGCGGCAACAAATATTATGCGGATAGCGTGAAAGGCCGCTTTACCATT GCGCGCGATAACGCGAAAAACACCGTGGATCTGCAGATGAACAGCCTGAAA CCGGAAGATACCGCGGTGTATTATTGCGCGGCGCGCTTTCATAGCTATGCGGC GAGCACCTATTATAGCGCGAGCACCTATAAATTTTGGGGCCAGGGCACCCAG GTGACCGTGAGCAGC (SEQ ID NO: 151)Exemplary anti-NKG2D VHH (anti-NKG2D clone #2)Nucleotide sequence encoding an anti-NKG2D VHH set forth in SEQ ID NO:58 CAGGTGCAGCTGGTGCAGAGCGGCGGCGGCCTGGTGCAGCCGGGCGGCAGC CTGCGCCTGAGCTGCGCGGCGAGCGGCTTTACCTTTGATGATTATGCGATGAG CTGGGTGCGCCAGGCGCCGGGCAAAGGCCTGGAATGGGTGAGCGCGATTAGC TGGAGCGGCCGCACCACCTATTATGCGGAAAGCATGAAAGGCCGCTTTACCA CCAGCCGCGATAACGCGAAAAACACCCTGTATCTGCAGATGAACAGCCTGAA ACCGGAAGATACCGCGCTGTATTATGCGCGCGGCGATGTGGCGATTCGCGGC AACCTGGATGCGTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGC (SEQ ID NO: 152)Example 17: Exemplary secreted tri-specific NK engager (STriKE) MoleculesThis Example provides amino acid sequences of STriKEs designed to bind a FAP polypeptide and to bind a NK cell and nucleotide sequences encoding such STriKEs. The various components of each STriKE (e.g., domains and linkers) are provided and delineated.STriKE molecule 1.1 designed using CDRs of anti-CD16a clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #2 (as shown in Example 6):IgK Leader+ anti -CD 16a VHH + Li+ IL-15 Polypeptide + LiFAP VHH + |6x His Tag|METDTLLLWVLLLWVPGSTGD|QVQLVESGGGLVQPGGSLRLSCAASGLTFSSYN MGWFRQAPGQGLEAVASITWSGRDTFYADSVKGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCAANPWPVAAPRSGTYWGQGTLVTVSS|PSGQAGAAASESLFVSNH ^Y|NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS|EASGGPE|QVQLQESGGGLVQTGGSLRLSCAASGSIFVGNAMGWYRQALGN QRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKPEDTAVYYCNLW PPRIGFASWGQGTQVTVSS|HHHHHH| (SEQ ID NO:75)Nucleotide sequence encoding a STriKE molecule 1.1 set forth in SEQ ID NO:75 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAACTTGTTGAGTCAGGTGGCGGACTTGTGCAGCCA GGAGGCTCTCTCCGCTTGTCATGTGCGGCGTCCGGTCTCACCTTCTCATCCTA CAATATGGGTTGGTTTAGACAAGCACCCGGGCAGGGACTGGAAGCGGTCGCA TCTATCACTTGGAGTGGACGGGACACCTTTTATGCCGATTCAGTCAAGGGGCG GTTCACGATTAGCAGGGATAACTCTAAGAATACATTGTATCTGCAGATGAATT CTCTTCGGGCGGAAGACACGGCGGTTTACTATTGTGCGGCAAACCCTTGGCC GGTTGCTGCTCCGCGATCAGGAACCTATTGGGGACAAGGTACGCTGGTAACG GTCTCCTCACCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTTTG TGAGCAACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAAAT TGAAGATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAAGC GATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGAAC TGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTGGA AAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGACC GAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAGAA TTTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAGGC GTCAGGAGGCCCGGAACAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTGGT GCAGACCGGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTTTT GTGGGCAACGCGATGGGCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGAAC TGGTGGCGGGCATTACCAGCGATGGCATTACCTATTATCCGGATAGCGTGAA AGGCCGCTTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGCAG ATGAACAGCCTGAAACCGGAAGATACCGCGGTGTATTATTGCAACCTGTGGC CGCCGCGCATTGGCTTTGCGAGCTGGGGCCAGGGCACCCAGGTGACCGTGAG CAGCCACCACCACCATCACCA (SEQ ID NO: 153)STriKE molecule 1.2 designed using CDRs of anti-CD16a clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #1 (as shown in Example 6):IgK Leader+ anti-CD16a VHH ++ IL-15 Polypeptide ++ anti- FAP VHH + |6x His Tag|METDTLLLWVLLLWVPGSTGD|QVQLVESGGGLVQPGGSLRLSCAASGLTFSSYN MGWFRQAPGQGLEAVASITWSGRDTFYADSVKGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCAANPWPVAAPRSGTYWGQGTLVTVSS|PSGQAGAAASESLFVSNH ^Y|NWVNVISDLICKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMF INTS|EASGGPE|QVQLQESGGGLVQAGGSLRLSCWSGSFDSRNAMAWYRQALGK ERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLKPEDTAVYYCN AWPPRIGLGSWGQGTQVTVSS|HHHHHH| (SEQ ID NO:76)Nucleotide sequence encoding a STriKE molecule 1.2 set forth in SEQ ID NO:76 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAACTTGTTGAGTCAGGTGGCGGACTTGTGCAGCCA GGAGGCTCTCTCCGCTTGTCATGTGCGGCGTCCGGTCTCACCTTCTCATCCTA CAATATGGGTTGGTTTAGACAAGCACCCGGGCAGGGACTGGAAGCGGTCGCA TCTATCACTTGGAGTGGACGGGACACCTTTTATGCCGATTCAGTCAAGGGGCG GTTCACGATTAGCAGGGATAACTCTAAGAATACATTGTATCTGCAGATGAATT CTCTTCGGGCGGAAGACACGGCGGTTTACTATTGTGCGGCAAACCCTTGGCC GGTTGCTGCTCCGCGATCAGGAACCTATTGGGGACAAGGTACGCTGGTAACG GTCTCCTCACCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTTTG TGAGCAACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAAAT TGAAGATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAAGC GATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGAAC TGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTGGA AAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGACC GAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAGAA TTTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAGGC GTCAGGAGGCCCGGAACAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTGTGCAAGCCGGCGGTTCTCTTAGACTTTCATGTTGGAGCGGTAGCTTCGACTCCCG AAACGCCATGGCCTGGTACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGGTC GCCGGCATAATTAGCGACGGCAGCACAAACTACGCAGATGCAGTGAAAGGC CGCTTTACTATTTCTAGAGATAACGATAAGAACACAGTCTATCTTCAGATGAA TTCCCTCAAGCCGGAAGACACCGCCGTATATTATTGCAACGCATGGCCTCCTA GGATAGGGCTTGGTAGTTGGGGGCAGGGTACTCAGGTTACAGTCAGCTCACA CCACCACCATCACCA (SEQ ID NO: 154)STriKE molecule 2.1 designed using CDRs of anti-CD16a clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #3 (as shown in Example 6):IgK Leader Sequence! + anti-CD16a VHH + [Linker] + IL- 15 Polypeptide + |Linker| + anti- FAP scFv + 6x HisMETDTLLLWVLLLWVPGSTGDIQVQLVESGGGLVQPGGSLRLSCAASGLTFSSYN MGWFRQAPGQGLEAVASITWSGRDTFYADSVKGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCAANPWPVAAPRSGTYWGQGTLVTVSS|PSGQAGAAASESLFVSNH ^Y|NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMF INTS|ASGGPfQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQ GLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCAR TLTAPFAFWGQGTLVTVSAGSTSGSGKPGSGEGSTKGQIVLTQSPAIMSASPGEK VTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSL TISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKR|HHHHHH| (SEQ ID NO:77)Nucleotide sequence encoding a STriKE molecule 2.1 set forth in SEQ ID NO:77 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAACTTGTTGAGTCAGGTGGCGGACTTGTGCAGCCA GGAGGCTCTCTCCGCTTGTCATGTGCGGCGTCCGGTCTCACCTTCTCATCCTA CAATATGGGTTGGTTTAGACAAGCACCCGGGCAGGGACTGGAAGCGGTCGCA TCTATCACTTGGAGTGGACGGGACACCTTTTATGCCGATTCAGTCAAGGGGCG GTTCACGATTAGCAGGGATAACTCTAAGAATACATTGTATCTGCAGATGAATT CTCTTCGGGCGGAAGACACGGCGGTTTACTATTGTGCGGCAAACCCTTGGCCGGTTGCTGCTCCGCGATCAGGAACCTATTGGGGACAAGGTACGCTGGTAACG GTCTCCTCACCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTTTG TGAGCAACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAAAT TGAAGATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAAGC GATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGAAC TGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTGGA AAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGACC GAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAGAT TTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAGGCG TCAGGAGGCCCGGAACAGGTGCAGCTCCAGCAGAGTGGCGCAGAGCTCGCTC GCCCAGGCGCTTCTGTGAATCTGAGTTGTAAGGCCTCCGGATATACTTTTACG AACAACGGCATCAACTGGCTGAAGCAGCGGACCGGCCAGGGCCTGGAGTGG ATCGGCGAAATATACCCCCGGTCCACAAACACTCTCTATAACGAGAAGTTTA AGGGCAAAGCAACTCTGACCGCGGACAGGTCCTCTAACACAGCCTATATGGA GCTGAGAAGCTTGACGAGTGAGGACTCCGCTGTCTATTTTTGCGCCCGAACTC TGACCGCTCCTTTTGCTTTTTGGGGCCAGGGCACGCTCGTGACCGTAAGTGCG GGCTCCACTAGCGGTTCCGGCAAACCTGGCAGCGGAGAAGGCAGCACCAAA GGGCAGATCGTCCTGACGCAGTCTCCAGCCATCATGAGCGCCTCACCCGGCG AAAAGGTGACCATGACCTGCTCAGCCTCTTCTGGTGTGAATTTCATGCACTGG TACCAGCAAAAAAGTGGGACCTCCCCTAAAAGGTGGATCTTCGATACCAGCA AACTGGCTTCTGGCGTTCCCGCAAGGTTTAGCGGCTCTGGTTCCGGCACATCA TACAGCCTGACGATCAGCAGCATGGAGGCAGAAGACGCAGCTACCTATTACT GCCAGCAATGGAGCTTTAACCCACCTACTTTCGGAGGAGGAACAAAGCTGGA AATAAAAAGACACCACCACCATCACCA (SEQ ID NO: 155)STriKE molecule 2.2 designed using CDRs of anti-CD16a clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #4 (as shown in Example 6):IgK Leader Sequence! + anti-CD16a VHH + |Linker| + IL-15 Polypeptide + |Linker| + anti- FAP VHH + |6x His Tag)METDTLLLWVLLLWVPGSTGDIQVQLVESGGGLVQPGGSLRLSCAASGLTFSSYN MGWFRQAPGQGLEAVASITWSGRDTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAANPWPVAAPRSGTYWGQGTLVTVSS|PSGQAGAAASESLFVSNH ^Y|NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGG GTKLEIKRGSTSGSGKPGSGEGSTKGQVQLQQSGAELARPGASVNLSCKASGYTF TNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMEL RSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSA|HHHHHH| (SEQ ID NO: 78)Nucleotide sequence encoding a STriKE molecule 2.2 set forth in SEQ ID NO:78 sATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCA GTACAGGTGATCAGGTGCAACTTGTTGAGTCAGGTGGCGGACTTGTGCAGCC AGGAGGCTCTCTCCGCTTGTCATGTGCGGCGTCCGGTCTCACCTTCTCATCCT ACAATATGGGTTGGTTTAGACAAGCACCCGGGCAGGGACTGGAAGCGGTCGC ATCTATCACTTGGAGTGGACGGGACACCTTTTATGCCGATTCAGTCAAGGGGC GGTTCACGATTAGCAGGGATAACTCTAAGAATACATTGTATCTGCAGATGAA TTCTCTTCGGGCGGAAGACACGGCGGTTTACTATTGTGCGGCAAACCCTTGGC CGGTTGCTGCTCCGCGATCAGGAACCTATTGGGGACAAGGTACGCTGGTAAC GGTCTCCTCACCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTTT GTGAGCAACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAAA TTGAAGATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAAG CGATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGAA CTGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTGG AAAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGAC CGAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAGA ATTTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAGG CGTCAGGAGGCCCGGAACAGATCGTCCTGACGCAGTCTCCAGCCATCATGAG CGCCTCACCCGGCGAAAAGGTGACCATGACCTGCTCAGCCTCTTCTGGTGTGA ATTTCATGCACTGGTACCAGCAAAAAAGTGGGACCTCCCCTAAAAGGTGGAT CTTCGATACCAGCAAACTGGCTTCTGGCGTTCCCGCAAGGTTTAGCGGCTCTG GTTCCGGCACATCATACAGCCTGACGATCAGCAGCATGGAGGCAGAAGACGC AGCTACCTATTACTGCCAGCAATGGAGCTTTAACCCACCTACTTTCGGAGGAGGAACAAAGCTGGAAATAAAAAGAGGCTCCACTAGCGGTTCCGGCAAACCTG GCAGCGGAGAAGGCAGCACCAAAGGGCAGGTGCAGCTCCAGCAGAGTGGCG CAGAGCTCGCTCGCCCAGGCGCTTCTGTGAATCTGAGTTGTAAGGCCTCCGGA TATACTTTTACGAACAACGGCATCAACTGGCTGAAGCAGCGGACCGGCCAGG GCCTGGAGTGGATCGGCGAAATATACCCCCGGTCCACAAACACTCTCTATAA CGAGAAGTTTAAGGGCAAAGCAACTCTGACCGCGGACAGGTCCTCTAACACA GCCTATATGGAGCTGAGAAGCTTGACGAGTGAGGACTCCGCTGTCTATTTTTG CGCCCGAACTCTGACCGCTCCTTTTGCTTTTTGGGGCCAGGGCACGCTCGTGA CCGTAAGTGCGCACCACCACCATCACCA (SEQ ID NO: 156)STriKE molecule 3.1 designed using CDRs of anti-FAP clone #3 (as shown in Example 6) and using CDRs of anti-CD16a clone #1 (as shown in Example 13): + anti-GYTFTNN GINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLT SEDSAVYFCARTLTAPFAFWGQGTLVTVSAGSTSGSGKPGSGEGSTKGQIVLTQS PAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARF SGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKR|PSGQAGAAA| SESLFVSNHAY|NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFL LELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQ SFVHIVQMFINTS|EASGGPE|QVQLVESGGGLVQPGGSLRLSCAASGLTFSSYNMG WFRQAPGQGLEAVASITWSGRDTFYADSVKGRFTISRDNSKNTLYLQMNSLRAE DT AVYYC AANP WP V AAPRSGTYWGQGTLVTV S S|HHHHHH| (SEQ ID NO:79)Nucleotide sequence encoding a STriKE molecule 3.1 set forth in SEQ ID NO:79 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTCCAGCAGAGTGGCGCAGAGCTCGCTCGCCCA GGCGCTTCTGTGAATCTGAGTTGTAAGGCCTCCGGATATACTTTTACGAACAA CGGCATCAACTGGCTGAAGCAGCGGACCGGCCAGGGCCTGGAGTGGATCGGC GAAATATACCCCCGGTCCACAAACACTCTCTATAACGAGAAGTTTAAGGGCAAAGCAACTCTGACCGCGGACAGGTCCTCTAACACAGCCTATATGGAGCTGAG AAGCTTGACGAGTGAGGACTCCGCTGTCTATTTTTGCGCCCGAACTCTGACCG CTCCTTTTGCTTTTTGGGGCCAGGGCACGCTCGTGACCGTAAGTGCGGGCTCC ACTAGCGGTTCCGGCAAACCTGGCAGCGGAGAAGGCAGCACCAAAGGGCAG ATCGTCCTGACGCAGTCTCCAGCCATCATGAGCGCCTCACCCGGCGAAAAGG TGACCATGACCTGCTCAGCCTCTTCTGGTGTGAATTTCATGCACTGGTACCAG CAAAAAAGTGGGACCTCCCCTAAAAGGTGGATCTTCGATACCAGCAAACTGG CTTCTGGCGTTCCCGCAAGGTTTAGCGGCTCTGGTTCCGGCACATCATACAGC CTGACGATCAGCAGCATGGAGGCAGAAGACGCAGCTACCTATTACTGCCAGC AATGGAGCTTTAACCCACCTACTTTCGGAGGAGGAACAAAGCTGGAAATAAA AAGACCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTTTGTGAG CAACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAA GATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAAGCGATG TGCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGAACTGCA GGTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAAC CTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAA GCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTC TGCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAGGCGTCA GGAGGCCCGGAACAGGTGCAACTTGTTGAGTCAGGTGGCGGACTTGTGCAGC CAGGAGGCTCTCTCCGCTTGTCATGTGCGGCGTCCGGTCTCACCTTCTCATCC TACAATATGGGTTGGTTTAGACAAGCACCCGGGCAGGGACTGGAAGCGGTCG CATCTATCACTTGGAGTGGACGGGACACCTTTTATGCCGATTCAGTCAAGGGG CGGTTCACGATTAGCAGGGATAACTCTAAGAATACATTGTATCTGCAGATGA ATTCTCTTCGGGCGGAAGACACGGCGGTTTACTATTGTGCGGCAAACCCTTGG CCGGTTGCTGCTCCGCGATCAGGAACCTATTGGGGACAAGGTACGCTGGTAA CGGTCTCCTCACACCACCACCATCACCA (SEQ ID NO: 157)STriKE molecule 3.2 designed using CDRs of anti-FAP clone #4 (as shown in Example 6) and using CDRs of anti-CD16a clone #1 (as shown in Example 13):IgK Leader Sequence, + anti-FAP scFv + |Linker| + IL- 15 Polypeptide + |Lin er| + anti- CD16a VHH + |6x His Tag|METDTLLLWVLLLWVPGSTGDlQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMH WYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQ QWSFNPPTFGGGTKLEIKRGSTSGSGKPGSGEGSTKGQVQLQQSGAELARPGASV NLSCKASGYTFTNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTA DRSSNTAYMELRSLTSEDSAVYFCA TLTAPFAFWGQGTLVTVSA|PSGQAGAAA| SESLFVSNHAY|NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFL LELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQ SFVHIVQMFINTS|EASGGPE|QVQLVESGGGLVQPGGSLRLSCAASGLTFSSYNMG WFRQAPGQGLEAVASITWSGRDTFYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCAANPWPVAAPRSGTYWGQGTLVTVSS|HHHHHH| (SEQ ID NO: 80)Nucleotide sequence encoding a STriKE molecule 3.2 set forth in SEQ ID NO:80 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGATCGTCCTGACGCAGTCTCCAGCCATCATGAGCGCCTCAC CCGGCGAAAAGGTGACCATGACCTGCTCAGCCTCTTCTGGTGTGAATTTCATG CACTGGTACCAGCAAAAAAGTGGGACCTCCCCTAAAAGGTGGATCTTCGATA CCAGCAAACTGGCTTCTGGCGTTCCCGCAAGGTTTAGCGGCTCTGGTTCCGGC ACATCATACAGCCTGACGATCAGCAGCATGGAGGCAGAAGACGCAGCTACCT ATTACTGCCAGCAATGGAGCTTTAACCCACCTACTTTCGGAGGAGGAACAAA GCTGGAAATAAAAAGAGGCTCCACTAGCGGTTCCGGCAAACCTGGCAGCGGA GAAGGCAGCACCAAAGGGCAGGTGCAGCTCCAGCAGAGTGGCGCAGAGCTC GCTCGCCCAGGCGCTTCTGTGAATCTGAGTTGTAAGGCCTCCGGATATACTTT TACGAACAACGGCATCAACTGGCTGAAGCAGCGGACCGGCCAGGGCCTGGA GTGGATCGGCGAAATATACCCCCGGTCCACAAACACTCTCTATAACGAGAAG TTTAAGGGCAAAGCAACTCTGACCGCGGACAGGTCCTCTAACACAGCCTATA TGGAGCTGAGAAGCTTGACGAGTGAGGACTCCGCTGTCTATTTTTGCGCCCGA ACTCTGACCGCTCCTTTTGCTTTTTGGGGCCAGGGCACGCTCGTGACCGTAAG TGCGCCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTTTGTGAGC AACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAG ATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGT GCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGAACTGCAG GTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAG CGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAGAATTTCT GCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAGGCGTCAG GAGGCCCGGAACAGGTGCAACTTGTTGAGTCAGGTGGCGGACTTGTGCAGCC AGGAGGCTCTCTCCGCTTGTCATGTGCGGCGTCCGGTCTCACCTTCTCATCCT ACAATATGGGTTGGTTTAGACAAGCACCCGGGCAGGGACTGGAAGCGGTCGC ATCTATCACTTGGAGTGGACGGGACACCTTTTATGCCGATTCAGTCAAGGGGC GGTTCACGATTAGCAGGGATAACTCTAAGAATACATTGTATCTGCAGATGAA TTCTCTTCGGGCGGAAGACACGGCGGTTTACTATTGTGCGGCAAACCCTTGGC CGGTTGCTGCTCCGCGATCAGGAACCTATTGGGGACAAGGTACGCTGGTAAC GGTCTCCTCACACCACCACCATCACCA (SEQ ID NO: 158)STriKE molecule 4.1 designed using CDRs of anti-Nkp30 clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #3 (as shown in Example 6):IgK Leader Sequence! + anti-Nkp3O VHH + |Linker| + IL-15 Polypeptide +FAP VHH + |6x His Ta^METDTLLLWVLLLWVPGSTGD|EVQLVESGGGVVQPGGSLRLSCATSGFTLDDY TIGWVRQAPGKEHEGVSCFSPSDGTTYYADSVKGRFTFSRDNAKNTVYLQMNSL RAEDTAVYYCAASFADGSSWCYDYWGQGTLVTVSS|PSGQAGAAASESLFVSNH| ^Y|NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMF INTS|ASGGPfQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQ GLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMELRSLTSEDSAVYFCAR TLTAPFAFWGQGTLVTVSAGSTSGSGKPGSGEGSTKGQIVLTQSPAIMSASPGEK VTMTCSASSGVNFMHWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSL TISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKRIHHHHHHI (SEQ ID NO:81)Nucleotide sequence encoding a STriKE molecule 4.1 set forth in SEQ ID NO:81 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATGAAGTGCAGCTGGTGGAAAGCGGCGGCGGCGTGGTGCAGCC GGGCGGCAGCCTGCGCCTGAGCTGCGCGACCAGCGGCTTTACCCTGGATGATTATACCATTGGCTGGGTGCGCCAGGCGCCGGGCAAAGAACATGAAGGCGTGA GCTGCTTTAGCCCGAGCGATGGCACCACCTATTATGCGGATAGCGTGAAAGG CCGCTTTACCTTTAGCCGCGATAACGCGAAAAACACCGTGTATCTGCAGATG AACAGCCTGCGCGCGGAAGATACCGCGGTGTATTATTGCGCGGCGAGCTTTG CGGATGGCAGCAGCTGGTGCTATGATTATTGGGGCCAGGGCACCCTGGTGAC CGTGAGCAGCCCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTT TGTGAGCAACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAA ATTGAAGATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAA GCGATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGA ACTGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTG GAAAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGA CCGAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAG AATTTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAG GCGTCAGGAGGCCCGGAACAGGTGCAGCTCCAGCAGAGTGGCGCAGAGCTC GCTCGCCCAGGCGCTTCTGTGAATCTGAGTTGTAAGGCCTCCGGATATACTTT TACGAACAACGGCATCAACTGGCTGAAGCAGCGGACCGGCCAGGGCCTGGA GTGGATCGGCGAAATATACCCCCGGTCCACAAACACTCTCTATAACGAGAAG TTTAAGGGCAAAGCAACTCTGACCGCGGACAGGTCCTCTAACACAGCCTATA TGGAGCTGAGAAGCTTGACGAGTGAGGACTCCGCTGTCTATTTTTGCGCCCGA ACTCTGACCGCTCCTTTTGCTTTTTGGGGCCAGGGCACGCTCGTGACCGTAAG TGCGGGCTCCACTAGCGGTTCCGGCAAACCTGGCAGCGGAGAAGGCAGCACC AAAGGGCAGATCGTCCTGACGCAGTCTCCAGCCATCATGAGCGCCTCACCCG GCGAAAAGGTGACCATGACCTGCTCAGCCTCTTCTGGTGTGAATTTCATGCAC TGGTACCAGCAAAAAAGTGGGACCTCCCCTAAAAGGTGGATCTTCGATACCA GCAAACTGGCTTCTGGCGTTCCCGCAAGGTTTAGCGGCTCTGGTTCCGGCACA TCATACAGCCTGACGATCAGCAGCATGGAGGCAGAAGACGCAGCTACCTATT ACTGCCAGCAATGGAGCTTTAACCCACCTACTTTCGGAGGAGGAACAAAGCT GGAAATAAAAAGACACCACCACCATCACCA (SEQ ID NO: 159)STriKE molecule 4.2 designed using CDRs of anti-Nkp30 clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #4 (as shown in Example 6):IgK Leader+ anti-Nkp30 VHH + Li+ IL-15 Polypeptide ++ anti- FAP scFv + |6x His Tag|METDTLLLWVLLLWVPGSTGD|EVQLVESGGGVVQPGGSLRLSCATSGFTLDDY TIGWVRQAPGKEHEGVSCFSPSDGTTYYADSVKGRFTFSRDNAKNTVYLQMNSL RAEDTAVYYCAASFADGSSWCYDYWGQGTLVTVSS|PSGQAGAAASESLFVSNH| ^Y|NWVNVISDLICKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMF INTS|EASGGPE|QIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPK RWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGG GTKLE1KRGSTSGSGKPGSGEGSTKGQVQLQQSGAELARPGASVNLSCKASGYTF TNNGINWLKQRTGQGLEWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMEL RSLTSEDSAVYFCARTLTAPFAFWGQGTLVTVSA|HHHHHH| (SEQ ID NO: 82)Nucleotide sequence encoding a STriKE molecule 4.2 set forth in SEQ ID NO:82 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATGAAGTGCAGCTGGTGGAAAGCGGCGGCGGCGTGGTGCAGCC GGGCGGCAGCCTGCGCCTGAGCTGCGCGACCAGCGGCTTTACCCTGGATGAT TATACCATTGGCTGGGTGCGCCAGGCGCCGGGCAAAGAACATGAAGGCGTGA GCTGCTTTAGCCCGAGCGATGGCACCACCTATTATGCGGATAGCGTGAAAGG CCGCTTTACCTTTAGCCGCGATAACGCGAAAAACACCGTGTATCTGCAGATG AACAGCCTGCGCGCGGAAGATACCGCGGTGTATTATTGCGCGGCGAGCTTTG CGGATGGCAGCAGCTGGTGCTATGATTATTGGGGCCAGGGCACCCTGGTGAC CGTGAGCAGCCCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTT TGTGAGCAACCATGCGTAT AACTGGGTGAACGTGATTAGCGATCTGAAAAAAATTGAAGATCTGATTCAGA GCATGCATATTGATGCGACCCTGTATACCGAAAGCGATGTGCATCCGAGCTG CAAAGTGACCGCGATGAAATGCTTTCTGCTGGAACTGCAGGTGATTAGCCTG GAAAGCGGCGATGCGAGCATTCATGATACCGTGGAAAACCTGATTATTCTGG CGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAGATTTCTGCAGAGCTTTGTG CATATTGTGCAGATGTTTATTAACACCAGCGAGGCGTCAGGAGGCCCGGAAC AGATCGTCCTGACGCAGTCTCCAGCCATCATGAGCGCCTCACCCGGCGAAAA GGTGACCATGACCTGCTCAGCCTCTTCTGGTGTGAATTTCATGCACTGGTACC AGCAAAAAAGTGGGACCTCCCCTAAAAGGTGGATCTTCGATACCAGCAAACT GGCTTCTGGCGTTCCCGCAAGGTTTAGCGGCTCTGGTTCCGGCACATCATACA GCCTGACGATCAGCAGCATGGAGGCAGAAGACGCAGCTACCTATTACTGCCA GCAATGGAGCTTTAACCCACCTACTTTCGGAGGAGGAACAAAGCTGGAAATA AAAAGAGGCTCCACTAGCGGTTCCGGCAAACCTGGCAGCGGAGAAGGCAGC ACCAAAGGGCAGGTGCAGCTCCAGCAGAGTGGCGCAGAGCTCGCTCGCCCAG GCGCTTCTGTGAATCTGAGTTGTAAGGCCTCCGGATATACTTTTACGAACAAC GGCATCAACTGGCTGAAGCAGCGGACCGGCCAGGGCCTGGAGTGGATCGGC GAAATATACCCCCGGTCCACAAACACTCTCTATAACGAGAAGTTTAAGGGCA AAGCAACTCTGACCGCGGACAGGTCCTCTAACACAGCCTATATGGAGCTGAG AAGCTTGACGAGTGAGGACTCCGCTGTCTATTTTTGCGCCCGAACTCTGACCG CTCCTTTTGCTTTTTGGGGCCAGGGCACGCTCGTGACCGTAAGTGCGCACCAC CACCATCACCA (SEQ ID NO 160)STriKE molecule 5.1 designed using CDRs of anti-Nkp30 clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #1 (as shown in Example 6):Leader Sequence! + anti-Nkp30 VHH + [Linker! + IL-15 Polypeptide + |Linker| + anti-FAP VHH + |6x His Tag|METDTLLLWVLLLWVPGSTGD|EVQLVESGGGVVQPGGSLRLSCATSGFTLDDY TIGWVRQAPGKEHEGVSCFSPSDGTTYYADSVKGRFTFSRDNAKNTVYLQMNSL RAEDTAVYYCAASFADGSSWCYDYWGQGTLVTVSS|PSGQAGAAASESLFVSNH| ^NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMF INTS|EASGGPE|QVQLQESGGGLVQAGGSLRLSCWSGSFDSRNAMAWYRQALGK ERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLKPEDTAVYYCN AWPPRIGLGSWGQGTQVTVSS (SEQ ID NO: 83)Nucleotide sequence encoding a STriKE molecule 5.1 set forth in SEQ ID NO:83 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATGAAGTGCAGCTGGTGGAAAGCGGCGGCGGCGTGGTGCAGCC GGGCGGCAGCCTGCGCCTGAGCTGCGCGACCAGCGGCTTTACCCTGGATGAT TATACCATTGGCTGGGTGCGCCAGGCGCCGGGCAAAGAACATGAAGGCGTGA GCTGCTTTAGCCCGAGCGATGGCACCACCTATTATGCGGATAGCGTGAAAGG CCGCTTTACCTTTAGCCGCGATAACGCGAAAAACACCGTGTATCTGCAGATG AACAGCCTGCGCGCGGAAGATACCGCGGTGTATTATTGCGCGGCGAGCTTTG CGGATGGCAGCAGCTGGTGCTATGATTATTGGGGCCAGGGCACCCTGGTGAC CGTGAGCAGCCCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTT TGTGAGCAACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAA ATTGAAGATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAA GCGATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGA ACTGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTG GAAAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGA CCGAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAG AATTTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAG GCGTCAGGAGGCCCGGAACAGGTTCAGTTGCAAGAATCTGGTGGCGGGCTTG TGCAAGCCGGCGGTTCTCTTAGACTTTCATGTTGGAGCGGTAGCTTCGACTCC CGAAACGCCATGGCCTGGTACCGACAAGCCCTTGGGAAGGAGAGAGTCTGGG TCGCCGGCATAATTAGCGACGGCAGCACAAACTACGCAGATGCAGTGAAAGG CCGCTTTACTATTTCTAGAGATAACGATAAGAACACAGTCTATCTTCAGATGA ATTCCCTCAAGCCGGAAGACACCGCCGTATATTATTGCAACGCATGGCCTCCT AGGATAGGGCTTGGTAGTTGGGGGCAGGGTACTCAGGTTACAGTCAGCTCAC ACCACCACCATCACCA (SEQ ID NO: 161)STriKE molecule 5.2 designed using CDRs of anti-Nkp30 clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #2 (as shown in Example 6):IgK Leader Sequence + anti-Nkp30 VHH + Linker + IL-15 Polypeptide + Linker + anti- FAP VHH + 6x HisMETDTLLLWVLLLWVPGSTGD|EVQLVESGGGVVQPGGSLRLSCATSGFTLDDY TIGWVRQAPGKEHEGVSCFSPSDGTTYYADSVKGRFTFSRDNAKNTVYLQMNSL RAEDTAVYYCAASFADGSSWCYDYWGQGTLVTVSS|PSGQAGAAASESLFVSNH| ^NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMF INTS|EASGGPE|QVQLQESGGGLVQTGGSLRLSCAASGSIFVGNAMGWYRQALGN QRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKPEDTAVYYCNLW PPRIGFASWGQGTQVTVSS|HHHHHH| (SEQ ID NO:84)Nucleotide sequence encoding a STriKE molecule 5.2 set forth in SEQ ID NO:84 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATGAAGTGCAGCTGGTGGAAAGCGGCGGCGGCGTGGTGCAGCC GGGCGGCAGCCTGCGCCTGAGCTGCGCGACCAGCGGCTTTACCCTGGATGAT TATACCATTGGCTGGGTGCGCCAGGCGCCGGGCAAAGAACATGAAGGCGTGA GCTGCTTTAGCCCGAGCGATGGCACCACCTATTATGCGGATAGCGTGAAAGG CCGCTTTACCTTTAGCCGCGATAACGCGAAAAACACCGTGTATCTGCAGATG AACAGCCTGCGCGCGGAAGATACCGCGGTGTATTATTGCGCGGCGAGCTTTG CGGATGGCAGCAGCTGGTGCTATGATTATTGGGGCCAGGGCACCCTGGTGAC CGTGAGCAGCCCGAGCGGCCAGGCGGGCGCGGCGGCGAGCGAAAGCCTGTT TGTGAGCAACCATGCGTATAACTGGGTGAACGTGATTAGCGATCTGAAAAAA ATTGAAGATCTGATTCAGAGCATGCATATTGATGCGACCCTGTATACCGAAA GCGATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAATGCTTTCTGCTGGA ACTGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCATTCATGATACCGTG GAAAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGA CCGAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGAAAAAAACATTAAAG AATTTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTATTAACACCAGCGAG GCGTCAGGAGGCCCGGAACAGGTGCAGCTGCAGGAAAGCGGCGGCGGCCTG GTGCAGACCGGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCAGCATTT TTGTGGGCAACGCGATGGGCTGGTATCGCCAGGCGCTGGGCAACCAGCGCGA ACTGGTGGCGGGCATTACCAGCGATGGCATTACCTATTATCCGGATAGCGTG AAAGGCCGCTTTACCATTAGCCGCGATAACGATAAAAACACCATTTATCTGC AGATGAACAGCCTGAAACCGGAAGATACCGCGGTGTATTATTGCAACCTGTGGCCGCCGCGCATTGGCTTTGCGAGCTGGGGCCAGGGCACCCAGGTGACCGTG AGCAGCCACCACCACCATCACCA (SEQ ID NO: 162)STriKE molecule 6.1 designed using CDRs of anti-NKG2D clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #1 (as shown in Example 6):IgK Leader Sequence + anti-NKG2D VHH + Linker + IL-15 Polypeptide + Linker + anti-FAP VHH + |6x His TagjMETDTLLLWVLLLWVPGSTGDIQVQLVQSGGGLVQAGGSLRLSCAASGLTISNY AMAWFRQAPGKEREFVALINWSGNKYYADSVKGRFTIARDNAKNTVDLQMNS LKPEDTAVYYCAARFHSYAASTYYSASTYKFWGQGTQVTVSS|PSGQAGAAASE| SLFVSNHAY|NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLE LQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSF VHIVQMFINTS|EASGGPE|QVQLQESGGGLVQAGGSLRLSCWSGSFDSRNAMAW YRQALGKERVWVAGIISDGSTNYADAVKGRFTISRDNDKNTVYLQMNSLKPEDT AVYYCNAWPPRIGLGSWGQGTQVTVSS|HHHHHH| (SEQ ID NO: 85)Nucleotide sequence encoding a STriKE molecule 6.1 set forth in SEQ ID NO:85 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTGGTGCAGAGCGGCGGCGGCCTGGTGCAGGCG GGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCCTGACCATTAGCAACT ATGCGATGGCGTGGTTTCGCCAGGCGCCGGGCAAAGAACGCGAATTTGTGGC GCTGATTAACTGGAGCGGCAACAAATATTATGCGGATAGCGTGAAAGGCCGC TTTACCATTGCGCGCGATAACGCGAAAAACACCGTGGATCTGCAGATGAACA GCCTGAAACCGGAAGATACCGCGGTGTATTATTGCGCGGCGCGCTTTCATAG CTATGCGGCGAGCACCTATTATAGCGCGAGCACCTATAAATTTTGGGGCCAG GGCACCCAGGTGACCGTGAGCAGCCCGAGCGGCCAGGCGGGCGCGGCGGCG AGCGAAAGCCTGTTTGTGAGCAACCATGCGTATAACTGGGTGAACGTGATTA GCGATCTGAAAAAAATTGAAGATCTGATTCAGAGCATGCATATTGATGCGAC CCTGTATACCGAAAGCGATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAA TGCTTTCTGCTGGAACTGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCA TTCATGATACCGTGGAAAACCTGATTATTCTGGCGAACAACAGCCTGAGCAGCAACGGCAACGTGACCGAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGA AAAAAACATTAAAGAATTTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTA TTAACACCAGCGAGGCGTCAGGAGGCCCGGAACAGGTTCAGTTGCAAGAATC TGGTGGCGGGCTTGTGCAAGCCGGCGGTTCTCTTAGACTTTCATGTTGGAGCG GTAGCTTCGACTCCCGAAACGCCATGGCCTGGTACCGACAAGCCCTTGGGAA GGAGAGAGTCTGGGTCGCCGGCATAATTAGCGACGGCAGCACAAACTACGCA GATGCAGTGAAAGGCCGCTTTACTATTTCTAGAGATAACGATAAGAACACAG TCTATCTTCAGATGAATTCCCTCAAGCCGGAAGACACCGCCGTATATTATTGC AACGCATGGCCTCCTAGGATAGGGCTTGGTAGTTGGGGGCAGGGTACTCAGG TTACAGTCAGCTCACACCACCACCATCACCA (SEQ ID NO: 163)STriKE molecule 6.2 designed using CDRs of anti-NKG2D clone #1 (as shown in Example 13) and using CDRs of anti-FAP clone #2 (as shown in Example 6):Leader Sequence) + anti-NKG2D VHH + |Linker| + IL-15 Polypeptide + |Linker| + anti-FAP VHH + 6x His TagMETDTLLLWVLLLWVPGSTGDIQVQLVQSGGGLVQAGGSLRLSCAASGLTISNY AMAWFRQAPGKEREFVALINWSGNKYYADSVKGRFTIARDNAKNTVDLQMNS LKPEDTAVYYCAARFHSYAASTYYSASTYKFWGQGTQVTVSS|PSGQAGAAASE| |SLFVSNHAY|NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLE LQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFYRQALGNQRELVAGITSDGITYYPDSVKGRFTISRDNDKNTIYLQMNSLKPEDTA VYYCNLWPPRIGFASWGQGTQVTVSS|HHHHHH| (SEQ ID NO: 86)Nucleotide sequence encoding a STriKE molecule 6.2 set forth in SEQ ID NO:86 ATGGAAACAGACACCCTCCTGCTGTGGGTTCTGTTGCTTTGGGTCCCAGGCAG TACAGGTGATCAGGTGCAGCTGGTGCAGAGCGGCGGCGGCCTGGTGCAGGCG GGCGGCAGCCTGCGCCTGAGCTGCGCGGCGAGCGGCCTGACCATTAGCAACT ATGCGATGGCGTGGTTTCGCCAGGCGCCGGGCAAAGAACGCGAATTTGTGGC GCTGATTAACTGGAGCGGCAACAAATATTATGCGGATAGCGTGAAAGGCCGC TTTACCATTGCGCGCGATAACGCGAAAAACACCGTGGATCTGCAGATGAACAGCCTGAAACCGGAAGATACCGCGGTGTATTATTGCGCGGCGCGCTTTCATAG CTATGCGGCGAGCACCTATTATAGCGCGAGCACCTATAAATTTTGGGGCCAG GGCACCCAGGTGACCGTGAGCAGCCCGAGCGGCCAGGCGGGCGCGGCGGCG AGCGAAAGCCTGTTTGTGAGCAACCATGCGTATAACTGGGTGAACGTGATTA GCGATCTGAAAAAAATTGAAGATCTGATTCAGAGCATGCATATTGATGCGAC CCTGTATACCGAAAGCGATGTGCATCCGAGCTGCAAAGTGACCGCGATGAAA TGCTTTCTGCTGGAACTGCAGGTGATTAGCCTGGAAAGCGGCGATGCGAGCA TTCATGATACCGTGGAAAACCTGATTATTCTGGCGAACAACAGCCTGAGCAG CAACGGCAACGTGACCGAAAGCGGCTGCAAAGAATGCGAAGAACTGGAAGA AAAAAACATTAAAGAATTTCTGCAGAGCTTTGTGCATATTGTGCAGATGTTTA TTAACACCAGCGAGGCGTCAGGAGGCCCGGAACAGGTGCAGCTGCAGGAAA GCGGCGGCGGCCTG...

Claims

WHAT is CLAIMED is:

1. AT cell comprising (a) an exogenous nucleotide sequence encoding a chimeric antigen receptor (CAR) having the ability to bind to a cancer antigen and (b) an exogenous nucleotide sequence encoding a cell engager having the ability to bind to (1) an antigen of an immunosuppressive cell of a tumor microenvironment (TME) and (2) an antigen of an innate immune cell or an adaptive immune cell of said TME, wherein said T cell expresses said CAR, and wherein said T cell expresses and secretes said cell engager.

2. The T cell of claim 1, wherein the immunosuppressive cell is selected from the group consisting of a cancer-associated fibroblast (CAF), an immunosuppressive macrophage, an immunosuppressive monocyte, a regulatory T cell, and a gamma-delta T cell.

3. The T cell of claim 1, wherein said nucleotide sequence encoding said CAR is integrated into the genome of said T cell.

4. The T cell of claim 1, wherein said nucleotide sequence encoding said cell engager is integrated into the genome of said T cell.

5. The T cell of claim 1, wherein said CAR is a BCMA-specific CAR or a CS1-specific CAR.

6. The T cell of claim 1, wherein said antigen of said immunosuppressive cell is a FAP polypeptide.

7. The T cell of claim 1, wherein said cell engager comprises a nanobody (VHH) or a single chain variable fragment (scFv).

8. The T cell of claim 1, wherein said antigen of said innate immune cell or said adaptive immune cell is a polypeptide selected from the group consisting of a Fc receptor, a signal regulatory protein alpha (SIRPa) polypeptide, a CD16a polypeptide, an IL-15molecule, an IL-12 molecule, a NKG2D polypeptide, a NKp30 polypeptide, a NKG3C polypeptide, a nkp64 polypeptide, and a siglec-10 polypeptide.

9. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide.

10. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule.

11. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by a Fc region polypeptide, followed by aP2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule.

12. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-SIRPa binding molecule.

13. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL- 15. followed by an anti-FAP binding molecule.

14. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL-15 polypeptide, followed by an anti-CD16a binding molecule.

15. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an IL- 15 polypeptide, followed by an anti-FAP binding molecule.

16. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule.

17. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an anti -FAP binding molecule.

18. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-CD16a binding molecule.

19. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an anti-FAP binding molecule.

20. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an anti-FAP binding molecule.

21. A method of making a T cell of claim 1, wherein said method comprises introducing said (a) and said (b) into said T cell.

22. The method of claim 21, wherein said introducing is done ex vivo or in vivo.

23. A nucleic acid construct comprising a promotor sequence operably linked to a nucleic acid comprising (a) a nucleotide sequence encoding a chimeric antigen receptor (CAR) having the ability to bind to a cancer antigen, and (b) a nucleotide sequence encoding a cell engager having the ability to bind to (1) an antigen of an immunosuppressive cell of a tumor microenvironment (TME) and (2) an antigen of aninnate immune cell or an adaptive immune cell of said TME, wherein said (a) and said (b) are separated by a nucleotide sequence encoding a 2A polypeptide.

24. The nucleic acid construct of claim 23. wherein said nucleic acid construct is in the form of a viral vector.

25. The nucleic acid construct of claim 23, wherein said CAR is a BCMA-specific CAR or a CSl-specific CAR.

26. The nucleic acid construct of claim 23, wherein said antigen of said immunosuppressive cell is a FAP polypeptide.

27. The nucleic acid construct of claim 23, wherein said cell engager comprises a nanobody (VHH) or a single chain variable fragment (scFv).

28. The nucleic acid construct of claim 23, wherein said antigen of said innate immune cell or said adaptive immune cell is a polypeptide selected from the group consisting of a Fc receptor, a signal regulatory protein alpha (SIRPa) polypeptide, a CD 16a polypeptide, an IL-15 receptor, a NKG2D polypeptide, a NKp30 polypeptide, a NKG3C polypeptide, ankp64 polypeptide, and a siglec-10 polypeptide.

29. The nucleic acid construct of claim 23, wherein said nucleic acid construct further comprises a nucleotide sequence encoding a polypeptide having the ability to bind a second antigen of said immunosuppressive cell.

30. The nucleic acid construct of claim 29, wherein said second antigen of said immunosuppressive cell is a CD47 polypeptide.

31. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti -FAP binding molecule, followed by a Fc region polypeptide.

32. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti -FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule.

33. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti -FAP binding molecule, followed by a Fc region polypeptide, followed by a P2A polypeptide, followed by an IgK leader sequence, followed by an anti-CD47 binding molecule.

34. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-SIRPa binding molecule.

35. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL-15, followed by an anti-FAP binding molecule.

36. The nucleic acid construct of any one of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL-15 poly peptide, followed by an anti-CD16a binding molecule.

37. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule.

38. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an IL-15 polypeptide, followed by an anti-FAP binding molecule.

39. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an anti-FAP binding molecule.

40. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an anti-CD16a binding molecule.

41. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-Nkp30 binding molecule, followed by an anti-FAP binding molecule.

42. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-NKG2D binding molecule, followed by an anti-FAP binding molecule.

43. A composition comprising aT cell of claim 1.

44. A composition comprising a nucleic acid construct of claim 23.

45. A method for treating a mammal having cancer, wherein said method comprises administering, to said mammal, a composition of any one of claims 43 or 44.

46. The method of claim 45, wherein said mammal is a human.

47. The method of claim 45, wherein said cancer is selected from the group consisting of a multiple myeloma, a pancreatic cancer, a breast cancer, and a leukemia.

48. The method of claim 45, wherein the number of cancer cells within said mammal is reduced following said administering step.

49. The method of claim 45, further comprising activating an innate immune cell or an adaptive immune cell in a tumor microenvironment (TME) of said cancer.

50. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL- 12, followed by an anti-FAP binding molecule.

51. The nucleic acid construct of claim 23, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL- 12, followed by an anti-CD16a binding molecule.

52. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-FAP binding molecule, followed by an IL-12 polypeptide, followed by an anti-CD16a binding molecule.

53. The T cell of claim 1, wherein said cell engager comprises an IgK leader sequence, followed by an anti-CD16a binding molecule, followed by an IL-12 polypeptide, followed by an anti-FAP binding molecule.

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