Novel CAR T cell engineering strategies for effective eradication of solid and liquid tumors

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY CAR T cell therapy has revolutionized the treatment of B cell malignancies but has yet to reach its full potential for patients with other tumor types, patients who are initially resistant, or patients who relapse following treatment. CAR T cells are hindered by a lack of tumor-specific antigens that are safe to target and/or homogenously expressed throughout the tumor and limited T cell persistence. To address these challenges during our previous award, we developed and optimized a new CAR T cell platform to express the CAR along with a T cell-engaging antibody molecule (TEAM) that targets a second antigen while engaging T cells (CAR and non-CAR) within the tumor. We used this platform to boost the killing of heterogeneous glioblastoma (GBM) tumors, prevent antigen escape in acute myeloid leukemia (AML), and target the tumor and suppressive tumor microenvironment in pancreatic cancer, in relevant preclinical models. We also used a genome-wide CRISPR screen in heterogeneous GBM tumors to determine cancer cell-intrinsic mechanisms of resistance to CAR T cells. We identified CAR T cell adhesion to the tumor cell as imperative for effective CAR T cell killing. Finally, we leveraged our CRISPR screening experience to perform an in vivo CRISPR screen in CAR T cells to identify genes that, when knocked out, increase CAR T cell persistence in models of pancreatic cancer and multiple myeloma. Building on the knowledge gained during the previous award period, we plan to further improve CAR T cell targeting of tumor cells by increasing their adhesion and using CRISPR editing to prolong persistence. We will accomplish these goals using novel engineering strategies to (1) modify our CAR-TEAM system to secrete engagers that target a 2nd tumor antigen while also increasing adhesion to tumor cells in models of GBM and lymphoma, (2) validate the results of our in vivo screens in their original tumor models (pancreatic cancer or multiple myeloma) and apply these gene KOs to other tumor types with similar solid vs. liquid histologies (GBM and lymphoma), and (3) combine these methods to create CAR T cells that secrete adhesion-enhancing engagers and have genetic KOs to increase persistence. We hypothesize that combining these approaches will create the best possible CAR T cells for overcoming the resistance mechanisms that are specific to the biology dictating how CAR T cells interact with different tumors. Overall, through rigorous preclinical testing during this award, we will identify CAR T cell engineering strategies for future translation to phase I clinical trials, as we have already done with the CAR-TEAM platforms developed during our previous award. Collectively, the results of the proposed projects will inform the optimal CAR T cell designs to target varying tumor types and make CAR T cell therapy more broadly applicable across patients.