Using Binary Activated T Cells Expressing Chimeric Antigen Receptors (BAT CARs) to Improve Brain Tumor Immunotherapy

Abstract

Chimeric antigen receptor (CAR) T cell therapy has proven to be a breakthrough technology against a range of hematological cancers, notably B cell acute lymphoblastic leukemias, non-Hodgkins lymphomas and chronic lymphocytic leukemias.1 Despite the unprecedented successes with these B cell tumors, increased complexity has hindered the translation of such success to solid tumors. CAR T cells have yet to demonstrate efficacy against solid tumors for several reasons. One reason is that virtually all targetable proteins on the membranes of tumor cells are also expressed on other normal tissues required for viability. Another reason is that T cell killing is slower in solid tumors compared to liquid tumors and thus antigen escape is an even bigger problem for solid tumors as compared to liquid tumors. A third reason is that there is significant variance in expression of such antigens, either within a single patient or among patients. To successfully apply CAR T cells technology to solid tumors, a new platform of CAR T cells capable of targeting tumors while minimizing off-tumor effects on healthy tissue is necessary. A CAR T cell that can target various antigens at once through multiplexing, providing an alternative path of killing while addressing the heterogeneity of the actual patient population may provide a solution for solid tumors. We developed a unique CAR T cell system that addresses these needs. In contrast to traditional scFv CAR T cell designs, BAT CAR disassociates CAR T cell targeting from CAR T cell-mediated killing, necessitating that these two independent events take place before T cell activation. In contrast to directly targeting the tumor cell, our CAR T cells target a synthetic antigen, which, when coupled to a tumor-targeting antibody, drives the CAR T cell mediated killing. This platform allows us to i) dose the tumor-targeting antibody to control the intensity of killing while avoiding on-target/off-tumor killing, ii) target multiple antigens to prevent antigen escape and, iii) adapt to intra- and interpatient cancer variability through multiplexing.