Exploring the heterogeneity of primary T cell activity and the implication for preclinical models of CAR T cell therapy 2123

Description Since Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized treatment for relapsed lymphoma and multiple myeloma patients, interest in exploring additional uses has grown dramatically. To explore these new approaches, xenograft preclinical models using immunocompromised mice with primary human T cells and human cancers remains one of the principal tools for evaluating the efficacy of CAR T cells. However, primary human T cells are notorious for their phenotypic variation and thus require the use of a couple of donors to demonstrate reliable results. Here we report variance in tumor clearance with mock CAR T cells from over ten unique T cell donors in a xenograft murine model for ovarian carcinoma. Specifically, we determined that some donors that are hyperactive, capable of clearing tumors without requiring the genetic modification of the CAR, while other donors induce no response within the mice. We characterized these donors in vitro using phenotypic markers, cell proliferation, and sequencing to determine if there are any correlative factors for this in vivo activity. This characterization is important for validating experimental controls and the potential for leveraging greater understanding of T cell persistence and anti-tumoral efficacy.