Preclinical Studies in CAR T Cell Development

Abstract

T cells that express chimeric antigen receptors (CARs) have shown remarkable efficacy against CD19 expressing hematological tumors1-3. Patients receive autologous T cells that are typically virally transduced to express a CAR that can recognize a specific antigen expressed on the surface of tumor cells and generates large numbers of effective tumor-specific T cells. The value of preclinical models is to establish some evidence for efficacy, uncover potential toxicities, and to study the mechanism of action. Ideally, preclinical models will provide predictive data that will guide the decision making on the best approach for CAR design, selection of targets, in vitro cell manufacturing processes, and identification of biomarkers of activity. At a minimum, CAR T cells should be specific for the target antigen(s) and induce potent T cell cytotoxicity and cytokine production when engaging with antigen-expressing tumor cells, including activity against tumor samples from clinical patients, such as bone marrow aspirates or patient-derived tumor specimens. Beyond targeting, research has been done in how to enhance CAR T cell activity through design alterations using different costimulation domains to trigger specific activation programs within the CAR T cells, use of specific T cell populations to enhance CAR T cell activity or persistence, targeting strategies to avoid off-tumor activity or tumor antigen escape, and modulation of CAR expression/activity to enhance efficacy and safety. In vivo preclinical tumor models have been valuable to test CAR designs because high activity in vitro has not been a strong of a predictor of in vivo efficacy. In general, the less activated and differentiated a CAR T cell population, the better the in vivo anti-tumor activity.