Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

Abstract

Chimeric antigen receptor (CAR) T cell therapy is a relatively new form of targeted therapy that has demonstrated impressive success in treating hematological malignancies. It has been challenging to translate this success to solid tumors. Reasons for this include barriers to delivery, tumor heterogeneity, cancer cells' ability to evade the immune system as well as identifying the optimal target. Most CAR T clinical trials have targeted well-characterized cancer targets with significant preclinical and in some cases clinical validation. Published results from some of these trials show signs of anti-cancer activity that warrant encouragement, but also caution, given instances of unacceptable toxicity. The narrow therapeutic window is complicated by the ability of CAR T cells to expand in patients regardless of dose. Here, we review those trials showing encouraging results in the context of target selection. It is clear that more specific tumor targeting is required, either by affinity tuning to avoid low-level target expression in healthy cells, logic gating, or the identification of new targets that are more cancer specific.