CAR T cell therapy has been transformative for hematological malignancies but has yet to achieve similar success in solid tumors, despite years of intensive research. Recent findings, however, suggest that certain solid tumors may be susceptible to CAR T therapy under the right conditions. Gastric cancers frequently aberrantly express CLDN18.2 on the cell surface, and anti-CLDN18.2 CAR T cells are poised to become the first CAR T therapy approved for a solid tumor following promising clinical trial results. Yet, current CLDN18.2 CAR T therapies are limited by poor persistence and efficacy, as well as significant toxicity risks for patients.
In this ASPIRE award, Jaehyuk Choi will address both of these challenges. He will use a computational approach to generate candidate antibodies with high affinity for CLDN18.2 and minimal cross-reactivity with CLDN18.1, followed by in vitro and in vivo testing for efficacy and safety. Dr. Choi will also build on his team’s discovery that certain mutations found in B cell lymphomas can enhance CAR T cell activity, despite originating from genes not typically expressed in T cells. They will engineer CLDN18.2 CAR T cells incorporating these mutations and assess their performance in preclinical models. If successful, this work could yield a new generation of more potent and selective CAR T therapies for solid tumors, accelerating their clinical translation and improving outcomes for patients with gastric cancer.