CAR-Ts with moderate affinity antigen binding domain persist longer and maintain better function in tumor lesions, generating potent antitumor effects in treating solid tumors 2663

Description The antigen-binding domain (ABD) is critical in chimeric antigen receptor (CAR) by rendering it specificity. Although most current CAR T cells (CAR-T) utilize high affinity ABD, how the affinity affects the persistence, function, and antitumor effects of CAR-Ts remains unknown. Based on the native T cell receptor (TCR), high affinity engagement is not required for T cell activation and function. In fact, TCR affinity is 3 logs lower than CAR. While high affinity ABD works for blood cancer CAR-Ts, it is too high for solid tumor CAR-Ts due to the different engagement style and stromal restriction. We hypothesize that the ABD affinity needs to be tuned down to allow for solid tumor CAR-Ts to generate effective antitumor effects. To test our hypothesis, 1) we did meta-analysis of solid tumor CAR-T trials and found that only moderate-affinity CAR-Ts generate clinical responses. 2) We developed moderate-affinity CAR-Ts against hepatocellular carcinoma (HCC). Our data showed that moderate-affinity CAR-Ts are less prone to activation induced cell death and exhaustion. They persist longer and maintain better function, generating stronger and durable antitumor effects. 3) Although moderate-affinity CAR-Ts are still unable to eradicate large solid tumors, they remain functional for prolonged time in tumor lesions, enabling them to durably produce immune modulators to improve tumor microenvironment, generating stronger antitumor effects. The latest data will be presented. Funding Sources 1. Georgia Research Alliance (GRA) award 2.