Pooled CAR-T cell screening in nonhuman primates to inform therapeutic design for cancer and HIV

Abstract

Chimeric antigen receptor (CAR)-T cell therapy represents a major milestone in immunotherapy, with the potential to durably treat, and in some cases cure, a range of hematologic malignancies, chronic infections, and autoimmune diseases. As powerful living drugs, CAR-T cells can recognize antigen-bearing cells with precision, expand upon engagement, and exert potent cytotoxic effects. Yet despite rapid innovation and the development of thousands of CAR constructs across diverse indications, relatively few have translated into clinical success. Many candidates fail due to insufficient persistence, poor efficacy in complex tissue environments, or immune-mediated toxicities such as cytokine release syndrome (CRS) and neurotoxicity—limitations that are often not predicted by preclinical models. These challenges reflect shortcomings not only in CAR design, but in the systems used to evaluate them. Large animal models, such as nonhuman primates (NHPs), may help bridge the gap between murine models and humans by offering greater immunological and physiological similarity, and by enabling long-term studies of CAR-T cell persistence, trafficking, and safety. By combining next-generation CAR designs with rigorous and reproducible testing in more predictive, human-relevant systems, we can begin to address longstanding barriers to translation and advance the development of safer, more durable, and clinically effective cell therapies.