Presetting CAR-T cells during ex vivo biomanufacturing.

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. However, it continues to encounter significant obstacles, including treatment relapse and limited efficacy in solid tumors. While effector T cells exhibit robust cytotoxicity, central memory T cells and stem cell-like T cells are essential for in vivo expansion, long-term survival, and persistence. Strategies such as genetic engineering to enhance CAR-T cell efficacy and durability are often accompanied by increased safety risks, which not only raise regulatory approval thresholds but also escalate CAR-T production costs. In contrast, optimizing ex vivo manufacturing conditions represents a more straightforward and practical approach, offering the potential for rapid application to commercially approved CAR-T products and enhancement of their clinical outcomes. This review examines several factors that have been shown to improve T cell memory phenotype and in vivo cytotoxic activity, including cytokines, electrolytes, signaling pathway inhibitors, metabolic modulators, and epigenetic agents. The insights provided will guide the optimization of CAR-T cell industrial production. Furthermore, considerations for selecting appropriate conditions are discussed, balancing effectiveness, cost-efficiency, safety, and regulatory compliance while addressing current challenges in the field.