Manufacturing strategies for prolonged CAR-T cell persistence

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, achieving durable remission in patients who are refractory to conventional therapies. However, the limited persistence of infused CAR-T cells, due to T-cell exhaustion and the loss of CAR-T cells, remains a major obstacle to sustained therapeutic efficacy. Recent studies have demonstrated that CAR-T cell products enriched for less-differentiated memory T cell subsets exhibit superior long-term persistence, greater cytotoxicity, and improved clinical outcomes compared with conventional CAR-T cell products. To enrich for less-differentiated memory T cells, various strategies have been explored throughout the manufacturing process. These strategies include selecting cell sources enriched for less-differentiated memory T cells and delaying their differentiation into terminally differentiated states by regulating signaling pathways, remodeling epigenetics, and modulating metabolism. This review provides an overview of current and emerging manufacturing strategies for CAR-T cells, focusing on enhancing their prolonged persistence. Further investigations are warranted to determine the optimal composition of differentiated and less-differentiated T cells in CAR-T cell products under the respective clinical conditions. This could facilitate the personalized manufacturing of CAR-T cell products with the ideal cell composition, thereby maximizing the efficacy of CAR-T cell therapy.