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 longterm 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 lessdifferentiated 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.