A groundbreaking study from the University of North Carolina Lineberger Comprehensive Cancer Center has unveiled a novel combination of three drugs that significantly enhances the production of CAR-T cells, a type of immunotherapy used to combat cancer. This research, published in Nature Immunology on January 8, highlights how this drug cocktail can improve the quality and longevity of CAR-T cells by preserving a crucial subset of immune cells known as T-memory stem cells (TSCM). The findings could revolutionize CAR-T cell manufacturing for clinical applications, offering hope for more effective cancer treatments.

The development of CAR-T cell therapy involves extracting T cells from a patient's immune system and genetically modifying them to target cancer cells. However, the variability in CAR-T cell production between patients and the lack of certain cell types can diminish their long-term effectiveness. The researchers discovered that adding specific kinase inhibitors during the re-engineering process helps maintain the critical TSCM subset, which is vital for sustained anti-cancer activity.

Dr. Gianpietro Dotti, a professor at UNC School of Medicine and co-leader of the UNC Lineberger immunology research program, emphasized the significance of this discovery. Through extensive lab and mouse experiments, the team identified several kinases—ITK, ADCK3, MAP3K4, and CDK13—that play a role in enriching TSCM-like CAR-T cells. Notably, ADCK3 and MAP3K4 emerged as potential new targets in T cells, suggesting that studying their functions and signaling pathways could provide deeper insights into T cell differentiation.

The identification of these kinases led to a sophisticated screening process aimed at finding kinase-inhibiting drugs that preserve TSCM-like cells in re-engineered CAR-T cells from both healthy donors and patients with chronic lymphocytic leukemia (CLL). The researchers found that targeting multiple, non-overlapping pathways with a three-drug cocktail was far more effective than using a single inhibitor. This approach consistently increased the frequency of TSCM-like CAR-T cells, even in patients with dysfunctional T cells.

This strategy holds promise beyond blood cancers, as it represents a general concept applicable to CAR-T cell manufacturing for various diseases. Dr. Dotti noted that pharmacological approaches offer advantages over genetic methods in enriching TSCM-like cells. Future research will focus on understanding how kinase inhibitors influence TSCM differentiation before clinical trials can begin. The team believes their findings could also benefit other T-cell therapies, such as tumor-infiltrating lymphocytes, enhancing the overall fight against cancer.