Reshaping CAR-T cells through overexpression of T cell factor 1 (TCF-1)

Hao Yao¹Yuntian Ding²Huixiu Han^1,3Qian Chen¹David Sedloev¹Carsten Müller-Tidow¹Tim Sauer¹Anita Schmitt¹Michael Schmitt^1*Lei Wang^1*

• ¹Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
• ²Department of Hematology, the Seventh Affiliated Hospital,Sun Yat-sen University, Guangzhou, China
• ³Department of Hematoogy, Beijing Tiantan Hospital, Captial Medical University, Beijing, China

Despite the remarkable success of CAR-T cell therapy in leukemia and lymphoma patients, lack of CAR-T cell persistence remains a significant clinical problem. T cell factor 1 (TCF-1) is essential for T cell development and survival. CAR-T cells often exhibit a deficiency in TCF-1 expression. Therefore, it is intriguing to modulate TCF-1 expression in CAR-T cells to improve persistence and thus therapeutic outcome. In this study, third generation CAR vectors were used and the effect of TCF-1 overexpression in CAR-T cells was comprehensively explored. TCF-1 overexpression enriched naïve and stem cell-like CAR-T cells, thus enhancing cytotoxic efficacy. Moreover, the cytokine profile of CAR-T cells switched from a proinflammatory or cytotoxic phenotype to a less active state. Additionally, TCF-1 overexpression modulated the apoptotic status of CAR-T cells, leading to improved long-term functionality in terms of tumor-killing capacity and reduced expression of various inhibitory receptors. In summary, TCF-1 overexpression reduced apoptosis, decreased incidence of cytokine release, and enhanced persistence CAR-T cells. These findings suggest that TCF-1 modulation might significantly improve efficacy of CAR-T cell therapy in patients with relapsed or refractory hematologic malignancies.