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Abstract

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. In particular, CAR-T cells often exhibit a deficiency in TCF-1 expression, rendering cells susceptible to TCF-1-associated pathways and consequently to short survival in the host. Therefore, it is intriguing to modulate TCF-1 expression in CAR-T cells to address the challenge of CAR-T cell persistence and further improve therapeutic outcomes. In this study, third generation CAR vectors were used, and a double transduction system was established. The effect of TCF-1 overexpression in CAR-T cells was comprehensively explored regarding various aspects. Given the phenotype and functionality of CAR-T cells after transduction, two different CAR models (CD19.CAR vector and CD33.CAR vector) were settled in the study to generalize the effect of overexpression of TCF-1. We found that (1) the overexpression of TCF-1 can enrich the naïve and stem cell-like CAR-T cells exhibiting a better killing efficacy; (2) the cytokine profile of CAR-T cells were switched from proinflammatory or killing related to inactive through overexpression of TCF-1; (3) the apoptotic status of CAR- T cells could be modulated by TCF-1 overexpression, thus resulting in a better long- term functionality in terms of repetitive tumor killing and reduced multiple inhibitory receptors. In summary, overexpression of TCF-1 in CAR-T cells could reduce apoptosis, occurrence of CRS and improve their persistence, resulting in enhanced antitumor efficacy of CAR-T cells. Thus, overexpression of TCF-1 might improve CAR-T cell persistence in vivo and enhance the effect of CAR-T cell therapy in patients with relapsed/refractory hematologic malignancies.