Afatinib boosts CAR-T cell antitumor therapeutic efficacy via metabolism and fate reprogramming

• DOI: 10.1136/jitc-2024-009949
• Publication Date: 2024-11-18T03:05:38Z
• Authors: Yueyu Dai; Yue Liu; Lingna An; Fangyuan Zhong; Xi Zhang; Shifeng Lou
• Keywords: Reprogramming

Background Chimeric antigen receptor T (CAR-T) cell therapy has been shown remarkable efficacy in the treatment of hematological malignancies recent years. However, a considerable proportion patients would experience tumor recurrence and deterioration. Insufficient CAR-T persistence is major reason for relapse. Multiple strategies to enhance long-term antitumor effects cells have explored developed. In this study, we focused on tyrosine kinase inhibitors (TKIs), which emerged immunomodulatory potential besides direct tumoricidal effects. Methods Here, screened 50 approved TKIs drugs identified that afatinib (AFA) markedly enhanced expressing CD62L inhibited reactive oxygen species level cells. And underlying mechanisms AFA medicating were by detecting signal transduction, metabolism pattern. Furthermore, co-cultured with during preparation stage multianalyses differentiation characteristics, metabolic profiling, RNA sequencing revealed induce comprehensive remodeling fate reprogramming. Based it, finally AFA-pretreatment compared negative-control CAR-T. Results We blocked T-cell (TCR) phosphoinositide 3-kinase-protein B-mechanistic target rapamycin signaling pathways, induced reprogramming modulated differentiation. When combined cells, exhaustion cytotoxicity. Our results pretreatment enables boost strong cytotoxicity leukemia mouse model. Conclusions study systematically demonstrated effectively performance, presents novel optimization strategy potent durable therapy.