Chimeric cytokine receptor enhancing PSMA-CAR-T cell-mediated prostate cancer regression

摘要

Objective: Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated an unprecedented therapeutic efficacy in hematological malignancies; however, its effectiveness in solid tumors remains elusive. In order to enable CAR-T cells more effective to solid tumors, a inverted chimeric cytokine receptor (ICR) was designed, which is consists of the TGF-beta extracellular domain, IL-7 receptor intracellular domain, and co-expression on CAR-T cells. Materials and Methods: We selected prostate specific membrane antigen (PSMA) as a target for CAR-T cells, constructed corresponding effector cells, and verified the anti-tumor activity of this enhanced PSMA-CAR-T cell by a series of repeated target cell stimulation experiments in vitro and the anti-tumor capabilities by using mice xenograft model in vivo. Results: In vitro experiments showed that co-expression of ICR could significantly enhance sustained anti-tumor capabilities of PSMA-CAR-T cells. Moreover, in vivo experiments also confirmed that the enhanced PSMA-CAR-T cells exhibited significant superior anti-tumor capabilities and could prolong the survival time in the xenograft and PDX models of prostate cancer. Conclusions: PSMA-CAR-T cells co-expressing ICR can be envisaged as a new therapeutic strategy for prostate cancer and support the translation of this enhanced approach in the clinical setting.