CELL INTELLIGENCE · 肿瘤细胞治疗研究

OBJECTIVE: The clinical studies of acute myeloid leukaemia (AML) revealed that antigen escaping variants cause cancer recurrence even after treatment with chimeric antigen receptor (CAR)-T cells that target a single tumour antigen. Due to the heterogeneous expression of antigens on leukaemia blasts, we hypothesized that a novel bispecific CAR, directed to the folate receptor beta (FR )-binding single-chain variable fragment (scFv) and an IL3 -binding receptor (CD123) that has more expression in AML blasts, can decrease CAR-T cell exhaustion and increase the efficacy of CAR-T cells to prevent antigen escaping and consequent recurrence of AML. MATERIALS AND METHODS: In this experimental study, the survival, proliferation, and cytolysis of CAR-T cells remains suboptimal even with a costimulatory endodomain. Hence, we designed and constructed a tandem CAR that joins an FR and CD123 in the second generation retroviral vector to generate a bispecific tandem CAR (TanCAR-T cell). RESULTS: TanCAR FR -CD123 T cells showed distinct binding to FR or CD123 expressing cells. They could lyse the leukaemia cell lines (66.1 11%) comparable to the single CAR-T cells against these determinants. TanCAR FR - CD123 T cells simultaneously engaged FR and CD123, which promoted T cell activation in targeting and lysis of the examined leukaemia cell lines. TanCAR-T cell significantly induced interferon gamma (IFN ) and interleukin 2 (IL-2) production more than single CAR-T cells, which produced a synergistic enhancement of TanCAR FR -CD123 T cell function when dual antigens faced simultaneously. CONCLUSION: Dual-specific TanCAR FR -CD123 T cells showed therapeutic potential to improve AML control by coengaging FR and CD123 molecules in a robust, divalent immune system. This strategy may be a useful therapeutic approach in patients with relapsed B-cell malignancies.