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Construction of CD38/CD138 dual-targeted CAR-T cell and it’s in vitro cytotoxicity against multiple myeloma cells
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Abstract:
[Abstract] Objective: To construct dual-targeting (CD38 and CD138) chimeric antigen receptor (CAR) gene-modified T cells (CD38/ CD138 CAR-T cells) and explore their in vitro cytotoxicity against multiple myeloma (MM) cells. Methods: Based on the high expression of CD38 and CD138 antigens in MM cells, CD38 CAR-T cells and CD138 CAR-T cells targeting CD38 and CD138 respectively, and CD38/CD138 dual-targeted CAR-T cells targeting both CD38 and CD138 were constructed using CAR-T cell technology. The experimental groups included untreated T cells, CD38 CAR-T, CD138 CAR-T, and CD38/CD138 CAR-T cells. The phenotype of CAR-T cells was detected by flow cytometry. The cytotoxicity of various CAR-T cells against MM cells (RPMI8226 and U266) was assessed using the LDH release assay. Results: Three types of CAR-T cells, CD38 CAR-T, CD138 CAR-T, and CD38/ CD138 CAR-T cells, were successfully constructed. The CD38/CD138 CAR-T cells tended to differentiate into a memory phenotype, expressing higher levels of proliferation marker (CD25), activation marker (CD27), and lower levels of exhaustion markers (PD-1, CTLA-4, TIM-3) (all P < 0.001). Moreover, CD38/CD138 CAR-T cells were less prone to exhaustion and senescence, and expressed lower levels of r-H2AX, p-p53, p21, and p16 proteins (all P < 0.01). Under different effector-to-target cell ratios, CD38/CD138 CAR-T cells exhibited stronger cytotoxic effects against RPMI8226 and U266 cells compared to CD38 CAR-T and CD138 CAR-T cells (all P < 0.001). Conclusion: CD38/CD138 CAR-T cells targeting both CD38 and CD138 demonstrate an optimal phenotype and enhanced anti-tumor activity in vitro, offering promising potential for immunotherapy in multiple myeloma.
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