Novel BCMA-OR-CD38 tandem-dual chimeric antigen receptor T cells robustly control multiple myeloma.
Novel BCMA-OR-CD38 tandem-dual chimeric antigen receptor T cells robustly control multiple myeloma.
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DOI：
10.1080/2162402x.2021.1959102
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发表时间：
2021
期刊：
影响因子：
7.2
通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Feng Y;Liu X;Li X;Zhou Y;Song Z;Zhang J;Shi B;Wang J
靶向BCMA的嵌合抗原受体（CAR）-T细胞疗法已显示出针对多发性骨髓瘤的显著临床疗效，但在使用这些疗法后仍发生抗原逃逸和肿瘤复发。设计同时靶向多种抗原的CAR-T疗法似乎是避免抗原逃逸的可行方法，在其他地方已经进行了广泛的研究。在这里，我们报告了新型BCMA-OR-CD 38 Tan CAR T细胞，其可以触发针对表达BCMA或CD 38的靶细胞的强大细胞毒性。我们证明，在体外研究中，与单靶向CAR T细胞或CD 38-OR-BCMA Tan CAR T细胞相比，这些BCMA-OR-CD 38 Tan CAR T细胞表现出相似的CAR表达、上级细胞毒性和抗原刺激的T细胞增殖。重要的是，这些BCMA-OR-CD 38 Tan CAR-T细胞可以在携带骨髓瘤的小鼠中实现完全的肿瘤清除，并且在这些实验过程中没有观察到复发。最后，这种BCMA-OR-CD 38 Tan CAR与现有的临床级T细胞制造程序完全兼容，并且可以使用当前的临床方案实施。总之，我们的结果为BCMA CAR T细胞疗法中抗原逃逸的挑战提供了有效的解决方案。
BCMA-targeting chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against multiple myeloma, yet antigen escape and tumor relapse still occur after the use of these therapies. Designing CAR-T therapies that targets multiple antigens simultaneously seems a feasible way to avoid antigen escape, and it has been extensively studied elsewhere. Here, we report novel BCMA-OR-CD38 Tan CAR T cells that can trigger robust cytotoxicity against target cells expressing either BCMA or CD38. We demonstrate that, in in vitro studies, these BCMA-OR-CD38 Tan CAR T cells exhibit similar CAR expression, superior cytotoxicity and antigen-stimulated T cell proliferation as compared to single-targeted CAR T cells or CD38-OR-BCMA Tan CAR T cells. Importantly, these BCMA-OR-CD38 Tan CAR-T cells can achieve complete tumor clearance in myeloma-bearing mice with no relapse observed through the course of these experiments. Finally, this BCMA-OR-CD38 Tan CAR was fully compatible with existing clinical grade T cell manufacturing procedures and can be implemented using current clinical protocols. Taken together, our results present an effective solution to the challenge of antigen escape in BCMA CAR T-cell therapies.