Department of Chemical and Biomolecular Engineering, University of California-Los Angeles, 420 Westwood Plaza, BH 5513, Los Angeles, CA, USA.
Amgen, Thousand Oaks, CA, USA.
Nat Commun. 2020 May 8;11(1):2283. doi: 10.1038/s41467-020-16160-5.
Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. Here we report the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multiple myeloma (MM) that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit superior CAR expression and function compared to T cells that co-express individual BCMA and CS1 CARs. Combination therapy with anti-PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, while CAR-T cell treatment alone achieves durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.
嵌合抗原受体 (CAR)-T 细胞疗法在对抗 B 细胞恶性肿瘤方面显示出显著的临床疗效，但存在明显的抗原逃逸和肿瘤复发的脆弱性。在这里，我们报告了针对异质性多发性骨髓瘤 (MM) 的双特异性 CAR-T 细胞的合理设计和优化，这种 MM 对针对 B 细胞成熟抗原 (BCMA) 的传统 CAR-T 细胞疗法具有抗性。我们证明了 BCMA/CS1 双特异性 CAR-T 细胞与共表达单个 BCMA 和 CS1 CAR 的 T 细胞相比，表现出更高的 CAR 表达和功能。与抗 PD-1 抗体联合治疗进一步加速了体内初始肿瘤清除的速度，而单独使用 CAR-T 细胞治疗甚至在肿瘤再次挑战时也能实现持久的无肿瘤存活。总之，BCMA/CS1 双特异性 CAR 为防止 CAR-T 细胞治疗 MM 中的抗原逃逸提供了一种有前途的治疗方法，并且垂直整合的优化过程可用于开发针对新型疾病靶点的强大细胞治疗方法。
