Chimeric antigen receptor T-cell (CAR T) therapy is a kind of effective cancer immunotherapy. However, designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches (e.g., daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing (fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies (clone MM12T or clone MM27) or proteins (H02H or H08H) were used to block CD38 or the CAR single-chain variable fragment (scFv) domain, respectively, on the T cell surface. The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38⁺ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-α, IFN-γ and IL-2 were significantly upregulated in the supernatants of A549^CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.

嵌合抗原受体T细胞（CAR T）疗法是一种有效的癌症免疫疗法。但是，设计CAR仍然是一个挑战，因为T细胞和肿瘤细胞共享许多可靶向的抗原。抗原的这种共享表达可引起CAR T细胞fratricide。靶向CD38的方法（例如daratumumab）已用于临床治疗，并显示出令人鼓舞的结果。CD38是存在于多种细胞（例如T淋巴细胞和肿瘤细胞）中的一种表面糖蛋白。先前已报道基于CD38的CAR T细胞在细胞制造过程中可能经历凋亡或T细胞介导的杀伤（杀灭）。在这项研究中，包含靶向人CD38的序列的CAR被设计为具有功能。为了避免CD38驱动的杀人分子，并确保CAR T细胞的产生，基于抗体（克隆MM12T或克隆MM27）或蛋白质（H02H或H08H）的两种不同策略分别用于在T细胞表面阻断CD38或CAR单链可变片段（scFv）域。结果表明，抗体或蛋白质，特别是抗体MM27，可以通过抑制杀杀杀伤剂同时促进扩增和富集来影响CAR T细胞。抗CD38 CAR T细胞对CD38表现出强大而特异性的细胞毒性⁺细胞系和肿瘤细胞。此外，在A549 ^{CD38 +}细胞的上清液中，促炎因子TNF-α，IFN-γ和IL-2的水平显着上调。最后，在异种移植小鼠模型中证明了疾病进展的显着控制。总之，这些发现将有助于在后续的临床试验中进一步增强抗CD38 CAR T细胞的扩增，持久性和功能。