Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells

• 作者: Chuan Tong Deyun Chen Weidong Han Yao Wang Zhiqiang Wu Zhitao Gao
• 来源期刊: 遗传学报
• 年，卷（期）: 2019,（8）
• 所属期刊栏目: Original Research
• 页码范围: 367-377
• 页数: 11页
• 语种: 英文

摘要

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 A549cD38+ 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.