Chuan Tong
Yao Wang
Deyun Chen
Zhiqiang Wu
Weidong Han
Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100086, China
More InformationCorresponding author: E-mail address: wuzhiqiang1006@163.com (Zhiqiang Wu);E-mail address: hanwdrsw69@yahoo.com (Weidong Han)
Received Date: 2019-04-03
Accepted Date:2019-06-17
Rev Recd Date:2019-06-09
Available Online: 2019-08-13 Publish Date:2019-08-20
Abstract
Abstract
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.Keywords: Chimeric antigen receptor,
CD38,
T cells,
Immunotherapy,
CD38 antibody
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