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

Zhitao Gao; Chuan Tong; Yao Wang; Deyun Chen; Zhiqiang Wu; Weidong Han

doi:10.1016/j.jgg.2019.06.007

Volume 46 Issue 8

Aug. 2019

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Article Navigation > Journal of Genetics and Genomics > 2019 > 46(8): 367-377

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

doi: 10.1016/j.jgg.2019.06.007

Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100086, China

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Corresponding 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 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.
- Chimeric antigen receptor,
- CD38,
- T cells,
- Immunotherapy,
- CD38 antibody

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