Journal
CELL REPORTS
Volume 20, Issue 13, Pages 3025-3033Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.002
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Funding
- NIH [2R01CA120409, T32 CA009140]
- Novartis Alliance
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The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR) T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-gamma secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE) CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors.
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