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B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity


Chimeric antigen receptor (CAR) T-cell therapies have demonstrated durable and potentially curative therapeutic efficacy against B-cell leukemia in clinical trials. A CAR strategy can target any tumor surface antigens as long as an antigen-binding receptor can be generated. New CARs that target solid tumors and have the potential to target multiple tumor types are needed. In this study, B7H6, a ligand for the NK cell activating receptor NKp30, was targeted to create a CAR that targets multiple tumor types. B7H6 is expressed on various primary human tumors, including leukemia, lymphoma and gastrointestinal stromal tumors, but it is not constitutively expressed on normal tissues. B7H6-specific CAR T cells have robust cellular cytotoxicity and interferon-γ secretion when co-cultured with B7H6+ tumor cells, and they exhibit little self-reactivity to immature dendritic cells or pro-inflammatory monocytes. In vivo, B7H6-specific CAR T cells greatly enhanced the survival of RMA/B7H6 lymphoma-bearing mice. The long-term survivor mice were protected against a B7H6-deficient tumor re-challenge. This CAR therapy also decreased tumor burden in a murine ovarian cancer model. In conclusion, B7H6-specific CARs have the potential to treat B7H6+ hematologic and solid tumors.

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We thank the National Cancer Institute Biological Resource Branch for providing recombinant human IL-2 and the staff of the Center for Comparative Medicine and Research in Dartmouth College for providing animal care. This work was supported by a grant from the NIH CA130911 and funds from the Center for Synthetic Immunity.

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Correspondence to C L Sentman.

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Competing interests

Tong Zhang and Charles Sentman are inventors on a patent application covering the B7H6 CAR described in this study. This technology has been licensed by Cardio3 Biosciences. This work is managed in compliance with the policies of Dartmouth College. Ming-Ru Wu and Leslie DeMars declare no potential conflict of interest.

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Wu, MR., Zhang, T., DeMars, L. et al. B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity. Gene Ther 22, 675–684 (2015).

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