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Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ

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Item Type:Article
Title:Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ
Creators Name:Textor, A. and Listopad, J.J. and Wührmann, L.L. and Perez, C. and Kruschinski, A. and Chmielewski, M. and Abken, H. and Blankenstein, T. and Charo, J.
Abstract:Adoptive T cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In a HER-2-dependent tumor model, tumor rejection by HER-2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve NK cells, but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFN{gamma} receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting.
Keywords:Chimeric Antigen Receptor, Solid Tumor, Adoptive T Cell Therapy, IFN{gamma}, Animals, Mice
Source:Cancer Research
ISSN:0008-5472
Publisher:American Association for Cancer Research (U.S.A.)
Volume:74
Number:23
Page Range:6796-6805
Date:1 December 2014
Official Publication:https://doi.org/10.1158/0008-5472.CAN-14-0079
PubMed:View item in PubMed

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