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Cancer Res. 2014 Dec 1;74(23):6796-805. doi: 10.1158/0008-5472.CAN-14-0079. Epub 2014 Oct 8.

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

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Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Department I of Internal Medicine, Tumor Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Institute of Immunology, Charite Campus Buch, Berlin, Germany.
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.


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 an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ 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.

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