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

Authors

  • A. Textor
  • J.J. Listopad
  • L.L. Wührmann
  • C. Perez
  • A. Kruschinski
  • M. Chmielewski
  • H. Abken
  • T. Blankenstein
  • J. Charo

Journal

  • Cancer Research

Citation

  • Canc Res 74 (23): 6796-6805

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.


DOI

doi:10.1158/0008-5472.CAN-14-0079