Universität zu Köln

Textor, Ana, Listopad, Joanna J., Le Wuehrmann, Lara, Perez, Cynthia ORCID: 0000-0002-2260-5428, Kruschinski, Anna, Chmielewski, Markus, Abken, Hinrich, Blankenstein, Thomas and Charo, Jehad (2014). Efficacy of CAR T-cell Therapy in Large Tumors Relies upon Stromal Targeting by IFN gamma. Cancer Res., 74 (23). S. 6796 - 6806. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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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 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 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. (C) 2014 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Textor, Ana UNSPECIFIED UNSPECIFIED UNSPECIFIED Listopad, Joanna J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Le Wuehrmann, Lara UNSPECIFIED UNSPECIFIED UNSPECIFIED Perez, Cynthia UNSPECIFIED orcid.org/0000-0002-2260-5428 UNSPECIFIED Kruschinski, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Chmielewski, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Blankenstein, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Charo, Jehad UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-421438
DOI:	10.1158/0008-5472.CAN-14-0079
Journal or Publication Title:	Cancer Res.
Volume:	74
Number:	23
Page Range:	S. 6796 - 6806
Date:	2014
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ANTIGEN-LOSS VARIANTS; ESTABLISHED TUMORS; ADOPTIVE IMMUNOTHERAPY; IN-VIVO; CANCER; ACTIVATION; RECEPTOR; RECOGNITION; ERADICATION; CD28 Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42143