Universität zu Köln

Chmielewski, Markus, Kopecky, Caroline, Hombach, Andreas A. and Abken, Hinrich (2011). IL-12 Release by Engineered T Cells Expressing Chimeric Antigen Receptors Can Effectively Muster an Antigen-Independent Macrophage Response on Tumor Cells That Have Shut Down Tumor Antigen Expression. Cancer Res., 71 (17). S. 5697 - 5707. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 0008-5472

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Abstract

During malignant progression cancer cells tend to lose cell surface expression of MHC and other immune antigens, making them invisible to cytotoxic T cells and therefore inaccessible to tumor antigen-directed immunotherapy. Moreover, cancer cell variants that have lost antigen expression frequently contribute to deadly tumor relapses that occur following treatments that had been initially effective. In an effort to destroy antigen-loss cancer cells in tumors, we created a strategy that combines a chimeric antigen receptor (CAR)redirected T-cell attack with an engineered local release of the cytokine interleukin 12 (IL-12), which recruits and reinforces macrophage function. Cytotoxic T cells were engineered to release inducible IL-12 upon CAR engagement in the tumor lesion, resulting in destruction of antigen-loss cancer cells that would normally escape. Importantly, elimination of the antigen-loss cancer cells was accompanied by an accumulation of activated macrophages that was critical to the antitumor response, because removing the macrophages abolished the response and restoring them reengaged it. Neutralizing TNF-alpha also abrogated the elimination of antigen-loss cancer cells, implying this proinflammatory factor in the process. Taken together, our results show how IL-12 supplementation by CAR T cells can target otherwise inaccessible tumor lesions, in a manner associated with reduced systemic toxicity, by recruiting and activating innate immune cells for a proinflammatory response. Cancer Res; 71(17); 5697-706. (C)2011 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chmielewski, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Kopecky, Caroline UNSPECIFIED UNSPECIFIED UNSPECIFIED Hombach, Andreas A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-489916
DOI:	10.1158/0008-5472.CAN-11-0103
Journal or Publication Title:	Cancer Res.
Volume:	71
Number:	17
Page Range:	S. 5697 - 5707
Date:	2011
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	0008-5472
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ANTITUMOR IMMUNITY; CANCER-IMMUNOTHERAPY; ESTABLISHED TUMORS; INTERLEUKIN-12; INDUCTION; THERAPY; ACTIVATION; STIMULATION; LYMPHOCYTES; ENVIRONMENT Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48991