Chmielewski, Markus and Abken, Hinrich (2017). CAR T Cells Releasing IL-18 Convert to T-Bet(high) FoxO1(low) Effectors that Exhibit Augmented Activity against Advanced Solid Tumors. Cell Reports, 21 (11). S. 3205 - 3220. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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Abstract

Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bet high FoxO1 low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines. IL-18 CAR T cell treatment was accompanied by an overall change in the immune cell landscape associated with the tumor. More specifically, CD206(-) M1 macrophages and NKG2D + NK cells increased in number, whereas Tregs, suppressive CD103(+) DCs, and M2 macrophages decreased, suggesting that iIL18 TRUCKs'' can be used to sensitize large solid tumor lesions for successful immune destruction.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chmielewski, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abken, HinrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-207987
DOI: 10.1016/j.celrep.2017.11.063
Journal or Publication Title: Cell Reports
Volume: 21
Number: 11
Page Range: S. 3205 - 3220
Date: 2017
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2211-1247
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NK CELLS; INTERLEUKIN-18; CANCER; SERUM; IMMUNOTHERAPY; EXPRESSION; THERAPY; LYMPHOCYTES; MAINTAIN; PARADOXMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/20798

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