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Cadilha, B.L.* ; Benmebarek, M.R.* ; Dorman, K.* ; Oner, A.* ; Lorenzini, T.* ; Obeck, H.* ; Vänttinen, M.* ; Pilato, M.D.* ; Pruessmann, J.N.* ; Stoiber, S.* ; Huynh, D.* ; Märkl, F.* ; Seifert, M.* ; Manske, K.* ; Suarez-Gosalvez, J.* ; Zeng, Y.* ; Lesch, S.* ; Karches, C.H.* ; Heise, C.* ; Gottschlich, A.* ; Thomas, M. ; Marr, C. ; Zhang, J.* ; Pandey, D.* ; Feuchtinger, T.* ; Subklewe, M.* ; Mempel, T.R.* ; Endres, S.* ; Kobold, S.

Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors.

Sci. Adv. 7:eabi5781 (2021)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Growth-factor-beta; Receptor; Driven
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Quellenangaben Volume: 7, Issue: 24, Pages: , Article Number: eabi5781 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)
Institute of Computational Biology (ICB)
Grants Ernst-Jung-Stiftung
Melanoma Research Alliance Grants
Marie-Sklodowska-Curie Program Training Network for the Immunotherapy of Cancer - H2020 Program of the European Union
Marie-Sklodowska-Curie Program Training Network for Optimizing Adoptive T Cell Therapy of Cancer - H2020 Program of the European Union
Hector foundation
Else Kroner-Fresenius-Stiftung
LMU Munich's Institutional Strategy LMUexcellent
Bundesministerium fur Bildung und Forschung Project Oncoattract
European Research Council
German Research Foundation (DFG)
NIH
Fritz-Bender Foundation
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program
Volkswagen Foundation (project OntoTime)
Jose-Carreras Foundation
Deutsche Gesellschaft fur Immun-und Targeted-therapie
German Cancer Aid
International Doctoral Program i-Target: Immunotargeting of Cancer - Elite Network of Bavaria