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

Cadilha, Bruno L.; Benmebarek, Mohamed-Reda; Dorman, Klara; Oner, Arman; Lorenzini, Theo; Obeck, Hannah; Vaenttinen, Mira; Di Pilato, Mauro; Pruessmann, Jasper N.; Stoiber, Stefan; Duc, Huynh; Maerkl, Florian; Seifert, Matthias; Manske, Katrin; Suarez-Gosalvez, Javier; Zeng, Yi; Lesch, Stefanie; Karches, Clara H.; Heise, Constanze; Gottschlich, Adrian; Thomas, Moritz; Marr, Carsten; Zhang, Jin; Pandey, Dharmendra; Feuchtinger, Tobias; Subklewe, Marion; Mempel, Thorsten R.; Endres, Stefan und Kobold, Sebastian (2021): Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors. In: Science Advances, Bd. 7, Nr. 24, eabi5781

Abstract

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (T-reg) cells suppress the immune response via inhibitory factors such as transforming growth factor-beta (TGF-beta). 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-beta receptor 2 (DNR) can simultaneously shield them from TGF-beta. 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-beta 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2375-2548
• Sprache: Englisch