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Dörr, J.* ; Gregor, L.* ; Lacher, S.B.* ; Oner, A.* ; Sun, Y.* ; Piseddu, I.* ; Fertig, L.* ; Spajic, S.* ; Lesch, S.* ; Michaelides, S.* ; Seifert, M.* ; Gottschlich, A.* ; Samson, N.* ; Majed, L.* ; Briukhovetska, D.* ; Simnica, D.* ; Hartmann, V.* ; Gabriel, K.* ; Cohen, S.* ; Boland, G.M.* ; Andreu-Sanz, D.* ; Carlini, E.* ; Stock, S.* ; Holtermann, A.* ; Müller, P.J.* ; Strzalkowski, T.* ; Trefny, M.P.* ; Endres, S. ; Jenkins, R.W.* ; Böttcher, J.P.* ; Kobold, S.

Ablation of prostaglandin E2 signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours.

Nat. Bio. Eng., DOI: 10.1038/s41551-025-01610-6 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumour microenvironment (TME). Prostaglandin E2 (PGE2) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE2 signalling in CAR T cells may enhance their activity in PGE2-rich solid tumours. Here we generate knockout CAR T cells double deficient for the PGE2 receptors EP2 and EP4 (EP2-/-EP4-/-) by CRISPR-Cas9 engineering. EP2-/-EP4-/- CAR T cells expanded unabatedly in the presence of PGE2. Further, they effectively controlled syngeneic and human xenograft tumour models in vivo, which was accompanied by intratumoural accumulation and persistence of modified T cells. Improved anti-tumour activity was also observed against patient-derived tumour samples from patients with pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC) and neuroendocrine (NET) cancer. Our data uncovers the detrimental impact of PGE2-mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as a potential strategy.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Checkpoint Blockade; Phase-ii; Cancer; Prostate; Growth; Chemoprevention; Chemotherapy; Combination; Activation; Inhibition
ISSN (print) / ISBN 2157-846X
e-ISSN 2157-846X
Journal Nature biomedical engineering
Publisher Nature Publishing Group
Publishing Place London ; New York NY ; Tokyo
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)
Grants EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)