Janina Dörr, Lisa Gregor, Sebastian Lacher, Arman Öner, Yi Sun, Ignazio Piseddu, Luisa Fertig, Sebastijan Spajic, Stefanie Lesch, Stefanos Michaelides, Matthias Seifert, Adrian Gottschlich, Natasha Samson, Lina Majed, Daria Briukhovetska, Donjetë Simnica, V. Hartmann, Kathrin Gabriel, Sonia Cohen, Genevieve M. Boland, David Andreu-Sanz, Emanuele Carlini, Sophia Stock, Anne Holtermann, Philipp Jie Müller, Thaddäus Strzalkowski, Marcel P. Trefny, Stefan Endres, Russell W. Jenkins, Jan P. Böttcher, Sebastian Kobold
Abstract The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumour microenvironment (TME). Prostaglandin E 2 (PGE 2 ) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE 2 signalling in CAR T cells may enhance their activity in PGE 2 -rich solid tumours. Here we generate knockout CAR T cells double deficient for the PGE 2 receptors EP2 and EP4 (EP2 −/− EP4 −/− ) by CRISPR–Cas9 engineering. EP2 −/− EP4 −/− CAR T cells expanded unabatedly in the presence of PGE 2 . 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 PGE 2 -mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as a potential strategy.