Ablation of prostaglandin E(2) signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours

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.

• 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.