10.01 Prostanoid-insensitive chimeric antigen receptor modified T cells mediate therapeutic efficacy in solid cancer models

• DOI: 10.1136/jitc-2024-itoc10.6
• Publication Date: 2024-03-20T11:50:15Z
• Authors: J Dörr; L Gregor; SB Lacher; A Öner; S Lesch; S Michaelides; L Majed; L Fertig; E Carlini; D Andreu Sanz; D Briukhovetska; S Stock; A Gottschlich; JP Böttcher; S Kobold
• Keywords: Prostanoid; Solid tumor

<h3>Background</h3> Chimeric antigen receptor (CAR) T cell therapy has transformed the landscape of hematologic malignancy treatment. However, its successful translation to solid cancer treatment remains challenging, primarily due immunosuppressive tumor microenvironment (TME). Prostaglandin E₂ (PGE₂) emerged as a pivotal player in TME immunosuppression, whereby impact on function been recognized novel immune checkpoint. This study focuses enhancing CAR efficacy against tumors by disrupting PGE₂ signaling through targeted knockout receptors, EP2 and EP4. <h3>Materials Methods</h3> Utilizing CRISPR/Cas9 technology, we generated double cells deficient <i>In vitro</i> analyses assessed functions, including proliferation, activation, cytotoxicity. To translate these findings human system, conducted growth survival experiments using xenograft mouse model. Additionally, tracking was performed elucidate fate EP2^-/-EP4^-/- <i>in vivo</i>. <h3>Results</h3> We could successfully generate murine well EP4 single cells, which showed complete abrogation signaling, indicated suppressed cAMP production CREB phosphorylation. While wild type were their proliferative abilities PGE₂, capacity become activated remained unaffected. PGE₂-induced reduction numbers ultimately compromised anti-tumor activity both effect rescued knockout, leading increased accumulation within tumors. As consequence, bettered therapeutic prolonged achieved <h3>Conclusions</h3> Our underscore detrimental PGE₂-mediated suppression TME, highlighting potential rescue knockout. Notably, knockouts either proved insufficient shield from PGE₂. Genetic ablation presents promising strategy without healthy encourages further exploration development this strategy. <b>J. Dörr:</b> None. <b>L. Gregor:</b> <b>S.B. Lacher:</b> <b>A. Öner:</b> <b>S. Lesch:</b> Michaelides:</b> Majed:</b> Fertig:</b> <b>E. Carlini:</b> <b>D. Andreu Sanz:</b> Briukhovetska:</b> Stock:</b> Gottschlich:</b> <b>J.P. Böttcher:</b> Kobold:</b> B. Research Grant (principal investigator, collaborator or consultant pending grants already received); Significant; TCR2 Inc, Catalym, Plectonic, Arcus Biosciences, Tabby Therapeutics. D. Speakers Bureau/Honoraria (speakers bureau, symposia, expert witness); GSK, BMS, Novartis, Miltenyi Biotherapeutics, Inc. E. Ownership Interest (stock, stock options, patent other intellectual property); Carina Biotech.