Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer
Piril Erler, Tomasz Kurćon, Hana Cho, Jordan Skinner, Chantel Dixon, Steven Grudman, Sandra Rozlan, Emilie Dessez, Ben Mumford, Sumin Jo, Alex Boyne, Alexandre Juillerat, Philippe Duchâteau, Laurent Poirot, Beatriz Aranda-Orgillés
Abstract
Solid tumors, such as triple-negative breast cancer (TNBC), are biologically complex due to cellular heterogeneity, lack of tumor-specific antigens, and an immunosuppressive tumor microenvironment (TME). These challenges restrain chimeric antigen receptor (CAR) T cell efficacy, underlining the importance of armoring. In solid cancers, a localized tumor mass allows alternative administration routes, such as intratumoral delivery with the potential to improve efficacy and safety but may compromise metastatic-site treatment. Using a multi-layered CAR T cell engineering strategy that allowed a synergy between attributes, we show enhanced cytotoxic activity of MUC1 CAR T cells armored with PD1 KO , tumor-specific interleukin-12 release, and TGFBR2 KO attributes catered towards the TNBC TME. Intratumoral treatment effectively reduced distant tumors, suggesting retention of antigen-recognition benefits at metastatic sites. Overall, we provide preclinical evidence of armored non-alloreactive MUC1 CAR T cells greatly reducing high TNBC tumor burden in a TGFB1- and PD-L1–rich TME both at local and distant sites while preserving safety.