Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer
Menée à l'aide de lignées cellulaires, de modèles murins de cancer du sein triple négatif et de cellules mononucléées issues de sang périphérique d'origine humaine, cette étude met en évidence l'intérêt thérapeutique de lymphocytes CAR-T modifiés par ingénierie pour cibler la glycoprotéine MUC1, sécréter l'interleukine IL-12 spécifique de la tumeur et ne plus exprimer la protéine PD1 ainsi que le récepteur TGFBR2
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 PD1KO, tumor-specific interleukin-12 release, and TGFBR2KO 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. MUC1 CAR T cells modified with TGFBR2KO, PD1KO, and IL-12KI eliminate local and distant tumors and improve safety via IT delivery.