Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer

• Published in: Science advances Vol. 10; no. 35; p. eadn9857
• Main Authors: Erler, Piril, Kurcon, Tomasz, Cho, Hana, Skinner, Jordan, Dixon, Chantel, Grudman, Steven, Rozlan, Sandra, Dessez, Emilie, Mumford, Ben, Jo, Sumin, Boyne, Alex, Juillerat, Alexandre, Duchateau, Philippe, Poirot, Laurent, Aranda-Orgilles, Beatriz
• Format: Journal Article
• Language: English
• Published: United States 30-08-2024
• Subjects: Animals; Cell Line, Tumor; Female; Humans; Immunotherapy, Adoptive - methods; Mice; Mucin-1 - genetics; Mucin-1 - immunology; Mucin-1 - metabolism; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - therapy; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adn9857

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
, tumor-specific interleukin-12 release, and TGFBR2
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.