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

Sci Adv. 2024 Aug 30;10(35):eadn9857. doi: 10.1126/sciadv.adn9857. Epub 2024 Aug 30.

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 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.

MeSH terms

  • 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

Substances

  • Mucin-1
  • Receptors, Chimeric Antigen
  • MUC1 protein, human