CAR T Cells Targeting the Tumor MUC1 Glycoprotein Reduce Triple-Negative Breast Cancer Growth

Front Immunol. 2019 May 24:10:1149. doi: 10.3389/fimmu.2019.01149. eCollection 2019.

Abstract

Antibody-derived chimeric antigen receptor (CAR) T cell therapy has achieved gratifying breakthrough in hematologic malignancies but has shown limited success in solid tumor immunotherapy. Monoclonal antibody, TAB004, specifically recognizes the aberrantly glycosylated tumor form of MUC1 (tMUC1) in all subtypes of breast cancer including 95% of triple-negative breast cancer (TNBC) while sparing recognition of normal tissue MUC1. We transduced human T cells with MUC28z, a chimeric antigen receptor comprising of the scFv of TAB004 coupled to CD28 and CD3ζ. MUC28z was well-expressed on the surface of engineered activated human T cells. MUC28z CAR T cells demonstrated significant target-specific cytotoxicity against a panel of human TNBC cells. Upon recognition of tMUC1 on TNBC cells, MUC28z CAR T cells increased production of Granzyme B, IFN-γ and other Th1 type cytokines and chemokines. A single dose of MUC28z CAR T cells significantly reduced TNBC tumor growth in a xenograft model. Thus, MUC28z CAR T cells have high therapeutic potential against tMUC1-positive TNBC tumors with minimal damage to normal breast epithelial cells.

Keywords: MUC1; MUC28z CAR T cells; TAB004; immunotherapy; triple-negative breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology*
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Female
  • Genetic Engineering
  • Humans
  • Immunophenotyping
  • Immunotherapy, Adoptive* / adverse effects
  • Immunotherapy, Adoptive* / methods
  • Lymphocyte Activation / immunology
  • Mice
  • Mucin-1 / immunology*
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Treatment Outcome
  • Triple Negative Breast Neoplasms / immunology*
  • Triple Negative Breast Neoplasms / therapy*
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, Neoplasm
  • Cytokines
  • MUC1 protein, human
  • Mucin-1
  • Receptors, Chimeric Antigen