Byrd et al. engineered CAR T cells targeting TEM8, a marker on triple-negative breast cancer (TNBC), breast cancer stem-like cells (BCSCs), and tumor endothelial cells (TEC). The CAR T cells effectively killed TEC and TNBC cells and reduced the formation of mammospheres by BCSCs in vitro. In vivo, the CAR T cells induced regression of established cell line- and patient-derived xenograft tumors, disrupted tumor vascularization and infrastructure, blocked metastasis in xenograft tumors derived from a lung metastatic TNBC cell line, and improved survival.

Triple-negative breast cancer (TNBC) is an aggressive disease lacking targeted therapy. In this study, we developed a CAR T cell-based immunotherapeutic strategy to target TEM8, a marker initially defined on endothelial cells in colon tumors that was discovered recently to be upregulated in TNBC. CAR T cells were developed that upon specific recognition of TEM8 secreted immunostimulatory cytokines and killed tumor endothelial cells as well as TEM8-positive TNBC cells. Notably, the TEM8 CAR T cells targeted breast cancer stem-like cells, offsetting the formation of mammospheres relative to non-transduced T cells. Adoptive transfer of TEM8 CAR T cells induced regression of established, localized patient-derived xenograft tumors (PDX) as well as lung metastatic TNBC cell line-derived xenograft tumors, by both killing TEM8+ TNBC tumor cells and targeting the tumor endothelium to block tumor neovascularization. Our findings offer a preclinical proof of concept for immunotherapeutic targeting of TEM8 as a strategy to treat TNBC.

Author Info: (1) Pediatric Hematology Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine ttbyrd@txch.org. (2) Center for Cell and Gene Therapy, Baylor College of

Author Info: (1) Pediatric Hematology Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine ttbyrd@txch.org. (2) Center for Cell and Gene Therapy, Baylor College of Medicine. (3) Pediatrics, Baylor College of Medicine. (4) Center for Cancer Research, National Cancer institute. (5) Children's Cancer Hospital Egypt (57357). (6) Center for Cancer Research, National Cancer Institute. (7) Lester and Sue Smith Breast Center, Baylor College of Medicine. (8) Baylor College of Medicine. (9) Department of Urologic Sciences, University of British Columbia. (10) Pediatrics, Baylor College of Medicine. (11) Pediatrics, Baylor College of Medicine. (12) Baylor College of Medicine. (13) Department of Pathology, Texas Children's Hospital. (14) Pathology and Genomic Medicine, Houston Methodist Hospital. (15) Biochemistry and Molecular Biology, Baylor College of Medicine. (16) Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus. (17) NK Cell Biology, Institut for Biomedical Research, Georg-Speyer-Haus. (18) Department of Molecular Oncology, British Columbia Cancer Research Centre. (19) Neuroscience, Baylor College of Medicine. (20) Lester and Sue Smith Breast Center, Baylor College of Medicine. (21) Lester and Sue Smith Breast Center, Baylor College of Medicine. (22) Pediatric Hematology Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine. (23) Medicine, Div. of Hem/Onc, University of Florida. (24) Center for Cancer Research, National Cancer Institute. (25) Center for Cell and Gene Therapy, Baylor College of Medicine.

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