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Cancer Res. 2018 Jan 15;78(2):489-500. doi: 10.1158/0008-5472.CAN-16-1911. Epub 2017 Nov 28.

TEM8/ANTXR1-Specific CAR T Cells as a Targeted Therapy for Triple-Negative Breast Cancer.

Author information

1
Department of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas. ttbyrd@txch.org nahmed@bcm.edu.
2
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children's Hospital, Houston, Texas.
3
Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas.
4
Department of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas.
5
Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
6
Children's Cancer Hospital Egypt (CCHE 57357), El-Saida Zenab, Cairo Governorate, Egypt.
7
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
8
Department of Urologic Sciences, University of British Columbia; Vancouver Prostate Centre, Vancouver, BC, Canada.
9
Department of Pediatric Pathology, Texas Children's Hospital, Houston, Texas.
10
Department of Pathology - Anatomic, Houston Methodist Hospital, Houston, Texas.
11
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas.
12
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Straße, Frankfurt am Main, Germany.
13
Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center Mainz, Germany.
14
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
15
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
16
Department of Neuroscience, Baylor College of Medicine, Houston, Texas.
17
Department of Medicine, University of Florida, Gainesville, Florida.

Abstract

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 nontransduced T cells. Adoptive transfer of TEM8 CAR T cells induced regression of established, localized patient-derived xenograft tumors, 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.Significance: These findings offer a preclinical proof of concept for immunotherapeutic targeting of an endothelial antigen that is overexpressed in triple-negative breast cancer and the associated tumor vasculature. Cancer Res; 78(2); 489-500. ©2017 AACR.

PMID:
29183891
PMCID:
PMC5771806
[Available on 2019-01-15]
DOI:
10.1158/0008-5472.CAN-16-1911

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