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TEM8/ANTXR1-Specific CAR T Cells as a Targeted Therapy for Triple-Negative Breast Cancer
Tiara T Byrd1,2,3, Kristen Fousek4,2,3, Antonella Pignata2,3
1Department of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas. ttbyrd@txch.org nahmed@bcm.edu.
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.
Insights
This study introduces a new immunotherapy for triple-negative breast cancer (TNBC) using CAR T cells targeting the TEM8 antigen. These engineered cells effectively kill TNBC cells and tumor blood vessels, offering a promising new treatment strategy.
Area of Science:
- Immunology
- Oncology
- Cancer Therapeutics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
- The TEM8 antigen is upregulated in TNBC and its associated tumor vasculature.
Purpose of the Study:
- To develop and evaluate a CAR T cell-based immunotherapy targeting TEM8 for TNBC treatment.
- To assess the efficacy of TEM8-targeted CAR T cells against TNBC cells, cancer stem cells, and tumor vasculature.
Main Methods:
- Development of chimeric antigen receptor (CAR) T cells engineered to recognize TEM8.
- In vitro assessment of CAR T cell activity against TNBC cells and mammosphere formation.
- In vivo evaluation of TEM8 CAR T cells in patient-derived xenograft and metastatic TNBC models.
Main Results:
- TEM8 CAR T cells specifically recognized and killed TEM8-positive TNBC cells and tumor endothelial cells.
- TEM8 CAR T cells inhibited the formation of mammospheres, indicating targeting of breast cancer stem-like cells.
- Adoptive transfer of TEM8 CAR T cells led to tumor regression in established xenograft models by direct tumor cell killing and anti-angiogenesis.
Conclusions:
- TEM8 CAR T cell therapy demonstrates preclinical efficacy against triple-negative breast cancer.
- Targeting TEM8 offers a dual strategy by attacking both tumor cells and tumor vasculature.
- This approach provides a proof of concept for a novel immunotherapeutic strategy for TNBC.
