301. Antitumor Effects of CAR T Cells Redirected to the EDB Splice Variant of Fibronectin.
- Author
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Wagner J, Wickman E, Shaw TI, Anido AA, Langfitt D, Zhang J, Porter SN, Pruett-Miller SM, Tillman H, Krenciute G, and Gottschalk S
- Subjects
- Animals, Antigens, Neoplasm, Cell Line, Tumor, Coculture Techniques, Feasibility Studies, Fibronectins genetics, Fibronectins immunology, Fibronectins metabolism, Healthy Volunteers, Human Umbilical Vein Endothelial Cells, Humans, Mice, Neoplasm Proteins genetics, Neoplasm Proteins immunology, Neoplasm Proteins metabolism, Neoplasms immunology, Neoplasms pathology, Primary Cell Culture, Protein Isoforms antagonists & inhibitors, Protein Isoforms genetics, Protein Isoforms immunology, Protein Isoforms metabolism, RNA Splicing, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology, Xenograft Model Antitumor Assays, Fibronectins antagonists & inhibitors, Immunotherapy, Adoptive methods, Neoplasm Proteins antagonists & inhibitors, Neoplasms therapy, T-Lymphocytes transplantation
- Abstract
Chimeric antigen receptor (CAR) T-cell therapy has had limited success in early-phase clinical studies for solid tumors. Lack of efficacy is most likely multifactorial, including a limited array of targetable antigens. We reasoned that targeting the cancer-specific extra domain B (EDB) splice variant of fibronectin might overcome this limitation because it is abundantly secreted by cancer cells and adheres to their cell surface. In vitro , EDB-CAR T cells recognized and killed EDB-positive tumor cells. In vivo , 1 × 10
6 EDB-CAR T cells had potent antitumor activity in both subcutaneous and systemic tumor xenograft models, resulting in a significant survival advantage in comparison with control mice. EDB-CAR T cells also targeted the tumor vasculature, as judged by IHC and imaging, and their antivascular activity was dependent on the secretion of EDB by tumor cells. Thus, targeting tumor-specific splice variants such as EDB with CAR T cells is feasible and has the potential to improve the efficacy of CAR T-cell therapy., (©2020 American Association for Cancer Research.)- Published
- 2021
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