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Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for
Claudia Rossig1, Catherine M Bollard, Jed G Nuchtern
1Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin Street, Houston, TX 77030, USA.
Abstract:
Primary T cells expressing chimeric receptors specific for tumor or viral antigens have considerable therapeutic potential. Unfortunately, their clinical value is limited by their rapid loss of function and failure to expand in vivo, presumably due to the lack of costimulator molecules on tumor cells and the inherent limitations of signaling exclusively through the chimeric receptor. Epstein-Barr virus (EBV) infection of B lymphocytes is near universal in humans and stimulates high levels of EBV-specific helper and cytotoxic T cells, which persist indefinitely. Our clinical studies have shown that EBV-specific T cells generated in vitro will expand, persist, and function for more than 6 years in vivo. We now report that EBV-specific (but not primary) T cells transduced with tumor-specific chimeric receptor genes can be expanded and maintained long-term in the presence of EBV-infected B cells. They recognize EBV-infected targets through their conventional T-cell receptor and tumor targets through their chimeric receptors. They efficiently lyse both. EBV-specific T cells expressing chimeric antitumor receptors may represent a new source of effector cells that would persist and function long-term after their transfer to cancer patients.
Insights
Epstein-Barr virus (EBV)-specific T cells engineered with chimeric antigen receptors demonstrate long-term persistence and function. This approach offers a promising strategy for durable cancer immunotherapy by overcoming limitations of primary T cells.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Chimeric antigen receptor (CAR) T cells show therapeutic promise but suffer from limited in vivo expansion and function.
- Tumor cells often lack costimulatory molecules, hindering CAR T cell efficacy.
- Epstein-Barr virus (EBV)-specific T cells exhibit robust long-term expansion and persistence in vivo.
Purpose of the Study:
- To investigate the potential of EBV-specific T cells engineered with tumor-specific CARs for long-term cancer immunotherapy.
- To determine if EBV-specific T cells can overcome the functional limitations observed in primary CAR T cells.
Main Methods:
- Transduction of EBV-specific T cells with tumor-specific chimeric receptor genes.
- Co-culture of engineered T cells with EBV-infected B cells and tumor targets.
- Assessment of T cell expansion, persistence, and cytotoxic function against both EBV-infected and tumor targets.
Main Results:
- EBV-specific T cells, but not primary T cells, transduced with tumor-specific CARs could be expanded and maintained long-term in the presence of EBV-infected B cells.
- These engineered cells recognized and efficiently lysed both EBV-infected targets via their native T-cell receptor and tumor targets via their CAR.
- Demonstrated sustained in vivo expansion and function exceeding 6 years in prior clinical studies.
Conclusions:
- EBV-specific T cells engineered with chimeric antitumor receptors represent a novel and potentially superior source of effector cells for cancer therapy.
- This approach may lead to durable persistence and function of transferred T cells in cancer patients, addressing key limitations of current CAR T cell therapies.