Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy.
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.
Rossig
Claudia
C
Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin Street, Houston, TX 77030, USA.
Bollard
Catherine M
CM
Nuchtern
Jed G
JG
Rooney
Cliona M
CM
Brenner
Malcolm K
MK
D000951:Antigens, Neoplasm / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins