Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma

• Published in: Nature medicine Vol. 14; no. 11; pp. 1264 - 1270
• Main Authors: Pule, Martin A, Savoldo, Barbara, Myers, G Doug, Rossig, Claudia, Russell, Heidi V, Dotti, Gianpietro, Huls, M Helen, Liu, Enli, Gee, Adrian P, Mei, Zhuyong, Yvon, Eric, Weiss, Heidi L, Liu, Hao, Rooney, Cliona M, Heslop, Helen E, Brenner, Malcolm K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2008; Nature Publishing Group
• Subjects: Adolescent; Antigen receptors, T cell; Antigens; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Care and treatment; Cell Line; Cell Proliferation; Cellular therapy; Child; Child, Preschool; Epstein-Barr virus; Female; Gene expression; Genetic aspects; Health aspects; Herpesvirus 4, Human - immunology; Humans; Immunotherapy; Infectious Diseases; Lymphocyte Activation - immunology; Lymphocytes; Male; Metabolic Diseases; Molecular Medicine; Neuroblastoma; Neuroblastoma - immunology; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblastoma - therapy; Neurosciences; Oncology; Phenotype; Receptors; Recoverin - immunology; T cells; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - virology; Tumors; Viruses; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.1882

The promise of engineered T cells for treating cancer has been mitigated by their poor persistence when transferred to patients. Pule et al . now show that dual-specific T cells that recognize an Epstein-Barr virus (EBV) antigen and a tumor antigen survive longer in individuals with neuroblastoma. Engineering virus-specific T cells to recognize tumor antigens may improve the efficacy of this immunotherapy in latently infected cancer patients ( pages 1148–1150 ). Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor–associated antigens do not survive long term and have limited antitumor activity in vivo , in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor–associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells.