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

Martin A. Pule, Barbara Savoldo, G. Doug Myers, Claudia Rossig, Heidi V. Russell, Gianpietro Dotti, M. Helen Huls, Enli Liu, Adrian P. Gee, Zhuyong Mei, Eric Yvon, Heidi L. Weiss, Hao Liu, Cliona M. Rooney, Helen E. Heslop, Malcolm K. Brenner

Research output: Contribution to journalArticle

773 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1264-1270
Number of pages7
JournalNature Medicine
Volume14
Issue number11
DOIs
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Pule, M. A., Savoldo, B., Myers, G. D., Rossig, C., Russell, H. V., Dotti, G., Huls, M. H., Liu, E., Gee, A. P., Mei, Z., Yvon, E., Weiss, H. L., Liu, H., Rooney, C. M., Heslop, H. E., & Brenner, M. K. (2008). Virus-specific T cells engineered to coexpress tumor-specific receptors: Persistence and antitumor activity in individuals with neuroblastoma. Nature Medicine, 14(11), 1264-1270. https://doi.org/10.1038/nm.1882