The Journal of Experimental Medicine
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Published 20 December 2004. doi:10.1084/jem.20040890
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 12, 1623-1633
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Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin's Disease

Catherine M. Bollard1,2, Laura Aguilar2, Karin C. Straathof1, Benedikt Gahn1, M. Helen Huls1, Alexandra Rousseau1, John Sixbey5, M. Victoria Gresik3, George Carrum1,4, Melissa Hudson5, Dagmar Dilloo6, Adrian Gee1,2, Malcolm K. Brenner1,2,4, Cliona M. Rooney1,2, and Helen E. Heslop1,2,4

1 Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030
2 Department of Pediatrics, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030
3 Department of Pathology, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030
4 Department of Medicine, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030
5 St. Jude Children's Research Hospital, Memphis, TN 38105
6 Heinrich Heine University, 40225 Dusseldorf, Germany

Address correspondence to Catherine M. Bollard, Center for Gene and Cell Therapy, Baylor College of Medicine, 6621 Fannin St., MC 3-3320, Houston, TX 77030. Phone: (832) 824-4781; Fax: (832) 825-4668; email: cmbollar{at}txccc.org

Epstein Barr virus (EBV)+ Hodgkin's disease (HD) expresses clearly identified tumor antigens derived from the virus and could, in principle, be a target for adoptive immunotherapy with viral antigen–specific T cells. However, like most tumor-associated antigens in immunocompetent hosts, these potential targets are only weakly immunogenic, consisting primarily of the latent membrane protein (LMP)1 and LMP2 antigens. Moreover, Hodgkin tumors possess a range of tumor evasion strategies. Therefore, the likely value of immunotherapy with EBV-specific cytotoxic effector cells has been questioned. We have now used a combination of gene marking, tetramer, and functional analyses to track the fate and assess the activity of EBV cytotoxic T lymphocyte (CTL) lines administered to 14 patients treated for relapsed EBV+ HD. Gene marking studies showed that infused effector cells could further expand by several logs in vivo, contribute to the memory pool (persisting up to 12 mo), and traffic to tumor sites. Tetramer and functional analyses showed that T cells reactive with the tumor-associated antigen LMP2 were present in the infused lines, expanded in peripheral blood after infusion, and also entered tumor. Viral load decreased, demonstrating the biologic activity of the infused CTLs. Clinically, EBV CTLs were well tolerated, could control type B symptoms (fever, night sweats, and weight loss), and had antitumor activity. After CTL infusion, five patients were in complete remission at up to 40 mo, two of whom had clearly measurable tumor at the time of treatment. One additional patient had a partial response, and five had stable disease. The performance and fate of these human tumor antigen–specific T cells in vivo suggests that they might be of value for the treatment of EBV+ Hodgkin lymphoma.

Key Words: immunotherapy • lymphoma • Epstein-Barr virus • LMP2 • gene marking

Abbreviations used in this paper: EBER, EBV-encoded small RNA; EBNA, EBV nuclear antigen; HD, Hodgkin's disease; LCL, lymphoblastoid cell line; LMP, latent membrane protein; Q-PCR, quantitative real-time PCR; SCT, stem cell transplant; SFC, spot-forming cell.


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