Cytotoxic T lymphocyte therapy for epstein-barr virus+ Hodgkin's disease

Catherine M. Bollard, Laura Aguilar, Karin C. Straathof, Benedikt Gahn, M. Helen Huls, Alexandra Rousseau, John Sixbey, M. Victoria Gresik, George Carrum, Melissa Hudson, Dagmar Dilloo, Adrian Gee, Malcolm Brenner, Cliona M. Rooney, Helen Heslop

Research output: Contribution to journalArticle

320 Scopus citations

Abstract

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 and tumor 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.

Original languageEnglish (US)
Pages (from-to)1623-1633
Number of pages11
JournalJournal of Experimental Medicine
Volume200
Issue number12
DOIs
StatePublished - Dec 20 2004

Keywords

  • Epstein-Barr virus
  • Gene marking
  • Immunotherapy
  • LMP2
  • Lymphoma

ASJC Scopus subject areas

  • Immunology

Fingerprint Dive into the research topics of 'Cytotoxic T lymphocyte therapy for epstein-barr virus<sup>+</sup> Hodgkin's disease'. Together they form a unique fingerprint.

Cite this