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* Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane, Australia;
Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia; and
Haematology Service, Peter MacCallum Cancer Centre, and University of Melbourne, Melbourne, Australia
Recent studies on Hodgkin’s lymphoma (HL) have indicated that patients with active disease display functional impairment of Ag-specific CD8+ T cells due to expansion of regulatory T cells at sites of disease and in the peripheral blood. Adoptive cellular immunotherapy based on EBV-specific CD8+ T cells has been explored with limited success to date. It has been proposed that improved targeting of these CD8+ T cells toward viral Ags that are expressed in HL may enhance future therapeutic vaccine strategies. In this study, we have developed a novel replication-deficient adenoviral Ag presentation system that is designed to encode glycine alanine repeat-deleted EBV nuclear Ag 1 covalently linked to multiple CD8+ T cell epitopes from latent membrane proteins 1 and 2. A single stimulation of CD8+ T cells from healthy virus carriers, and patients with HL with this adenoviral construct in combination with IL-2, was sufficient to reverse the functional T cell impairment and restored both IFN-
production and cytolytic function. More importantly, these activated CD8+ T cells responded to tumor cells expressing membrane proteins and recognized novel EBNA1 epitopes. Flow cytometric analysis revealed that a large proportion of T cells expanded from patients with HL were CD62Lhigh and CD27high, and CCR7low, consistent with early to mid effector T cells. These findings provide an important platform for translation of Ag-specific adoptive immunotherapy for the treatment of EBV-associated malignancies such as HL and nasopharyngeal carcinoma.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The study was supported by the National Health and Medical Research Council (Australia), Queensland Cancer Fund, and the British Society for Haematology. M.G. is a National Institutes of Health/Medical Research Council Clinical Research Fellow, and R.K. is a National Institutes of Health/Medical Research Council Principal Research Fellow.
2 Address correspondence and reprint requests to Dr. Rajiv Khanna, Queensland Institute of Medical Research, Bancroft Centre, 300 Herston Road, Brisbane, Australia 4029. E-mail address: rajivK{at}qimr.edu.au
3 Abbreviations used in this paper: HL, Hodgkin’s lymphoma; NPC, nasopharyngeal carcinoma; LMP, latent membrane protein; EBNA1, EBV nuclear Ag 1; LCL, lymphoblastoid cell line; GA, glycine alanine; EBNA1
GA, EBNA1-coding DNA without the GA repeat; HEK, human embryonic kidney; MOI, multiplicity of infection; SFC, spot-forming cell.
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