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Epitope Specificity and Clonality of EBV-Specific CTLs Used to Treat Posttransplant Lymphoproliferative Disease¹

Karen A. McAulay^2,*, Tanzina Haque, Gillian Urquhart^*, Christopher Bellamy, Deisy Guiretti^* and Dorothy H. Crawford^*

^* Clinical and Basic Virology Laboratory, School of Biomedical Sciences, University of Edinburgh, Summerhall, Edinburgh, Centre for Virology, Royal Free and University College Medical School, Hampstead, London, NW3 2PF, and Department of Pathology, Edinburgh Royal Infirmary, Little France, Edinburgh, United Kingdom

In a recent phase II clinical trial using banked allogeneic CTL lines to treat EBV-associated posttransplant lymphoproliferative disease, a response rate of 52% was recorded 6 mo posttreatment. Tumor response was associated with an increase in both CTL/recipient HLA matches and CD4⁺ T cells within the infused CTL lines. The present study was undertaken to correlate tumor response with CTL specificity. The majority of CTL lines infused recognized EBV-encoded nuclear Ag-3 proteins, but CTL protein specificity itself did not correlate with tumor response. Specificity in conjunction with donor/recipient functional HLA matching as opposed to HLA matching alone, however, was important for tumor response. CTL receptor TCR β-chain variable gene subfamilies were polyclonal, with no preferential use of a particular family. However, tumor response was improved in those receiving CTL lines with polyclonal vs clonal distribution for subfamilies 2, 3, and 9. Interestingly, in five of six tumors (five Hodgkin’s-like and one Burkitt’s-like posttransplant lymphoproliferative disease) with restricted viral gene expression a complete response was recorded, although in some cases the tumor cells did not express the proteins recognized by the infused CTL. Thus CTL were advantageous when functionally HLA matched but for certain tumor types complete responses occurred in the absence of detectable specific CTL/tumor recognition. We suggest that either the allogenic CTL contained small, undetectable, EBV-specific, HLA-matched T cell populations or perhaps they stimulated nonspecific inflammatory responses in vivo, which were beneficial for tumor regression. These observations should be considered when designing and implementing CTL therapies.

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 This study was supported by funding from Grant C307/A3869 by The Cancer Research U.K.

² Address correspondence and reprint requests to Dr. Karen A. McAulay, Clinical and Basic Virology Laboratory, School of Biomedical Sciences, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, U.K. E-mail address: kmcaulay{at}ed.ac.uk

³ Abbreviations used in this paper: PTLD, posttransplant lymphoproliferative disease; DC, dendritic cell; EBNA, EBV-encoded nuclear Ag; LCL, lymphoblastoid cell line; LMP, latent membrane protein; EBER, Epstein-Barr-encoded small nonpolyadenylated RNA.

⁴ The online version of this article contains supplemental material.