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Research Articles

The HLA A*0201–restricted hTERT_540–548 peptide is not detected on tumor cells by a CTL clone or a high-affinity T-cell receptor

¹ Avidex Ltd., Abingdon, Oxon, United Kingdom and ² Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

Requests for reprints: Bent K. Jakobsen, Avidex Ltd., 57-59 Milton Park, Abingdon, OX14 4RX, United Kingdom. Phone: 44-1235-438603; Fax: 11-44-1235-438601. E-mail: bent.jakobsen{at}avidex.com

Abstract

Tumor-associated human telomerase reverse transcriptase (hTERT) is expressed in >85% of human tumors but not in most normal cells. As a result, this antigen has received considerable attention from those interested in cancer immunotherapy. Specifically, there has been strong interest in MHC class I–associated peptides derived from hTERT because these are expressed on the cell surface and thus may enable the targeting of tumor cells. Much of this interest has focused on peptide 540–548, ILAKFLHWL, which was predicted to exhibit the strongest binding to the common HLA A*0201 presenting molecule. The hTERT_540–548 peptide is currently being assessed in therapeutic vaccination trials; however, there is controversy surrounding whether it is naturally processed and presented on the surface of neoplastic cells. Here, we generate two highly sensitive reagents to assess the presentation of hTERT_540–548 on tumor cells: (a) a CD8⁺ CTL clone, and (b) a recombinant T-cell receptor (TCR) that binds with picomolar affinity and a half-life exceeding 14 h. This TCR enables the identification of individual HLA A2-hTERT_540–548 complexes on the cell surface. The use of both this TCR and the highly antigen-sensitive CTL clone shows that the hTERT_540–548 peptide cannot be detected on the surface of tumor cells, indicating that this peptide is not a naturally presented epitope. We propose that, in future, rigorous methods must be applied for the validation of peptide epitopes used for clinical applications. [Mol Cancer Ther 2007;6(7):2081–91]

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.

Note: M.A. Purbhoo, Y. Li, and D.H. Sutton contributed equally to this work. Current address for M.A. Purbhoo: Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, United Kingdom. Current address for B.J. Classon: Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543. Current address for A.K. Sewell: Department of Medical Biochemistry and Immunology, Henry Wellcome Building, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. A.K. Sewell is a Welcome Trust Senior Fellow; D.A. Price is an Medical Research Council Senior Clinical Fellow.

Received 2/ 7/07; revised 4/18/07; accepted 5/30/07.

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