Vaccination of Patients With Advanced Non–Small-Cell Lung Cancer With an Optimized Cryptic Human Telomerase Reverse Transcriptase Peptide Irini Bolonaki, Athanassios Kotsakis, Elsa Papadimitraki, Despoina Aggouraki, George Konsolakis, Aphrodite Vagia, Charalambos Christophylakis, Irini Nikoloudi, Elefterios Magganas, Athanassios Galanis, Paul Cordopatis, Kostas Kosmatopoulos, Vassilis Georgoulias, and Dimitris Mavroudis A B S T R A C T Purpose To evaluate the immunological and clinical response as well as the safety of the optimized peptide telomerase reverse transcriptase p572Y (TERT 572Y ) presented by HLA-A*0201 in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Twenty-two patients with advanced NSCLC and residual (n = 8) or progressive disease (PD; n = 14) following chemotherapy and/or radiotherapy received two subcutaneous injections of the optimized TERT 572Y peptide followed by four injections of the native TERT 572 peptide adminis- tered every 3 weeks. Peptide-specific immune responses were monitored by enzyme-linked immunosorbent spot assay and/or TERT 572Y pentamer staining. Results Twelve (54.5%) of 22 patients completed the vaccination program. Toxicity consisted primarily of local skin reactions. TERT 572 -specific CD8 + cells were detected in 16 (76.2%) of 21 patients after the second vaccination, and 10 (90.9%) of 11 patients after the sixth vaccination. Stable disease (SD) occurred in eight (36.4%) of 22 vaccinated patients, with three (13.6%) having had PD before entering the study. The median duration of SD was 11.2 months. After a median follow-up of 10.0 months, patients with early developed immunological response (n = 16) had a significantly longer time to progression and overall survival (OS) than nonresponders (n = 5; log-rank tests P = .046 and P = .012, respectively). The estimated median OS was 30.0 months (range, 2.8 to 40.0 months) and 4.1 months (range, 2.4 to 10.9 months) for responders and nonresponders, respectively. Conclusion TERT 572Y peptide vaccine is well tolerated and effective in eliciting a specific T cell immunity. Immunological response is associated with prolonged survival. These results are encouraging and warrant further evaluation in a randomized study. J Clin Oncol 25:2727-2734. © 2007 by American Society of Clinical Oncology INTRODUCTION Non–small-cell lung cancer (NSCLC) represents 80% of lung cancer cases. Most patients present with stage III/IV disease and have a median survival of less than 12 months with chemotherapy and radiother- apy. Recently, biologic agents have been evaluated with promising results. 1 Although NSCLC was initially considered weakly immunogenic or non- immunogenic, recent studies with vaccines have shown encouraging efficacy. 2-4 Antitumor immunotherapy is mainly based on the activation of cytotoxic T lymphocytes (CTL) recognizing endogenously processed peptides de- rived from tumor antigens and presented at the cell surface in association with HLA class I molecules (HLA I). Dominant peptides exhibit high HLA I affinity and immunogenicity, but most vaccines tar- geting dominant peptides gave relatively disap- pointing results in clinical studies due to the presence of tolerance. 5-6 One simple way to break tolerance to tumor antigens is to use cryptic peptides. Indeed, we and others have shown that the T cell repertoire specific for cryptic peptides partially or completely escapes tolerance mechanisms. 7-10 This suggests that cryptic peptides would be good tumor vaccines provided they are rendered immunogenic. Cryptic peptides, which have low HLA I affinity, and therefore are not immunogenic, have to be optimized by altering their From the Departments of Transfusion Medicine, Medical Oncology, and Radi- ology, University General Hospital of Heraklion; Laboratory of Tumor Biology, School of Medicine, University of Crete, Heraklion, Crete; “Iaso” General Hospital, Athens, Greece; and the Department of Pharmacy, University of Patras, Patras; Vaxon Biotech, Genopole, Evry, France. Submitted December 27, 2006; accepted April 2, 2007. Supported in part by grants from the Cretan Association for Biomedical Research. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Dimitris Mavroudis, MD, PhD, Department of Medical Oncology, University Hospital of Heraklion, Voutes, 71110, Crete, Greece; e-mail: mavrudis@med.uoc.gr. © 2007 by American Society of Clinical Oncology 0732-183X/07/2519-2727/$20.00 DOI: 10.1200/JCO.2006.10.3465 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 25  NUMBER 19  JULY 1 2007 2727 Downloaded from jco.ascopubs.org on December 3, 2014. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved.