Safety and Immunogenicity Study of NY-ESO-1b Peptide and Montanide ISA-51 Vaccination of Patients with Epithelial Ovarian Cancer in High-Risk First Remission Catherine S.M. Diefenbach, 1 Sacha Gnjatic, 4 Paul Sabbatini, 1 Carol Aghajanian, 1 Martee L. Hensley, 1 David R. Spriggs, 1 Alexia Iasonos, 3 Helen Lee, 1 Bo Dupont, 2 Sandra Pezzulli, 1 Achim A. Jungbluth, 4 Lloyd J. Old, 4 and Jakob Dupont 1 Abstract Purpose: The cancer-testis antigen NY-ESO-1 is expressed by >40% of advanced epithelial ovarian cancers and is a promising immunotherapeutic target. In this study, we describe the effects of vaccination with the HLA-A*0201^ restricted NY-ESO-1b peptide on patients with epithelial ovarian cancer in high-risk first remission. Experimental Design: After primary surgery and chemotherapy, high-risk epithelial ovarian cancer patients in first clinical remission received NY-ESO-1b peptide and Montanide every 3 weeks for five vaccinations. Tumor expression was evaluated by immunohistochemistry. Toxicity was monitored using National Cancer Institute Common Toxicity Criteria Scale Version 2. NY-ESO-1 specific humoral immunity (ELISA), T-cell immunity (tetramer and ELISPOT), and delayed-type hypersensitivity were assessed on weeks 0, 1, 4, 7, 10, 13, and 16. Results: Treatment-related adverse events included grade 1 fatigue, anemia, pruritus, myalgias, and hyperthyroidism and grade 2 hypothyroidism. There were no grade 3/grade 4 adverse events. Three of four patients (75%) with NY-ESO-1^ positive tumor showed T-cell immunity by tetramer (0.6-9.5%) and ELISPOT (range, 35-260 spots). Four of five patients (80%) with NY-ESO-1^ negative tumor showed T-cell immunity by tetramer (1.0-12.1%) and/or ELISPOT (range, 35-400 spots). With a median follow-up of 11.3 months, six of nine patients (67%) have recurred, with a median progression-free survival of 13 months (95% confidence interval, 11.2 months ^ not reached). Three of nine patients remain in complete clinical remission at 25, 38, and 52 months. Conclusion: Vaccination of high-risk HLA-A*0201 ^ positive epithelial ovarian cancer patients with NY-ESO-1b and Montanide has minimal toxicity and induces specific T-cell immunity in patients with both NY-ESO-1^ positive and NY-ESO-1^ negative tumors. Additional study is warranted. Epithelial ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. More than 25,000 cases are diagnosed annually, and there are an estimated 14,000 deaths/y due to this disease (1). Greater than 70% of ovarian cancer patients have advanced-stage disease at the time of diagnosis (2). Although a complete clinical remission (cCR) to initial chemotherapy can be anticipated for most patients, strategies to decrease recurrence are needed for >80% of patients with advanced ovarian cancer that will recur. Despite improvements in surgery and chemotherapy, the long- term survival rate remains at f20% to 30% for advanced ovarian cancer (2 – 4). Suboptimal initial tumor debulking surgery, failure to normalize CA-125 after three cycles of chemotherapy, or positive second-look surgery are considered high-risk indications of recurrence due to micrometastatic disease despite apparent cCR; these ‘‘high-risk’’ patients have a short remission duration of 10 to 12 months and a recurrence rate of >70% (5 – 7). Given the minimal disease burden in the setting of cCR, these high-risk patients are ideal candidates for evaluating immune-modulating strategies. Cancer Therapy: Clinical Authors’Affiliations: Departments of 1 Medicine, 2 Immunology, and 3 Biostatistics, Memorial Sloan-Kettering Cancer Center and the Joan and Sanford I. Weill Medical College of Cornell University; and 4 Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center, NewYork, NewYork Received 10/12/07; revised 12/20/07; accepted 1/4/08. Grant support: Cancer Research Institute (S. Gnjatic and J. Dupont), Damon Runyon-Lilly Clinical Investigator Program (J. Dupont), and Cancer Vaccine Collaborative funded by the Cancer Research Institute and Ludwig Institute for Cancer Research. 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: C.S.M. Diefenbach and S. Gnjatic are co-first authors and contributed equally to the manuscript. Current address for J. Dupont: Genentech, San Francisco, California. Requests for reprints: Sacha Gnjatic, Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 32-Room Z- 1502, NewYork, NY 10065. Phone: 646-888-2339; Fax: 646-422-0492; E-mail: gnjatics@mskcc.org or Catherine S.M. Diefenbach, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 917-783-7776; Fax: 212-717-3214; E-mail: magidc@mskcc.org. F 2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-4619 www.aacrjournals.org Clin Cancer Res 2008;14(9) May 1, 2008 2740 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/14/9/2740/1981875/2740.pdf by guest on 14 June 2022