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
ABSTRACT 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.
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.
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.
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.
- SourceAvailable from: Camilla Foged
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- "Montanide has been tested in clinical trials (Diefenbach et al., 2008; Fourcade et al., 2008; Kakimi et al., 2011) and is the adjuvant component of the CIMAvax EGF therapeutic anticancer vaccine licensed in Latin America for use in adult patients with stage IIIB/ IV non-small-cell lung cancer (Rodriguez et al., 2010). In addition, Montanide in combination with CpG ODN and the recombinant NY-ESO-1 protein induced antigen-specific CD8 + T-cell responses in cancer patients, presumably via cross-presentation (Table 1) (Karbach et al., 2010; Valmori et al., 2007). "
ABSTRACT: Induction of CD8(+) T-cell responses is critical for the immunological control of a variety of diseases upon vaccination. Modern subunit vaccines are based on highly purified recombinant proteins. The high purity represents a major advancement in terms of vaccine safety compared to previous vaccination strategies with live attenuated or whole killed pathogens, but typically renders vaccine antigens poorly immunogenic and insufficient in mobilizing protective immunity. Adjuvants are therefore needed in vaccine formulations to enhance, direct and maintain the immune response to vaccine antigens. However, a weakness of many adjuvants is the lack of induction of CD8(+) T-cell responses against protein antigens, which are required for protection against challenging and difficult infectious diseases such as AIDS and for therapeutic cancer vaccination. Within the last decade, adjuvant systems that can induce CD8(+) T-cell responses have been developed and the first clinical trials demonstrating the clinical relevance of such formulations have been performed. This paper reviews the current status of lipid- and polymer-based particulate antigen delivery systems capable of stimulating CD8(+) T-cell immunity with special focus on mechanisms of priming and pharmaceutical requirements for optimal activation of cytotoxic T-lymphocytes that can kill virus-infected or abnormal (cancer) cells.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 08/2011; 45(4):482-91. DOI:10.1016/j.ejps.2011.08.016 · 3.01 Impact Factor
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- "Therefore, discovery of multiple tumor antigens in EOC may provide opportunities for multiantigen immunotherapeutic strategies that can induce sufficient clinical responses. Tumor antigens that are inherently immunogenic and oncogenic in ovarian cancer are p53   , Sperm Protein 17 (SP17)   , Wilms' tumor gene 1 (WT1)   , survivin   , and NY-ESO-1   . "
ABSTRACT: The prognosis of epithelial ovarian cancer (EOC), the primary cause of death from gynaecological malignancies, has only modestly improved over the last decades. Immunotherapeutic treatment using a cocktail of antigens has been proposed as a "universal" vaccine strategy. We determined the expression of tumor antigens in the context of MHC class I expression in 270 primary tumor samples using tissue microarray. Expression of tumor antigens p53, SP17, survivin, WT1, and NY-ESO-1 was observed in 120 (48.0%), 173 (68.9%), 208 (90.0%), 129 (56.3%), and 27 (11.0%) of 270 tumor specimens, respectively. In 93.2% of EOC, at least one of the investigated tumor antigens was (over)expressed. Expression of MHC class I was observed in 78.1% of EOC. In 3 out 4 primary tumors, (over)expression of a tumor antigen combined with MHC class I was observed. These results indicate that a multiepitope vaccine, comprising these antigens, could serve as a universal therapeutic vaccine for the vast majority of ovarian cancer patients.Clinical and Developmental Immunology 09/2010; 2010:891505. DOI:10.1155/2010/891505 · 2.93 Impact Factor
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ABSTRACT: Background Up-regulated gene in lung cancer 10 (URLC10), confirmed to be lymphocyte antigen 6 complex locus K and defined as an oncoantigen, has been identified as a tumor-associated antigen by systematic analysis of expression levels of thousands of genes in lung cancer tissues and esophageal squamous cell carcinoma tissues, which were compared with those of normal human tissues by use of cDNA microarray analysis. Human leukocyte antigen (HLA)-A*2402-positive dendritic cells pulsed with URLC10-derived epitope peptide induced CD8+ cytotoxic T lymphocytes to exert specific cytotoxicity against the HLA-A*2402-positive URLC10-expressing esophageal carcinoma cell lines. Methods In a phase I clinical trial we evaluated the safety and immunogenicity of a URLC10-177 peptide vaccine emulsified with Montanide ISA51 for patients with unresectable advanced esophageal cancer. One milligram of URLC10-177 peptide in 1 mL sterile saline was emulsified with 1 mL incomplete Freund’s adjuvant and administered subcutaneously to the inguinal region or axilla of the patients. One course of treatment comprised four vaccinations, which were performed every week in the first and second treatment courses and subsequently every 2 weeks after the first vaccination in the third treatment course. Results Redness and induration of the skin were the only adverse events at the injection site and were believed to be a delayed-type hypersensitivity (DTH) reaction against the peptide vaccine. A URLC10-177-specific immune reaction in the enzyme-linked immunospot assay was detected in three of four DTH-positive patients (75 %) and in one of three DTH-negative patients (33 %). Furthermore, patients who had a DTH reaction seemed to survive longer than those who had no DTH reaction. Conclusion URLC10-177 peptide/Montanide vaccine therapy was well tolerated and induced a URLC10-177 peptide-specific immune response. Therapeutic URLC10-177 peptide vaccination is expected to have clinical benefit in prolonging the survival of patients with unresectable advanced esophageal cancer.Esophagus 06/2012; 9(2). DOI:10.1007/s10388-012-0315-y · 0.74 Impact Factor