Abstract 5371: Immune correlates of survival in advanced hepatocellular carcinoma patients treated with glypican-3-derived peptide vaccine: Results from phase I trial
Authors: Sawada Yu , Nobuoka Daisuke , Yoshikawa Toshiaki , Shimomura Manami , Saito Keigo , Mizuno Shoichi , Nakatsura Tetsuya 
Published: August 2012

Abstract
Introduction: Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC), because it is overexpressed specifically in HCC and correlates to a poor prognosis. In a preclinical study using a mouse model, we identified HLA-A24:02-restricted GPC3298-306 (EYILSLEEL) and HLA-A02:01-restricted GPC3144-152 (FVGEFFTDV) peptides, both of which can induce GPC3-reactive cytotoxic T-lymphocytes (CTLs) without inducing autoimmunity. On the basis of these results, we conducted a clinical trial of GPC3-derived peptide vaccine for advanced HCC patients to evaluate the vaccine's safety, tolerability, and immunological and clinical responses. Methods: Thirty-three advanced HCC patients were enrolled in this non-randomized, open-label, dose escalation phase I trial. GPC3-derived peptide was administered in a liquid form emulsified with incomplete Freund's adjuvant, and intradermally injected on days 1, 15, and 29. PBMCs, obtained from all patients before and after vaccination, were examined by ex vivo IFN-γ enzyme-linked immunospot (ELISPOT) assay. The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by ex vivo IFN-γ ELISPOT assay, and clinical outcomes, as measured by tumor response, time to tumor progression, and overall survival (OS). Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 18 patients showed stable disease 2 months after initiation of treatment. Four patients, of which 18 had stable disease, had tumor regression or necrosis not meeting the criteria for partial response. The median time to tumor progression was 3.4 months (95% CI, 2.1 to 4.6). The median OS was 9.0 months (95% CI, 8.0 to 10.0). Tumor biopsy was performed with adequate informed consent in 7 patients for the evaluation of the therapeutic effect after vaccination. In 5 out of 7 cases, infiltration of CD8-positive T cells into the tumor was increased after vaccination. GPC3 peptide vaccine could induce the GPC3-specific CTL response in 30 of 33 patients by ex vivo IFN-γ ELISPOT assay, and the GPC3-specific CTL frequency after vaccination correlated with overall survival. The analysis of all 33 patients showed that the median OS was 12.2 months (95% CI, 6.5 to 18.0) in patients with high frequency of GPC3-specfic CTL, compared with 8.5 months (95% CI, 3.7 to 13.1) in those with low frequency of GPC3-specfic CTL (p = 0.033). Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. Furthermore, this study shows that peptide-specific CTL frequency can be a predictive marker for overall survival in HCC patients receiving peptide vaccination.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5371. doi:1538-7445.AM2012-5371