Abstract B60: A potential of glypican-3-derived peptide vaccine therapy against cancer.
Authors: Tetsuya Nakatsura, Toshiaki Yoshikawa, Yu Sawada
Journal: Cancer Research (2013)

Abstract Introduction: Glypican-3 (GPC3) is a member of the glypican family of heparan sulfate proteoglycans, which are attached to the cell surface via the glycosylphosphatidylinositol (GPI) anchor. We reported its identification as a carcinoembryonic antigen, an ideal target for anticancer immunotherapy against HCC due to its specific overexpression in HCC (80%) and its correlation with a poor prognosis. Furthermore, we identified both HLA-A24(A*24:02) and H-2Kd-restricted GPC3298-306 (EYILSLEEL), as well as HLA-A2(A*02:01)-restricted GPC3144-152 (FVGEFFTDV), as peptides that can induce GPC3-reactive cytotoxic T lymphocytes (CTLs) without inducing autoimmunity. Phase-I trial: 33 patients with advanced Hepatocellular carcinoma (HCC) were administered GPC3 peptide vaccination with dose-escalation. Peptides were emulsified with IFA and administered in liquid form by intradermal injection on days 1, 15, and 29. We collected immunological evidence, demonstrated antitumor effects, and showed the safety of the GPC3-derived peptide vaccine. One patient showed a partial response (PR) and 4 of the 19 patients with stable disease (SD) had tumor necrosis or regression that did not meet the criteria for a partial response. We also analyzed the GPC3-specific CTL frequency ex vivo by IFN-γ enzyme-linked immunospot (ELISPOT) assay. In most patients, GPC3 peptide-specific CTLs appeared in the peripheral blood. Tumor biopsies were performed in seven patients to evaluate infiltration of CD8-positive T cells by immunohistochemical staining. The results in five cases showed marked infiltration of CD8-positive T cells into the tumor after vaccination. The GPC3 peptide-specific CTL frequency in peripheral blood was correlated with overall survival in patients with HCC who received the peptide vaccination. In multivariate analysis, the frequency of GPC3-peptide-specific CTLs was the predictive factor for overall survival in this trial. These observations suggest that GPC3-derived peptide vaccines represent a novel therapy for patients with HCC, with the potential to improve overall survival. Ongoing trial: We subsequently conducted a phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for patients with HCC. Forty patients with initial HCC who had undergone surgery or radiofrequency ablation were enrolled in this phase II, open-label, single-arm trial. We did not confirm whether the tumor-infiltrating lymphocytes detected after vaccination were GPC3 peptide-specific CTLs in Phase I. Therefore, we are initiating a pilot study of liver biopsies performed before and after GPC3 peptide vaccination for advanced HCC. GPC3 is overexpressed in several malignant tumors, including ovarian clear cell carcinoma (CCC), which had a poor prognosis due to low sensitivity to conventional chemotherapy. In a phase II study in ovarian CCC patients, one patient showed PR. Development of a novel strategy: Although the peptide vaccine is a potentially attractive treatment modality, the antitumor effects of the peptide vaccine alone are not dramatic for advanced HCC. Therefore, we aim to develop combinational approaches or strong antigen-specific immunotherapies, such as adoptive cell therapy following lymphodepletion. The density of endogenously presented antigen-derived peptides on tumor cells is generally sparse, resulting in the inability of antigen-specific CTLs to work effectively. To address this problem, we are performing intratumoral peptide injection in our ongoing study using mice. Intratumoral peptide injection enhances tumor cell antigenicity and may be a useful option for improving antigen-specific cancer immunotherapy. Conclusion: We might show the potential of GPC3 peptide vaccine therapy in these clinical trials. Citation Format: Tetsuya Nakatsura, Toshiaki Yoshikawa, Yu Sawada. A potential of glypican-3-derived peptide vaccine therapy against cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B60.