Phase I Trial of a Glypican-3–Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival

Abstract

Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC.Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-g ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS).Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers a-fetoprotein and/or des-g-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N ¼ 15) than in those with low frequencies (N ¼ 18; P ¼ 0.033).Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination.

Development of T Cells Redirected to Glypican-3 for the Treatment of Hepatocellular Carcinoma

“…Multiple studies have demonstrated that GPC3 is an attractive liver cancer-specific target because it is highly expressed in HCC but limited expressed in normal tissues (7). Currently, GPC3-targeted immunotherapeutic strategies utilizing antibodies or a peptide vaccine have been explored for HCC treatment (8)(9)(10)(11)(12). The clinical data of the monoclonal antibody GC33 indicated that it was well tolerated in advanced HCC, suggesting that GPC3 is a relatively safe target.…”

Recent advances in immunotherapy for non-small-cell lung cancer

“…Several recent studies including our own have shown that good PS is a significant prognostic factor. 29,43,44 Regarding multiple peptide therapy, as we mentioned previously, recent data showed the effectiveness of vaccines containing multiple epitopes. More recently, dendritic cell immunotherapy using multiple epitopes has also been reported in the treatment of brain tumors.…”

Immunobiology of hepatocarcinogenesis: Ways to go or almost there?

“…One was a nonrandomized, open-label phase 1 clinical trial against GPC3 peptides, which proved to be safe and showed a measurable immune response with higher CTL activity. However, only one of the 33 patients treated had objective tumor response [150] . The second vaccine was with an hTERTderived peptide that revealed no signs of clinical or CTL activity [151] .…”