Efficacy of glypican-3-derived peptide vaccine therapy on the survival of patients with refractory ovarian clear cell carcinoma

Abstract

Compared with other epithelial ovarian carcinoma subtypes, ovarian clear cell carcinoma (OCCC) has been recognized to show chemoresistance. Therefore, new treatment modalities are required for patients with OCCC that is refractory to chemotherapy. The carcinoembryonic antigen glypican-3 (GPC3) is expressed by approximately half of OCCC and is a promising immunotherapeutic target. The purpose of this study was to evaluate the effect of GPC3 peptide vaccine against refractory OCCC patients. We conducted a phase II trial with a GPC3-derived peptide vaccine in OCCC patients. Immunological responses were analyzed by ex vivo IFNγ ELISPOT assay. We also evaluated control subjects, who received best supportive care without vaccinations during the same period. Thirty-two patients with refractory OCCC were enrolled between July 2010 and September 2015, and underwent GPC3 peptide vaccination. Fifteen patients were vaccinated less than six times because their general condition progressively deteriorated, and 17 patients were vaccinated at least six times. Three patients showed a partial response as the best overall response. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 15 out of 24 patients who had PBMCs collected three times or more. The prognosis of palliative care patients without GPC3 peptide vaccinations was significantly poorer than that of those with GPC3 peptide vaccinations (post cancer-treatment survival: p = 0.002). Although the disease control rate was not high, our results suggest that GPC3 peptide vaccinations may hold a significant impact to prolong survival of patients with refractory OCCC, allowing them to maintain quality of life with no serious toxicities.

Keywords: Clear cell carcinoma; cytotoxic T lymphocyte; glypican-3; peptide vaccine; refractory ovarian cancer.

Figure 1.

Trial profile. Fifteen patients stopped treatment. Worsening of PS: 13, brain infarction: 2, adverse effects: 0 (treatment related). Seventeen patients received six vaccinations or more.

Figure 2.

Kaplan–Meier curves for post cancer-treatment survival. Thirty-two patients treated with BSC and GPC3 vaccinations had significantly longer post cancer-treatment survival rates than the 33 patients who underwent BSC only (p = 0.002).

Figure 3.

Clinical and immunological response in the patient who achieved a PR (case 13). (A) Serum levels of CA125 and CA19-9 decreased after the initiation of therapy. Black arrows indicate vaccinations. (B) Contrast-enhanced CT scan showing lymph node (red circle) and disseminations (yellow, blue and green circles) metastases. (C) Pathological findings of primary OCCC. Immunohistochemical staining for GPC3 and HLA class I showed positivity in the primary tumor, respectively. There was little infiltration of CD8-positive T cells in the primary OCCC tissue. Original magnification, ×200. (D) Ex vivo IFNγ ELISPOT assays for GPC3 were performed before and after vaccination. The number of IFNγ-positive spots increased in the wells pre-incubated with GPC3 peptide.