Significant clinical response of progressive recurrent ovarian clear cell carcinoma to glypican-3-derived peptide vaccine therapy: two case reports

Abstract

Carcinoembryonic antigen glypican-3 (GPC3) is expressed by>40% of ovarian clear cell carcinoma (CCC) and is a promising immunotherapeutic target. We previously reported the safety of and immunological and clinical responses to a GPC3-derived peptide vaccine in a phase I clinical trial of patients with advanced hepatocellular carcinoma (HCC). Although the efficacy of the GPC3-derived peptide vaccine against HCC patients was evaluated, other GPC3-positive cancer patients have not yet been investigated. Therefore, we conducted a phase II trial to evaluate the clinical outcome of ovarian CCC patients treated with a GPC3-derived peptide vaccine. The GPC3 peptide was administered at a dose of 3 mg per body. Patients received an intradermal injection of the GPC3 peptide emulsified with incomplete Freund's adjuvant. Vaccinations were performed biweekly from the first until the 6th injection and were then repeated at 6-week intervals after the 7th injection. Treatment continued until disease progression. We herein present two patients with chemotherapy-refractory ovarian CCC who achieved a significant clinical response in an ongoing trial of a GPC3 peptide vaccine. Case 1, a 42-year-old patient with advanced recurrent ovarian CCC with liver and retroperitoneal lymph node metastases, received the HLA-A24-restricted GPC3 peptide vaccine. Contrast-enhanced CT at week 10 revealed a partial response (PR) using RECIST criteria. Case 2 was a 67-year-old female with multiple lymph node metastases. She was injected with the HLA-A2-restricted GPC3 peptide vaccine. According to RECIST, PR was achieved at week 37. The stabilization of their diseases over one year provided us with the first clinical evidence to demonstrate that GPC3 peptide-based immunotherapy may significantly prolong the overall survival of patients with refractory ovarian CCC.

Keywords: Glypican-3; clinical response; ovarian clear cell carcinoma; peptide vaccine; refractory disease.

Figure 1. (A) Clinical course from the beginning of the GPC3 peptide vaccination. Serum levels of CA125 and CA72–4 decreased after the initiation of therapy. Black arrows indicate vaccinations. The asterisk indicates right inguinal lymph node resection biopsy. The double asterisk indicates bilateral inguinal lymphadenectomy. (B) Contrast-enhanced CT scan showing liver (white, red, blue, and orange arrows) and paraaortic lymph node (yellow arrows) metastases. The size of metastases increased immediately following the initiation of the GPC3 peptide vaccination; however, tumor sizes decreased markedly within three months. (C, D) Pathological findings of primary ovarian carcinoma (C) and right inguinal lymph node biopsy specimens (D). A microscopy image of a hematoxylin and eosin (H&E)-stained section shows CCC (a, i). Immunohistochemical staining for GPC3 and HLA class I showed positivity in the primary ovarian carcinoma, respectively (b, c). Most CCC cells in the resected right inguinal lymph node metastasis appeared to lack GPC3 expression and a reduction in the expression of HLA class I (ii, iii). Immunohistochemical analysis showed a few CD8-positive T cells in the primary ovarian CCC tissue (d), whereas there was little infiltration of CD8-positive T cells in the resected right inguinal lymph node metastasis (iv). Original magnification, x200.

Figure 2. (A) Clinical course from the beginning of the GPC3 peptide vaccination. Serum levels of CA19–9 and CA125 decreased after the 7th vaccination. The CA19–9 level decreased to within the normal range. Black arrows indicate vaccinations. (B) Plain CT and ¹⁸F-FDG PET/CT scans showing retroperitoneal lymph node (white, red, blue and orange arrows) and Virchow's node (yellow arrows) metastases. These metastases were negative on ¹⁸F-FDG PET/CT at week 49. (C) Pathological findings of primary ovarian carcinoma. A microscopy image of a hematoxylin and eosin (H&E)-stained section shows CCC (a). Immunohistochemical staining was performed for GPC3, HLA class I, and CD8. (b, c, d). The expression of HLA class I was positive, while that of GPC3 was not, and there was no infiltration of CD8-positive T cells. Original magnification, x200.