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Abstract
Preclinical tumor models show that chemotherapy has immune modulatory properties which can be exploited in the context of immunotherapy. The purpose of this study was to determine the feasibility and immunogenicity of combinations of such an immunomodulatory chemotherapeutic agent with immunotherapy, p53 synthetic long peptide (SLP) vaccine and Pegintron (IFN-α) in patients with platinum-resistant p53-positive epithelial ovarian cancer (EOC). This is a phase 1/2 trial in which patients sequential 6 cycles of gemcitabine (1000 mg/kg2 iv; n = 3), gemcitabine with Pegintron before and after the first gemcitabine cycle (Pegintron 1 μg/kg sc; n = 6), and gemcitabine and Pegintron combined with p53 SLP vaccine (0.3 mg/peptide, 9 peptides; n = 6). At baseline, 22 days after the 2nd and 6th cycle, blood was collected for immunomonitoring. Toxicity, CA-125, and radiologic response were evaluated after 3 and 6 cycles of chemotherapy. None of the patients enrolled experienced dose-limiting toxicity. Predominant grade 3/4 toxicities were nausea/vomiting and dyspnea. Grade 1/2 toxicities consisted of fatigue (78%) and Pegintron-related flu-like symptoms (72%). Gemcitabine reduced myeloid-derived suppressor cells (p = 0.0005) and increased immune-supportive M1 macrophages (p = 0.04). Combination of gemcitabine and Pegintron stimulated higher frequencies of circulating proliferating CD4+ and CD8+ T-cells but not regulatory T-cells. All vaccinated patients showed strong vaccine-induced p53-specific T-cell responses. Combination of gemcitabine, the immune modulator Pegintron and therapeutic peptide vaccination is a viable approach in the development of combined chemo-immunotherapeutic regimens to treat cancer.
Highlights
Ovarian cancer has a dismal prognosis, with a 5-years survival of 30% [1, 2]
Combination of gemcitabine, the immune modulator Pegintron and therapeutic peptide vaccination is a viable approach in the development of combined chemo-immunotherapeutic regimens to treat cancer
Epithelial ovarian cancer (EOC) is likely to benefit from T-cell-based immunotherapy as it was observed that strong infiltration with CD8+ T-cells is correlated with enhanced survival and response to chemotherapy [6, 7]
Summary
Ovarian cancer has a dismal prognosis, with a 5-years survival of 30% [1, 2]. These cancer patients are treated with platinum-based chemotherapy but the majority develops recurrences and die because of treatment failure, indicating that other treatment strategies are warranted. Epithelial ovarian cancer (EOC) is likely to benefit from T-cell-based immunotherapy as it was observed that strong infiltration with CD8+ T-cells is correlated with enhanced survival and response to chemotherapy [6, 7]. The path to clinical success in patients with EOC requires a strategy that increases the frequency and activity of antitumor T-cells while eliminating suppressive immune cells and providing enough time for a fully developed antitumor response, treatment should start as early as possible
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