Abstract 2420: Modified vaccinia Ankara (MVA) expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model

Abstract

Abstract Survivin is overexpressed by 70-80% of pancreatic cancers, and is associated with resistance to chemotherapy and a poor prognosis. Gemcitabine has been a standard treatment for patients with advanced pancreatic cancer for a decade. Recent reports have demonstrated that gemcitabine treatment attenuates the tumor-suppressive environment by eliminating CD11b+/Gr-1+ myeloid derived suppressor cells (MDSCs). It may also enhance the effect of cancer vaccines. The highly attenuated strain of vaccinia, modified vaccinia Ankara (MVA) has been employed as a vaccine vector to deliver a tumor associated antigen, and MVA vaccines have demonstrated safety, immunogenicity, and evidence of clinical benefit in patients with cancer. We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when use in combination with gemcitabine. In this study, we tested this hypothesis using an MVA expressing full-length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which express murine survivin and syngeneic to C57BL/6, was used for this study. To develop an established tumor model, mice were challenged with 2.5 × 105 Pan02 cells by subcutaneous injection. When the tumors were palpable and reached 4 to 5 mm in diameter, mice were immunized twice at a 1-week interval with 5 × 107 pfu of MVA-survivin or control MVA. Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. Gemcitabine (60mg/kg) was administrated 48 hours before first immunization. Mice treated with a control MVA or PBS with gemcitabine all died of progressive tumor by day 35. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy is in part due to decreased CD11b+/Gr-1+ MDSCs. To analyze the survivin specific immune response to MVA-survivin immunization, we utilized a peptide library of 15mers with 11 residues overlapping from full-length murine survivin. Splencytes from mice immunized with MVA-survivin produced intracellular γ-interferon in response to in vitro stimulation with the overlapping peptide library. These data suggest that vaccination with MVA-survivin in combination with gemcitabine represents an attractive strategy to overcome tumor-induced peripheral immune tolerance, and this effect may be associated with a clinical benefit in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2420.