Original Article

Cancer Immunology, Immunotherapy

, Volume 60, Issue 1, pp 99-109

Modified vaccinia Ankara expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model

  • Hidenobu IshizakiAffiliated withDivision of General and Oncologic Surgery, City of Hope National Medical Center
  • , Edwin R. ManuelAffiliated withDivision of Translational Vaccine Research, City of Hope National Medical Center
  • , Guang-Yun SongAffiliated withDivision of General and Oncologic Surgery, City of Hope National Medical Center
  • , Tumul SrivastavaAffiliated withDivision of Translational Vaccine Research, City of Hope National Medical Center
  • , Sabrina SunAffiliated withDivision of Translational Vaccine Research, City of Hope National Medical Center
  • , Don J. DiamondAffiliated withDivision of Translational Vaccine Research, City of Hope National Medical Center
  • , Joshua D. I. EllenhornAffiliated withDivision of General and Oncologic Surgery, City of Hope National Medical Center Email author 

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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). We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when combined with gemcitabine. In this study, we tested this hypothesis using modified vaccinia Ankara (MVA) expressing full-length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which expresses murine survivin and is syngeneic to C57BL/6, was used for this study. Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy was associated with 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. Splenocytes from mice immunized with MVA-survivin produced intracellular γ-interferon in response to in vitro stimulation with the overlapping peptide library. Increased survivin-specific CD8+ T cells that specifically recognized the Pan02 tumor line were seen in mice treated with MVA-survivin and gemcitabine. 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 has potential for clinical benefit in pancreatic cancer.

Keywords

Modified vaccinia Ankara (MVA) Survivin Gemcitabine Pancreatic cancer Cancer vaccine