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Cancer Immunology, Immunotherapy

, Volume 60, Issue 1, pp 99–109 | Cite as

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

  • Hidenobu Ishizaki
  • Edwin R. Manuel
  • Guang-Yun Song
  • Tumul Srivastava
  • Sabrina Sun
  • Don J. Diamond
  • Joshua D. I. Ellenhorn
Original Article

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 

Notes

Acknowledgments

The authors thank the staff of the Animal Resource Center at City of Hope for their expert animal handling and assistance in husbandry. Grant support for these studies was from NCI (CA077544 and CA030206) to Don J. Diamond, a minority supplement award to E. Manuel (CA030206S2) and a RAID supplement (CA030206S3) to DJD. Grants from the Riley Foundation and FAMRI also provided partial support for the project to Joshua D. I. Ellenhorn. The COH Cancer Center is supported by CA033572. D. Diamond dedicates this report to the memory of his dear friend, David VP Marks.

Conflict of interest

The authors declare that there are no conflicts of interest in regard to this work.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Hidenobu Ishizaki
    • 1
  • Edwin R. Manuel
    • 2
  • Guang-Yun Song
    • 1
  • Tumul Srivastava
    • 2
  • Sabrina Sun
    • 2
  • Don J. Diamond
    • 2
  • Joshua D. I. Ellenhorn
    • 1
  1. 1.Division of General and Oncologic SurgeryCity of Hope National Medical CenterDuarteUSA
  2. 2.Division of Translational Vaccine ResearchCity of Hope National Medical CenterDuarteUSA

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