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

Cancer Immunol Immunother. 2011 Jan;60(1):99-109. doi: 10.1007/s00262-010-0923-0. Epub 2010 Oct 20.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy*
  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • Antigens, Neoplasm / metabolism*
  • CD11b Antigen / biosynthesis
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • Cancer Vaccines*
  • Cell Line, Tumor
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Genetic Vectors
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / immunology
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / drug effects
  • Myeloid Cells / pathology
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism*
  • Peptide Library
  • Receptors, Cell Surface / biosynthesis
  • Remission Induction
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology
  • Repressor Proteins / metabolism*
  • Survivin
  • Vaccination
  • Vaccinia virus / genetics*
  • Vaccinia virus / immunology

Substances

  • Antigens, Neoplasm
  • Birc5 protein, mouse
  • CD11b Antigen
  • Cancer Vaccines
  • Inhibitor of Apoptosis Proteins
  • Peptide Fragments
  • Peptide Library
  • Receptors, Cell Surface
  • Repressor Proteins
  • Survivin
  • granulocyte receptor 1, mouse
  • Deoxycytidine
  • Interferon-gamma
  • gemcitabine