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

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.

• Authors: Hidenobu Ishizaki, Edwin R Manuel, Guang-Yun Song, Tumul Srivastava, Sabrina Sun, Don J Diamond, Joshua D I Ellenhorn
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 60 Issue 1 Pg. 99-109 (Jan 2011) ISSN: 1432-0851 [Electronic] Germany
• PMID: 20960189 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

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