Modified vaccinia Ankara expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model.
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.
Division of General and Oncologic Surgery, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA.
Hidenobu
H
Ishizaki
Edwin R
ER
Manuel
Guang-Yun
GY
Song
Tumul
T
Srivastava
Sabrina
S
Sun
Don J
DJ
Diamond
Joshua D I
JD
Ellenhorn
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D039481:CD11b Antigen / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005822:Genetic Vectors; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D019151:Peptide Library; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D012074:Remission Induction; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000077022:Survivin; D014611:Vaccination; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology; D000093542:Gemcitabine
D000951:Antigens, Neoplasm; C117749:Birc5 protein, mouse; D039481:CD11b Antigen; D019496:Cancer Vaccines; D051034:Inhibitor of Apoptosis Proteins; D010446:Peptide Fragments; D019151:Peptide Library; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D000077022:Survivin; C551746:granulocyte receptor 1, mouse; D003841:Deoxycytidine; D007371:Interferon-gamma; D000093542:Gemcitabine