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.
Ishizaki
Hidenobu
H
Division of General and Oncologic Surgery, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA.
Manuel
Edwin R
ER
Song
Guang-Yun
GY
Srivastava
Tumul
T
Sun
Sabrina
S
Diamond
Don J
DJ
Ellenhorn
Joshua D I
JD
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