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

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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.

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References

  1. Jemal A, Siegel R, Ward E et al (2009) Cancer statics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  2. Sohn TA, Yeo CJ, Cameron JL et al (2000) Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 4:567–579

    Article  CAS  PubMed  Google Scholar 

  3. Li D, Xie K, Wolff R et al (2004) Pancreatic cancer. Lancet 363:1049–1057

    Article  CAS  PubMed  Google Scholar 

  4. Griffin JF, Smalley SR, Jewell W et al (1990) Patterns of failure after curative resection of pancreatic carcinoma. Cancer 66:56–61

    Article  CAS  PubMed  Google Scholar 

  5. Sperti C, Pasquali C, Piccoli A et al (1997) Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg 21:195–200

    Article  CAS  PubMed  Google Scholar 

  6. Burris HA, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413

    CAS  PubMed  Google Scholar 

  7. Louvet C, Labianca R, Hammel P et al (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516

    Article  CAS  PubMed  Google Scholar 

  8. Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966

    Article  CAS  PubMed  Google Scholar 

  9. Plate JM, Shott S, Harris JE (1999) Immunoregulation in pancreatic cancer patients. Cancer Immunol Immunother 48:270–279

    Article  CAS  PubMed  Google Scholar 

  10. Daikeler T, Maas K, Hartmann JT et al (1997) Weekly short infusions of gemcitabine are not associated with suppression of lymphatic activity in patients with solid tumors. Anticancer Drugs 8:643–644

    Article  CAS  PubMed  Google Scholar 

  11. Plate JM, Plate AE, Shott S et al (2005) Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother 54:915–925

    Article  CAS  PubMed  Google Scholar 

  12. Casneuf VF, Demetter P, Boterberg T et al (2009) Antiangiogenic versus cytotoxic therapeutic approaches in a mouse model of pancreatic cancer: An experimental study with multitarget tyrosine kinase inhibitor (sunitinib), gemcitabine and radiotherapy. Oncol Rep 22:105–113

    Article  CAS  PubMed  Google Scholar 

  13. Nowak AK, Robinson BW, Lake RA (2003) Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 63:4490–4496

    CAS  PubMed  Google Scholar 

  14. Nowak AK, Lake RA, Marzo AL et al (2003) Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol 170:4905–4913

    CAS  PubMed  Google Scholar 

  15. Suzuki E, Kapoor V, Jassar AS et al (2005) Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11:6713–6721

    Article  CAS  PubMed  Google Scholar 

  16. Ko HJ, Kim YJ, Kim YS et al (2007) A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res 67:7477–7486

    Article  CAS  PubMed  Google Scholar 

  17. Ito M, Shichijo S, Tsuda N et al (2001) Molecular basis of T cell-mediated recognition of pancreatic cancer cells. Cancer Res 61:2038–2046

    CAS  PubMed  Google Scholar 

  18. Schnurr M, Galambos P, Scholz C et al (2001) Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines. Cancer Res 61:6445–6450

    CAS  PubMed  Google Scholar 

  19. Schmitz-Winnenthal FH, Volk C, Z’graggen K et al (2005) High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 65:10079–10087

    Article  CAS  PubMed  Google Scholar 

  20. Fukunaga A, Miyamoto M, Cho Y et al (2004) CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 28:e26–e31

    Article  PubMed  Google Scholar 

  21. Altieri DC (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8:61–70

    Article  CAS  PubMed  Google Scholar 

  22. Adida C, Crotty PL, McGrath J et al (1998) Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol 152:43–49

    CAS  PubMed  Google Scholar 

  23. Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921

    Article  CAS  PubMed  Google Scholar 

  24. Velculescu VE, Madden SL, Zhang L et al (1999) Analysis of human transcriptomes. Nat Genet 23:387–388

    Article  CAS  PubMed  Google Scholar 

  25. Yamamoto H, Ngan CY, Monden M (2008) Cancer cells survive with survivin. Cancer Sci 99:1709–1714

    Article  CAS  PubMed  Google Scholar 

  26. Altieri DC (2006) Targeted therapy by disabling crossroad signaling networks: the survivin paradigm. Mol Cancer Ther 5:478–482

    Article  CAS  PubMed  Google Scholar 

  27. Andersen MH, Pedersen LO, Capeller B et al (2001) Spontaneous cytotoxic T-cell responses against survivin-derived MHC class I-restricted T-cell epitopes in situ as well as ex vivo in cancer patients. Cancer Res 61:5964–5968

    CAS  PubMed  Google Scholar 

  28. Rohayem J, Diestelkoetter P, Weigle B et al (2000) Antibody response to the tumor-associated inhibitor of apoptosis protein survivin in cancer patients. Cancer Res 60:1815–1817

    CAS  PubMed  Google Scholar 

  29. Xiang R, Mizutani N, Luo Y et al (2005) A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. Cancer Res 65:553–561

    CAS  PubMed  Google Scholar 

  30. Zeis M, Siegel S, Wagner A et al (2003) Generation of cytotoxic responses in mice and human individuals against hematological malignancies using survivin-RNA-transfected dendritic cells. J Immunol 170:5391–5397

    CAS  PubMed  Google Scholar 

  31. Sarela AI, Verbeke CS, Ramsdale J et al (2002) Expression of survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, in pancreatic adenocarcinoma. Br J Cancer 86:886–892

    Article  CAS  PubMed  Google Scholar 

  32. Kami K, Doi R, Koizumi M et al (2005) Downregulation of survivin by siRNA diminishes radioresistance of pancreatic cancer cells. Surgery 138:299–305

    Article  PubMed  Google Scholar 

  33. Satoh K, Kaneko K, Hirota M et al (2001) Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 92:271–278

    Article  CAS  PubMed  Google Scholar 

  34. Espenschied J, Lamont J, Longmate J et al (2003) CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. J Immunol 170:3401–3407

    CAS  PubMed  Google Scholar 

  35. Daftarian P, Song GY, Ali S et al (2004) Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors. Cancer Res 64:5407–5414

    Article  CAS  PubMed  Google Scholar 

  36. Song GY, Gibson G, Haq W et al (2007) An MVA vaccine overcomes tolerance to human p53 in mice and humans. Cancer Immunol Immunother 56:1193–1205

    Article  CAS  PubMed  Google Scholar 

  37. Harrop R, Connolly N, Redchenko I et al (2006) Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. Clin Cancer Res 12:3416–3424

    Article  CAS  PubMed  Google Scholar 

  38. Corbett TH, Roberts BJ, Leopold WR et al (1984) Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 44:717–726

    CAS  PubMed  Google Scholar 

  39. Tan MC, Goedegebuure PS, Belt BA et al (2009) Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol 182:1746–1755

    CAS  PubMed  Google Scholar 

  40. Macpherson I, Stoker M (1962) Polyoma transformation of hamster cell clones—an investigation of genetic factors affecting cell competence. Virology 16:147–151

    Article  CAS  PubMed  Google Scholar 

  41. Dialynas DP, Wilde DB, Marrack P et al (1983) Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev 74:29–56

    Article  CAS  PubMed  Google Scholar 

  42. Miconnet I, Coste I, Beermann F et al (2001) Cancer vaccine design: a novel bacterial adjuvant for peptide-specific CTL induction. J Immunol 166:4612–4619

    CAS  PubMed  Google Scholar 

  43. Wang Z, La Rosa C, Mekhoubad S et al (2004) Attenuated poxviruses generate clinically relevant frequencies of CMV-specific T cells. Blood 104:847–856

    Article  CAS  PubMed  Google Scholar 

  44. Manuel ER, Wang Z, Li Z et al (2010) Intergenic region 3 of modified vaccinia Ankara is a functional site for insert gene expression and allows for potent antigen-specific immune responses. Virology 403:155–162

    Article  CAS  PubMed  Google Scholar 

  45. Ishizaki H, Song GY, Srivastava T et al (2010) Heterologous prime/boost with p53-based vaccines combined with toll-like receptor stimulation enhances tumor regression. J Immunother 33:609–617

    Article  CAS  PubMed  Google Scholar 

  46. Gallina G, Dolcetti L, Serafini P et al (2006) Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 116:2777–2790

    Article  CAS  PubMed  Google Scholar 

  47. Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296

    Article  CAS  PubMed  Google Scholar 

  48. Gabrilovich DI, Velders MP, Sotomayor EM et al (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 166:5398–5406

    CAS  PubMed  Google Scholar 

  49. Serafini P, Borrello I, Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16:53–65

    Article  CAS  PubMed  Google Scholar 

  50. Kusmartsev S, Cheng F, Yu B et al (2003) All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 63:4441–4449

    CAS  PubMed  Google Scholar 

  51. Serafini P, Meckel K, Kelso M et al (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203:2691–2702

    Article  CAS  PubMed  Google Scholar 

  52. Ozao-Choy J, Ma G, Kao J et al (2009) The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69:2514–2522

    Article  CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Division of General and Oncologic Surgery, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010-3000, USA

    Hidenobu Ishizaki, Guang-Yun Song & Joshua D. I. Ellenhorn

  2. Division of Translational Vaccine Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010-3000, USA

    Edwin R. Manuel, Tumul Srivastava, Sabrina Sun & Don J. Diamond

Authors
  1. Hidenobu Ishizaki
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  2. Edwin R. Manuel
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  3. Guang-Yun Song
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  4. Tumul Srivastava
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  5. Sabrina Sun
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  6. Don J. Diamond
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  7. Joshua D. I. Ellenhorn
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Correspondence to Joshua D. I. Ellenhorn.

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H. Ishizaki and E. R. Manuel contributed equally to this work.

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Ishizaki, H., Manuel, E.R., Song, GY. et al. Modified vaccinia Ankara expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model. Cancer Immunol Immunother 60, 99–109 (2011). https://doi.org/10.1007/s00262-010-0923-0

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  • DOI: https://doi.org/10.1007/s00262-010-0923-0

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