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Cancer Immunology, Immunotherapy

, Volume 58, Issue 9, pp 1355–1362 | Cite as

The immunologic aspects of poxvirus oncolytic therapy

  • Andrea Worschech
  • D. Haddad
  • D. F. Stroncek
  • E. Wang
  • Francesco M. MarincolaEmail author
  • Aladar A. SzalayEmail author
Review

Abstract

The concept of using replicating oncolytic viruses in cancer therapy dates to the beginning of the twentieth century. However, in the last few years, an increasing number of pre-clinical and clinical trials have been carried out with promising preliminarily results. Novel, indeed, is the suggestion that viral oncolytic therapy might not operate exclusively through an oncolysis-mediated process but additionally requires the “assistance” of the host’s immune system. Originally, the host’s immune response was believed to play a predominant obstructive role against viral replication, hence limiting the anti-tumor efficacy of viral vectors. Recent data, however, suggest that the immune response may also play a key role in promoting tumor destruction in association with the oncolytic process. In fact, immune effector pathways activated during oncolytic virus-induced tumor rejection seem to follow a similar pattern to those observed when the broader phenomenon of immune-mediated tissue-specific rejection occurs in other immune-related pathologies. We recently formulated the “Immunologic Constant of Rejection” hypothesis, emphasizing commonalties in transcriptional patterns observed when tissue-destruction occurs: whether with a favorable outcome, such as in tumor rejection and pathogen clearance; or a destructive one, such as in allograft rejection or autoimmunity. Here, we propose that a similar mechanism induces clearance of virally infected tumors and that such a mechanism is primarily dependent on innate immune functions.

Keywords

Vaccinia virus Oncolytic therapy Innate immunity Tumor rejection 

Notes

Conflict of interest statement

This work was supported by Genelux Co.; Andrea Worschech, Dana Haddad and Aladar A Szalay have received payment or are employees of Genelux Co.

References

  1. 1.
    Sinkovics J, Horvath J (1993) New developments in the virus therapy of cancer: a historical review. Intervirology 36:193–214PubMedGoogle Scholar
  2. 2.
    Dock G (1904) The influence of complicating diseases upon leukaemia. Am J Med Sci 127:563CrossRefGoogle Scholar
  3. 3.
    Parato KA, Senger D, Forsyth PA, Bell JC (2005) Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 5:965–976PubMedCrossRefGoogle Scholar
  4. 4.
    Vaha-Koskela MJ, Heikkila JE, Hinkkanen AE (2007) Oncolytic viruses in cancer therapy. Cancer Lett 254:178–216PubMedCrossRefGoogle Scholar
  5. 5.
    Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A et al (1996) An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274:373–376PubMedCrossRefGoogle Scholar
  6. 6.
    Lin E, Nemunaitis J (2004) Oncolytic viral therapies. Cancer Gene Ther 11:643–664PubMedCrossRefGoogle Scholar
  7. 7.
    Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM (1991) Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252:854–856PubMedCrossRefGoogle Scholar
  8. 8.
    O’Shea CC (2005) DNA tumor viruses—the spies who lyse us. Curr Opin Genet Dev 15:18–26PubMedCrossRefGoogle Scholar
  9. 9.
    Mastrangelo MJ, Eisenlohr LC, Gomella L, Lattime EC (2000) Poxvirus vectors: orphaned and underappreciated. J Clin Invest 105:1031–1034PubMedCrossRefGoogle Scholar
  10. 10.
    Smith GL, Moss B (1983) Infectious poxvirus vectors have capacity for at least 25,000 base pairs of foreign DNA. Gene 25:21–28PubMedCrossRefGoogle Scholar
  11. 11.
    Kirn DH, Wang Y, Le BF, Bell J, Thorne SH (2007) Targeting of interferon-beta to produce a specific, multi-mechanistic oncolytic vaccinia virus. PLoS Med 4:e353PubMedCrossRefGoogle Scholar
  12. 12.
    McCart JA, Ward JM, Lee J, Hu Y, Alexander HR, Libutti SK, Moss B, Bartlett DL (2001) Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res 61:8751–8757PubMedGoogle Scholar
  13. 13.
    Zhang Q, Yu YA, Wang E, Chen N, Danner RL, Munson PJ, Marincola FM, Szalay AA (2007) Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus. Cancer Res 67:10038–10046PubMedCrossRefGoogle Scholar
  14. 14.
    Lee HK, Iwasaki A (2008) Autophagy and antiviral immunity. Curr Opin Immunol 20:23–29PubMedCrossRefGoogle Scholar
  15. 15.
    Reading PC, Smith GL (2003) A kinetic analysis of immune mediators in the lungs of mice infected with vaccinia virus and comparison with intradermal infection. J Gen Virol 84:1973–1983PubMedCrossRefGoogle Scholar
  16. 16.
    Jacobs N, Chen RA, Gubser C, Najarro P, Smith GL (2006) Intradermal immune response after infection with Vaccinia virus. J Gen Virol 87:1157–1161PubMedCrossRefGoogle Scholar
  17. 17.
    Selin LK, Santolucito PA, Pinto AK, Szomolanyi-Tsuda E, Welsh RM (2001) Innate immunity to viruses: control of vaccinia virus infection by gamma delta T cells. J Immunol 166:6784–6794PubMedGoogle Scholar
  18. 18.
    Karupiah G, Blanden RV, Ramshaw IA (1990) Interferon gamma is involved in the recovery of athymic nude mice from recombinant vaccinia virus/interleukin 2 infection. J Exp Med 172:1495–1503PubMedCrossRefGoogle Scholar
  19. 19.
    Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M (1993) Immune response in mice that lack the interferon-gamma receptor. Science 259:1742–1745PubMedCrossRefGoogle Scholar
  20. 20.
    Smith GL, Symons JA, Khanna A, Vanderplasschen A, Alcami A (1997) Vaccinia virus immune evasion. Immunol Rev 159:137–154PubMedCrossRefGoogle Scholar
  21. 21.
    Alcami A, Smith GL (1995) Vaccinia, cowpox, and camelpox viruses encode soluble gamma interferon receptors with novel broad species specificity. J Virol 69:4633–4639PubMedGoogle Scholar
  22. 22.
    Mossman K, Upton C, Buller RM, McFadden G (1995) Species specificity of ectromelia virus and vaccinia virus interferon-gamma binding proteins. Virology 208:762–769PubMedCrossRefGoogle Scholar
  23. 23.
    Farrar MA, Schreiber RD (1993) The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol 11:571–611PubMedCrossRefGoogle Scholar
  24. 24.
    Schellekens H, de Reus A, Bolhuis R, Fountoulakis M, Schein C, Ecsodi J, Nagata S, Weissmann C (1981) Comparative antiviral efficiency of leukocyte and bacterially produced human alpha-interferon in rhesus monkeys. Nature 292:775–776PubMedCrossRefGoogle Scholar
  25. 25.
    Deonarain R, Alcami A, Alexiou M, Dallman MJ, Gewert DR, Porter AC (2000) Impaired antiviral response and alpha/beta interferon induction in mice lacking beta interferon. J Virol 74:3404–3409PubMedCrossRefGoogle Scholar
  26. 26.
    Garcia-Sastre A, Biron CA (2006) Type 1 interferons and the virus-host relationship: a lesson in detente. Science 312:879–882PubMedCrossRefGoogle Scholar
  27. 27.
    Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220PubMedCrossRefGoogle Scholar
  28. 28.
    Biron CA, Brossay L (2001) NK cells and NKT cells in innate defense against viral infections. Curr Opin Immunol 13:458–464PubMedCrossRefGoogle Scholar
  29. 29.
    Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A (2007) Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26:503–517PubMedCrossRefGoogle Scholar
  30. 30.
    Martinez J, Huang X, Yang Y (2008) Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo. J Immunol 180:1592–1597PubMedGoogle Scholar
  31. 31.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998PubMedCrossRefGoogle Scholar
  32. 32.
    Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360PubMedCrossRefGoogle Scholar
  33. 33.
    Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148PubMedCrossRefGoogle Scholar
  34. 34.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedCrossRefGoogle Scholar
  35. 35.
    Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217PubMedCrossRefGoogle Scholar
  36. 36.
    Mantovani A, Romero P, Palucka AK, Marincola FM (2008) Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet 371:771–783PubMedCrossRefGoogle Scholar
  37. 37.
    Wolfel T, Klehmann E, Muller C, Schutt KH, Meyer zum Buschenfelde KH, Knuth A (1989) Lysis of human melanoma cells by autologous cytolytic T cell clones. Identification of human histocompatibility leukocyte antigen A2 as a restriction element for three different antigens. J Exp Med 170:797–810PubMedCrossRefGoogle Scholar
  38. 38.
    Marincola FM, Rivoltini L, Salgaller ML, Player M, Rosenberg SA (1996) Differential anti-MART-1/MelanA CTL activity in peripheral blood of HLA-A2 melanoma patients in comparison to healthy donors: evidence for in vivo priming by tumor cells. J Immunother 19:266–277CrossRefGoogle Scholar
  39. 39.
    Fuchs EJ, Matzinger P (1996) Is cancer dangerous to the immune system? Semin Immunol 8:271–280PubMedCrossRefGoogle Scholar
  40. 40.
    Aptsiauri N, Carretero R, Garcia-Lora A, Real LM, Cabrera T, Garrido F (2008) Regressing and progressing metastatic lesions: resistance to immunotherapy is predetermined by irreversible HLA class I antigen alterations. Cancer Immunol Immunother 57:1727–1733PubMedCrossRefGoogle Scholar
  41. 41.
    Seliger B (2008) Molecular mechanisms of MHC class I abnormalities and APM components in human tumors. Cancer Immunol Immunother 57:1719–1726PubMedCrossRefGoogle Scholar
  42. 42.
    Menard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F (2008) Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 57:1579–1587PubMedCrossRefGoogle Scholar
  43. 43.
    Ramakrishnan R, Antonia S, Gabrilovich DI (2008) Combined modality immunotherapy and chemotherapy: a new perspective. Cancer Immunol Immunother 57:1523–1529PubMedCrossRefGoogle Scholar
  44. 44.
  45. 45.
    Kaufman HL, Taback B, Sherman W, Kim DW, Shingler WH, Moroziewicz D, DeRaffele G, Mitcham J, Carroll MW, Harrop R et al (2009) Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high dose Interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma. J Transl Med 7:2PubMedCrossRefGoogle Scholar
  46. 46.
    Stanford MM, Breitbach CJ, Bell JC, McFadden G (2008) Innate immunity, tumor microenvironment and oncolytic virus therapy: friends or foes? Curr Opin Mol Ther 10:32–37PubMedGoogle Scholar
  47. 47.
    Amato RJ (2008) Vaccine therapy for renal cancer. Expert Rev Vaccines 7:925–935PubMedCrossRefGoogle Scholar
  48. 48.
    Harrop R, Drury N, Shingler W, Chikoti P, Redchenko I, Carroll MW, Kingsman SM, Naylor S, Griffiths R, Steven N et al (2008) Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses. Cancer Immunol Immunother 57:977–986PubMedCrossRefGoogle Scholar
  49. 49.
    Kaufman HL, Kim-Schulze S, Manson K, DeRaffele G, Mitcham J, Seo KS, Kim DW, Marshall J (2007) Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med 5:60PubMedCrossRefGoogle Scholar
  50. 50.
    Croft M (2003) Costimulation of T cells by OX40, 4-1BB, and CD27. Cytokine Growth Factor Rev 14:265–273PubMedCrossRefGoogle Scholar
  51. 51.
    Monsurro’ V, Wang E, Yamano Y, Migueles SA, Panelli MC, Smith K, Nagorsen D, Connors M, Jacobson S, Marincola FM (2004) Quiescent phenotype of tumor-specific CD8+ T cells following immunization. Blood 104:1970–1978CrossRefGoogle Scholar
  52. 52.
    Marincola FM, Wang E, Herlyn M, Seliger B, Ferrone S (2003) Tumors as elusive targets of T cell-based active immunotherapy. Trends Immunol 24:335–342PubMedCrossRefGoogle Scholar
  53. 53.
    Monsurro’ V, Wang E, Panelli MC, Nagorsen D, Jin P, Smith K, Ngalame Y, Even J, Marincola FM (2003) Active-specific immunization against melanoma: is the problem at the receiving end? Semin Cancer Biol 13:473–480CrossRefGoogle Scholar
  54. 54.
    Wang E, Miller LD, Ohnmacht GA, Mocellin S, Petersen D, Zhao Y, Simon R, Powell JI, Asaki E, Alexander HR et al (2002) Prospective molecular profiling of subcutaneous melanoma metastases suggests classifiers of immune responsiveness. Cancer Res 62:3581–3586PubMedGoogle Scholar
  55. 55.
    Panelli MC, Wang E, Phan G, Puhlman M, Miller L, Ohnmacht GA, Klein H, Marincola FM (2002) Gene-expression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2 administration. Genome Biol 3:RESEARCH0035Google Scholar
  56. 56.
    Panelli MC, Stashower M, Slade HB, Smith K, Norwood C, Abati A, Fetsch PA, Filie A, Walters SA, Astry C et al (2006) Sequential gene profiling of basal cell carcinomas treated with Imiquimod in a placebo-controlled study defines the requirements for tissue rejection. Genome Biol 8:R8CrossRefGoogle Scholar
  57. 57.
    Wang E, Worschech A, Marincola FM (2008) The immunologic constant of rejection. Trends Immunol 29:256–262PubMedCrossRefGoogle Scholar
  58. 58.
    Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915PubMedCrossRefGoogle Scholar
  59. 59.
    Griffioen AW (2008) Anti-angiogenesis: making the tumor vulnerable to the immune system. Cancer Immunol Immunother 57:1553–1558PubMedCrossRefGoogle Scholar
  60. 60.
    Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du E, Kim J et al (2006) Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc Natl Acad Sci USA 103:7753–7758PubMedCrossRefGoogle Scholar
  61. 61.
    Shanker A, Verdeil G, Buferne M, Inderberg-Suso EM, Puthier D, Joly F, Nguyen C, Leserman L, uphan-Anezin N, Schmitt-Verhulst AM (2007) CD8 T cell help for innate antitumor immunity. J Immunol 179:6651–6662PubMedGoogle Scholar
  62. 62.
    Urosevic M, Fujii K, Calmels B, Laine E, Kobert N, Acres B, Dummer R (2007) Type I IFN innate immune response to adenovirus-mediated IFN-gamma gene transfer contributes to the regression of cutaneous lymphomas. J Clin Invest 117:2834–2846PubMedCrossRefGoogle Scholar
  63. 63.
    Marleau AM, Lipton JH, Riordan NH, Ichim TE (2007) Therapeutic use of Aldara in chronic myeloid leukemia. J Transl Med 5:4PubMedCrossRefGoogle Scholar
  64. 64.
    Torres A, Storey L, Anders M, Miller RL, Bulbulian BJ, Jin J, Raghavan S, Lee J, Slade HB, Birmachu W (2007) Immune-mediated changes in actinic Keratosis following topical treatment with Imiquimod 5% cream. J Transl Med 5:7PubMedCrossRefGoogle Scholar
  65. 65.
    Zhu X, Nishimura F, Sasaki K, Fujita M, Dusak JE, Eguchi J, Fellows-Mayle W, Storkus WJ, Walker PR, Salazar AM et al (2007) Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. J Transl Med 5:10PubMedCrossRefGoogle Scholar
  66. 66.
    Kirn DH, Wang Y, Liang W, Contag CH, Thorne SH (2008) Enhancing poxvirus oncolytic effects through increased spread and immune evasion. Cancer Res 68:2071–2075PubMedCrossRefGoogle Scholar
  67. 67.
    Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H et al (2008) Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facts of oncolytic therapy (submitted)Google Scholar
  68. 68.
    Salk J (1969) Immunological paradoxes: theoretical considerations in the rejection or retention of grafts, tumors, and normal tissue. Ann NY Acad Sci 164:365–380PubMedCrossRefGoogle Scholar
  69. 69.
    Rehermann B, Nascimbeni M (2005) Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5:215–229PubMedCrossRefGoogle Scholar
  70. 70.
    Kawakami Y, Robbins P, Wang RF, Parkhurst MR, Kang X, Rosenberg SA (1998) Tumor antigens recognized by T cells. The use of melanosomal proteins in the immunotherapy of melanoma. J Immunother 21:237–246PubMedCrossRefGoogle Scholar
  71. 71.
    Robbins PF, el-Gamil M, Li YF, Kawakami Y, Loftus D, Appella E, Rosenberg SA (1996) A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med 183:1185–1192PubMedCrossRefGoogle Scholar
  72. 72.
    Butterfield LH, Disis ML, Fox BA, Lee PP, Khleif SN, Thurin M, Trinchieri G, Wang E, Wigginton J, Chaussabel D et al (2008) A systematic approach to biomarker discovery: preamble to “the iSBTc-FDA taskforce on Immunotherapy Biomarkers”. J Transl Med 6:81PubMedCrossRefGoogle Scholar

Copyright information

© US Government 2009

Authors and Affiliations

  • Andrea Worschech
    • 1
    • 2
    • 3
  • D. Haddad
    • 1
    • 2
    • 4
  • D. F. Stroncek
    • 5
  • E. Wang
    • 3
  • Francesco M. Marincola
    • 3
    Email author
  • Aladar A. Szalay
    • 1
    • 2
    Email author
  1. 1.Genelux CorporationSan Diego Science CenterSan DiegoUSA
  2. 2.Institute for Biochemistry, Virchow Center for Experimental BiomedicineUniversity of WuerzburgWuerzburgGermany
  3. 3.Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine and Center for Human Immunology (CHI)Clinical Center, National Institutes of Health (NIH)BethesdaUSA
  4. 4.Department of SurgeryMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  5. 5.Cell Therapy Section, Department of Transfusion MedicineClinical Center, NIHBethesdaUSA

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