Skip to main content

Advertisement

SpringerLink
Log in

The immunologic aspects of poxvirus oncolytic therapy

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Sinkovics J, Horvath J (1993) New developments in the virus therapy of cancer: a historical review. Intervirology 36:193–214

    PubMed  CAS  Google Scholar 

  2. Dock G (1904) The influence of complicating diseases upon leukaemia. Am J Med Sci 127:563

    Article  Google Scholar 

  3. Parato KA, Senger D, Forsyth PA, Bell JC (2005) Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 5:965–976

    Article  PubMed  CAS  Google Scholar 

  4. Vaha-Koskela MJ, Heikkila JE, Hinkkanen AE (2007) Oncolytic viruses in cancer therapy. Cancer Lett 254:178–216

    Article  PubMed  CAS  Google Scholar 

  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 274:373–376

    Article  PubMed  CAS  Google Scholar 

  6. Lin E, Nemunaitis J (2004) Oncolytic viral therapies. Cancer Gene Ther 11:643–664

    Article  PubMed  CAS  Google Scholar 

  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 252:854–856

    Article  PubMed  CAS  Google Scholar 

  8. O’Shea CC (2005) DNA tumor viruses—the spies who lyse us. Curr Opin Genet Dev 15:18–26

    Article  PubMed  CAS  Google Scholar 

  9. Mastrangelo MJ, Eisenlohr LC, Gomella L, Lattime EC (2000) Poxvirus vectors: orphaned and underappreciated. J Clin Invest 105:1031–1034

    Article  PubMed  CAS  Google Scholar 

  10. Smith GL, Moss B (1983) Infectious poxvirus vectors have capacity for at least 25,000 base pairs of foreign DNA. Gene 25:21–28

    Article  PubMed  CAS  Google Scholar 

  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:e353

    Article  PubMed  CAS  Google Scholar 

  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 61:8751–8757

    PubMed  CAS  Google Scholar 

  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 67:10038–10046

    Article  PubMed  CAS  Google Scholar 

  14. Lee HK, Iwasaki A (2008) Autophagy and antiviral immunity. Curr Opin Immunol 20:23–29

    Article  PubMed  CAS  Google Scholar 

  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 84:1973–1983

    Article  PubMed  CAS  Google Scholar 

  16. Jacobs N, Chen RA, Gubser C, Najarro P, Smith GL (2006) Intradermal immune response after infection with Vaccinia virus. J Gen Virol 87:1157–1161

    Article  PubMed  CAS  Google Scholar 

  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 166:6784–6794

    PubMed  CAS  Google Scholar 

  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 172:1495–1503

    Article  PubMed  CAS  Google Scholar 

  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 259:1742–1745

    Article  PubMed  CAS  Google Scholar 

  20. Smith GL, Symons JA, Khanna A, Vanderplasschen A, Alcami A (1997) Vaccinia virus immune evasion. Immunol Rev 159:137–154

    Article  PubMed  CAS  Google Scholar 

  21. Alcami A, Smith GL (1995) Vaccinia, cowpox, and camelpox viruses encode soluble gamma interferon receptors with novel broad species specificity. J Virol 69:4633–4639

    PubMed  CAS  Google Scholar 

  22. Mossman K, Upton C, Buller RM, McFadden G (1995) Species specificity of ectromelia virus and vaccinia virus interferon-gamma binding proteins. Virology 208:762–769

    Article  PubMed  CAS  Google Scholar 

  23. Farrar MA, Schreiber RD (1993) The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol 11:571–611

    Article  PubMed  CAS  Google Scholar 

  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 292:775–776

    Article  PubMed  CAS  Google Scholar 

  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 74:3404–3409

    Article  PubMed  CAS  Google Scholar 

  26. Garcia-Sastre A, Biron CA (2006) Type 1 interferons and the virus-host relationship: a lesson in detente. Science 312:879–882

    Article  PubMed  CAS  Google Scholar 

  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 17:189–220

    Article  PubMed  CAS  Google Scholar 

  28. Biron CA, Brossay L (2001) NK cells and NKT cells in innate defense against viral infections. Curr Opin Immunol 13:458–464

    Article  PubMed  CAS  Google Scholar 

  29. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A (2007) Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26:503–517

    Article  PubMed  CAS  Google Scholar 

  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 180:1592–1597

    PubMed  CAS  Google Scholar 

  31. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998

    Article  PubMed  CAS  Google Scholar 

  32. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360

    Article  PubMed  CAS  Google Scholar 

  33. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148

    Article  PubMed  CAS  Google Scholar 

  34. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545

    Article  PubMed  CAS  Google Scholar 

  35. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217

    Article  PubMed  CAS  Google Scholar 

  36. Mantovani A, Romero P, Palucka AK, Marincola FM (2008) Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet 371:771–783

    Article  PubMed  CAS  Google Scholar 

  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 170:797–810

    Article  PubMed  CAS  Google Scholar 

  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 19:266–277

    Article  CAS  Google Scholar 

  39. Fuchs EJ, Matzinger P (1996) Is cancer dangerous to the immune system? Semin Immunol 8:271–280

    Article  PubMed  CAS  Google Scholar 

  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 57:1727–1733

    Article  PubMed  CAS  Google Scholar 

  41. Seliger B (2008) Molecular mechanisms of MHC class I abnormalities and APM components in human tumors. Cancer Immunol Immunother 57:1719–1726

    Article  PubMed  CAS  Google Scholar 

  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 57:1579–1587

    Article  PubMed  CAS  Google Scholar 

  43. Ramakrishnan R, Antonia S, Gabrilovich DI (2008) Combined modality immunotherapy and chemotherapy: a new perspective. Cancer Immunol Immunother 57:1523–1529

    Article  PubMed  CAS  Google Scholar 

  44. Cancer Vaccine Fact Sheet (2008). http://www.cancer.gov/cancertopics/factsheet/cancervaccine

  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 7:2

    Article  PubMed  CAS  Google Scholar 

  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 10:32–37

    PubMed  CAS  Google Scholar 

  47. Amato RJ (2008) Vaccine therapy for renal cancer. Expert Rev Vaccines 7:925–935

    Article  PubMed  CAS  Google Scholar 

  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 57:977–986

    Article  PubMed  CAS  Google Scholar 

  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 5:60

    Article  PubMed  CAS  Google Scholar 

  50. Croft M (2003) Costimulation of T cells by OX40, 4-1BB, and CD27. Cytokine Growth Factor Rev 14:265–273

    Article  PubMed  CAS  Google Scholar 

  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 104:1970–1978

    Article  CAS  Google Scholar 

  52. Marincola FM, Wang E, Herlyn M, Seliger B, Ferrone S (2003) Tumors as elusive targets of T cell-based active immunotherapy. Trends Immunol 24:335–342

    Article  PubMed  CAS  Google Scholar 

  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 13:473–480

    Article  CAS  Google Scholar 

  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 62:3581–3586

    PubMed  CAS  Google Scholar 

  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:RESEARCH0035

    Google Scholar 

  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:R8

    Article  CAS  Google Scholar 

  57. Wang E, Worschech A, Marincola FM (2008) The immunologic constant of rejection. Trends Immunol 29:256–262

    Article  PubMed  CAS  Google Scholar 

  58. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915

    Article  PubMed  CAS  Google Scholar 

  59. Griffioen AW (2008) Anti-angiogenesis: making the tumor vulnerable to the immune system. Cancer Immunol Immunother 57:1553–1558

    Article  PubMed  CAS  Google Scholar 

  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 103:7753–7758

    Article  PubMed  CAS  Google Scholar 

  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 179:6651–6662

    PubMed  CAS  Google Scholar 

  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 117:2834–2846

    Article  PubMed  CAS  Google Scholar 

  63. Marleau AM, Lipton JH, Riordan NH, Ichim TE (2007) Therapeutic use of Aldara in chronic myeloid leukemia. J Transl Med 5:4

    Article  PubMed  CAS  Google Scholar 

  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 5:7

    Article  PubMed  CAS  Google Scholar 

  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 5:10

    Article  PubMed  CAS  Google Scholar 

  66. Kirn DH, Wang Y, Liang W, Contag CH, Thorne SH (2008) Enhancing poxvirus oncolytic effects through increased spread and immune evasion. Cancer Res 68:2071–2075

    Article  PubMed  CAS  Google Scholar 

  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)

  68. Salk J (1969) Immunological paradoxes: theoretical considerations in the rejection or retention of grafts, tumors, and normal tissue. Ann NY Acad Sci 164:365–380

    Article  PubMed  CAS  Google Scholar 

  69. Rehermann B, Nascimbeni M (2005) Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5:215–229

    Article  PubMed  CAS  Google Scholar 

  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 21:237–246

    Article  PubMed  CAS  Google Scholar 

  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 183:1185–1192

    Article  PubMed  CAS  Google Scholar 

  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 6:81

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Genelux Corporation, San Diego Science Center, 3030 Bunker Hill St., Suite 310, San Diego, CA, 92109, USA

    Andrea Worschech, D. Haddad & Aladar A. Szalay

  2. Institute for Biochemistry, Virchow Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany

    Andrea Worschech, D. Haddad & Aladar A. Szalay

  3. Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine and Center for Human Immunology (CHI), Clinical Center, National Institutes of Health (NIH), Bldg 10, R1C711, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    Andrea Worschech, E. Wang & Francesco M. Marincola

  4. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA

    D. Haddad

  5. Cell Therapy Section, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, 20892, USA

    D. F. Stroncek

Authors
  1. Andrea Worschech
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Haddad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. F. Stroncek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco M. Marincola
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aladar A. Szalay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Francesco M. Marincola or Aladar A. Szalay.

Additional information

A. A. Szalay and F. M. Marincola are co-senior authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Worschech, A., Haddad, D., Stroncek, D.F. et al. The immunologic aspects of poxvirus oncolytic therapy. Cancer Immunol Immunother 58, 1355–1362 (2009). https://doi.org/10.1007/s00262-009-0686-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-009-0686-7

Keywords

Search

Navigation