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Going viral with cancer immunotherapy

Nature Reviews Cancer volume 14, pages 559–567 (2014)Cite this article

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Abstract

Recent clinical data have emphatically shown the capacity of our immune systems to eradicate even advanced cancers. Although oncolytic viruses (OVs) were originally designed to function as tumour-lysing therapeutics, they have now been clinically shown to initiate systemic antitumour immune responses. Cell signalling pathways that are activated and promote the growth of tumour cells also favour the growth and replication of viruses within the cancer. The ability to engineer OVs that express immune-stimulating 'cargo', the induction of immunogenic tumour cell death by OVs and the selective targeting of OVs to tumour beds suggests that they are the ideal reagents to enhance antitumour immune responses. Coupling of OV therapy with tumour antigen vaccination, immune checkpoint inhibitors and adoptive cell therapy seems to be ready to converge towards a new generation of multimodal therapeutics to improve outcomes for cancer patients.

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Figure 1: Oncolytic virus (OV) infection of the tumour niche and principles of 'oncolytic vaccines'.
Figure 2: Combining oncolytic viruses (OVs) with new immunotherapeutics.

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References

  1. Glenney, J. R. Jr., Zokas, L. & Kamps, M. P. Monoclonal antibodies to phosphotyrosine. J. Immunol. Methods 109, 277–285 (1988).

    Article  CAS  PubMed  Google Scholar 

  2. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nature Rev. Cancer 12, 252–264 (2012).

    Article  CAS  Google Scholar 

  3. Kreiter, S., Castle, J. C., Tureci, O. & Sahin, U. Targeting the tumor mutanome for personalized vaccination therapy. Oncoimmunology 1, 768–769 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Russell, S. J., Peng, K. W. & Bell, J. C. Oncolytic virotherapy. Nature Biotech. 30, 658–670 (2012).

    Article  CAS  Google Scholar 

  5. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  6. Kelly, E. & Russell, S. J. History of oncolytic viruses: genesis to genetic engineering. Mol. Ther. 15, 651–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Parato, K. A. et al. The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers. Mol. Ther. 4, 749–758 (2011).

    Google Scholar 

  8. Stojdl, D. F. et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 4, 263–275 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Breitbach, C. J. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Liu, T. C., Hwang, T., Park, B. H., Bell, J. & Kirn, D. H. The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol. Ther. 16, 1637–1642 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Breitbach, C. J. et al. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res. 73, 1265–1275 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Breitbach, C. J. et al. Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow. Mol. Ther. 15, 1686–1693 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Breitbach, C. J. et al. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19, 886–894 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu, T. C., Galanis, E. & Kirn, D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nature Clin. Pract. Oncol. 4, 101–117 (2007).

    Article  CAS  Google Scholar 

  15. Vacchelli, E. et al. Trial watch: oncolytic viruses for cancer therapy. Oncoimmunology 2, e24612 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Miest, T. S. & Cattaneo, R. New viruses for cancer therapy: meeting clinical needs. Nature Rev. Microbiol. 12, 23–34 (2013).

    Article  CAS  Google Scholar 

  17. Atherton, M. J. & Lichty, B. D. Evolution of oncolytic viruses: novel strategies for cancer treatment. Immunotherapy 5, 1191–1206 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Kaufman, H. L. & Bines, S. D. OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol. 6, 941–949 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Garber, K. China approves world's first oncolytic virus therapy for cancer treatment. J. Natl Cancer Inst. 98, 298–300 (2006).

    Article  PubMed  Google Scholar 

  20. Senzer, N. N. et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J. Clin. Oncol. 27, 5763–5771 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Nemunaitis, J. et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Ther. 8, 746–759 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Park, B. H. et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 9, 533–542 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Heo, J. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nature Med. 19, 329–336 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Ingemar Andtbacka, R. H. et al. OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C & IV melanoma. J. Clin. Oncol. 31, abstract LBA9008 (2013).

  25. Harrington, K. J. et al. Phase I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck. Clin. Cancer Res. 16, 4005–4015 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Harrington, K. J. et al. Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers. Clin. Cancer Res. 16, 3067–3077 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Heo, J. et al. Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy. Mol. Ther. 19, 1170–1179 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cerullo, V. et al. Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus. Mol. Ther. 19, 1737–1746 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New Engl. J. Med. 363, 411–422 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Small, E. J. et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J. Clin. Oncol. 24, 3089–3094 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. New Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dudley, M. E. & Rosenberg, S. A. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nature Rev. Cancer 3, 666–675 (2003).

    Article  CAS  Google Scholar 

  34. Kershaw, M. H., Westwood, J. A. & Darcy, P. K. Gene-engineered T cells for cancer therapy. Nature Rev. Cancer 13, 525–541 (2013).

    Article  CAS  Google Scholar 

  35. Adair, R. A. et al. Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients. Sci. Transl. Med. 4, 138ra77 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. Kottke, T. et al. Treg depletion-enhanced IL-2 treatment facilitates therapy of established tumors using systemically delivered oncolytic virus. Mol. Ther. 16, 1217–1226 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Diaz, R. M. et al. Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res. 67, 2840–2848 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Liu, B. L. et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 10, 292–303 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Moehler, M. H. et al. Parvovirus H-1-induced tumor cell death enhances human immune response in vitro via increased phagocytosis, maturation, and cross-presentation by dendritic cells. Hum. Gene Ther. 16, 996–1005 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Mastrangelo, M. J. et al. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther. 6, 409–422 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Hwang, T. H. et al. A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma. Mol. Ther. 19, 1913–1922 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim, M. K. et al. Oncolytic and immunotherapeutic vaccinia induces antibody-mediated complement-dependent cancer cell lysis in humans. Sci. Transl. Med. 5, 185ra63 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Sukkurwala, A. Q. et al. Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8. Cell Death Differ. 21, 59–68 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nature Med. 15, 1170–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Zelenay, S. et al. The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J. Clin. Invest. 122, 1615–1627 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lee, B. H. et al. Activation of P2X(7) receptor by ATP plays an important role in regulating inflammatory responses during acute viral infection. PLoS ONE 7, e35812 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Huang, B., Sikorski, R., Kirn, D. H. & Thorne, S. H. Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1. Gene Ther. 18, 164–172 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Miyamoto, S. et al. Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma. Cancer Res. 72, 2609–2621 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Galivo, F. et al. Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus. Hum. Gene Ther. 21, 439–450 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schirrmacher, V., Griesbach, A. & Ahlert, T. Antitumor effects of Newcastle disease virus in vivo: local versus systemic effects. Int. J. Oncol. 18, 945–952 (2001).

    CAS  PubMed  Google Scholar 

  52. Diallo, J. S. et al. A high-throughput pharmacoviral approach identifies novel oncolytic virus sensitizers. Mol. Ther. 18, 1123–1129 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nguyen, T. L. et al. Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis. Proc. Natl Acad. Sci. USA 105, 14981–14986 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jha, B. K., Dong, B., Nguyen, C. T., Polyakova, I. & Silverman, R. H. Suppression of antiviral innate immunity by sunitinib enhances oncolytic virotherapy. Mol. Ther. 21, 1749–1757 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bose, A. et al. Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination. Int. J. Cancer 129, 2158–2170 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Beug, S. T. et al. Smac mimetics and innate immune stimuli synergize to promote tumor death. Nature Biotech. 32, 182–190 (2014).

    Article  CAS  Google Scholar 

  57. Hu, J. C. et al. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin. Cancer Res. 12, 6737–6747 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Curran, M. A. & Allison, J. P. Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors. Cancer Res. 69, 7747–7755 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Epardaud, M. et al. Interleukin-15/interleukin-15Rα complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res. 68, 2972–2983 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Liu, R. B. et al. IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner. Proc. Natl Acad. Sci. USA 110, 8158–8163 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Onu, A., Pohl, T., Krause, H. & Bulfone-Paus, S. Regulation of IL-15 secretion via the leader peptide of two IL-15 isoforms. J. Immunol. 158, 255–262 (1997).

    CAS  PubMed  Google Scholar 

  62. Yu, F. et al. T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol. Ther. 22, 102–111 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Amato, R. J. et al. Vaccination of renal cell cancer patients with modified vaccinia ankara delivering tumor antigen 5T4 (TroVax) administered with interleukin 2: a phase II trial. Clin. Cancer Res. 14, 7504–7510 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Harrop, R. et al. 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 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Horig, H. et al. Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule. Cancer Immunol. Immunother. 49, 504–514 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Jager, E. et al. Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients. Proc. Natl Acad. Sci. USA 103, 14453–14458 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kaufman, H. L. et al. Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer. Clin. Cancer Res. 14, 4843–4849 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Madan, R. A. et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 13, 501–508 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Morse, M. A. et al. Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients. Cancer Immunol. Immunother. 62, 1293–1301 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Odunsi, K. et al. Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients. Proc. Natl Acad. Sci. USA 109, 5797–5802 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Harrop, R., John, J. & Carroll, M. W. Recombinant viral vectors: cancer vaccines. Adv. Drug Deliv. Rev. 58, 931–947 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Elzey, B. D., Siemens, D. R., Ratliff, T. L. & Lubaroff, D. M. Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors. Int. J. Cancer 94, 842–849 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Hodge, J. W., McLaughlin, J. P., Kantor, J. A. & Schlom, J. Diversified prime and boost protocols using recombinant vaccinia virus and recombinant non-replicating avian pox virus to enhance T-cell immunity and antitumor responses. Vaccine 15, 759–768 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Hodge, J. W. et al. Modified vaccinia virus ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses. Cancer Res. 63, 7942–7949 (2003).

    CAS  PubMed  Google Scholar 

  75. Irvine, K. R. et al. Enhancing efficacy of recombinant anticancer vaccines with prime/boost regimens that use two different vectors. J. Natl Cancer Inst. 89, 1595–1601 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Marshall, J. L. et al. Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J. Clin. Oncol. 18, 3964–3973 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Naslund, T. I. et al. Comparative prime-boost vaccinations using Semliki Forest virus, adenovirus, and ALVAC vectors demonstrate differences in the generation of a protective central memory CTL response against the P815 tumor. J. Immunol. 178, 6761–6769 (2007).

    Article  PubMed  Google Scholar 

  78. Bridle, B. W. et al. Potentiating cancer immunotherapy using an oncolytic virus. Mol. Ther. 18, 1430–1439 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vigil, A., Martinez, O., Chua, M. A. & Garcia-Sastre, A. Recombinant Newcastle disease virus as a vaccine vector for cancer therapy. Mol. Ther. 16, 1883–1890 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Pol, J. G. et al. Maraba virus as a potent oncolytic vaccine vector. Mol. Ther. 22, 420–429 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Loi, S. Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy. Oncoimmunology 2, e24720 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6, 226ra32 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Puzanov, I. et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. J Clin. Oncol. 32 (suppl; abstr 9029^) (2014).

    Article  Google Scholar 

  84. Pule, M. A. et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nature Med. 14, 1264–1270 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Martins, I. et al. Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene 30, 1147–1158 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Galluzzi, L. & Kroemer, G. Autophagy mediates the metabolic benefits of endurance training. Circ. Res. 110, 1276–1278 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Kaczmarek, A., Vandenabeele, P. & Krysko, D. V. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209–223 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Krysko, D. V. et al. Immunogenic cell death and DAMPs in cancer therapy. Nature Rev. Cancer 12, 860–875 (2012).

    Article  CAS  Google Scholar 

  89. Kaufman, H. L. et al. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann. Surg. Oncol. 17, 718–730 (2010).

    Article  PubMed  Google Scholar 

  90. Kim, J. H. et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol. Ther. 14, 361–370 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Lee, J. H. et al. Oncolytic and immunostimulatory efficacy of a targeted oncolytic poxvirus expressing human GM-CSF following intravenous administration in a rabbit tumor model. Cancer Gene Ther. 17, 73–79 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Cerullo, V. et al. Oncolytic adenovirus coding for granulocyte macrophage colony-stimulating factor induces antitumoral immunity in cancer patients. Cancer Res. 70, 4297–4309 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Chang, J. et al. A Phase I study of KH901, a conditionally replicating granulocyte-macrophage colony-stimulating factor: armed oncolytic adenovirus for the treatment of head and neck cancers. Cancer Biol. Ther. 8, 676–682 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Robinson, M. et al. Novel immunocompetent murine tumor model for evaluation of conditionally replication-competent (oncolytic) murine adenoviral vectors. J. Virol. 83, 3450–3462 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Vigil, A. et al. Use of reverse genetics to enhance the oncolytic properties of Newcastle disease virus. Cancer Res. 67, 8285–8292 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Grote, D., Cattaneo, R. & Fielding, A. K. Neutrophils contribute to the measles virus-induced antitumor effect: enhancement by granulocyte macrophage colony-stimulating factor expression. Cancer Res. 63, 6463–6468 (2003).

    CAS  PubMed  Google Scholar 

  97. Bergman, I., Griffin, J. A., Gao, Y. & Whitaker-Dowling, P. Treatment of implanted mammary tumors with recombinant vesicular stomatitis virus targeted to Her2/neu. Int. J. Cancer 121, 425–430 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Bernt, K. M., Ni, S., Tieu, A. T. & Lieber, A. Assessment of a combined, adenovirus-mediated oncolytic and immunostimulatory tumor therapy. Cancer Res. 65, 4343–4352 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Ramakrishna, E. et al. Antitumoral immune response by recruitment and expansion of dendritic cells in tumors infected with telomerase-dependent oncolytic viruses. Cancer Res. 69, 1448–1458 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Leveille, S., Goulet, M. L., Lichty, B. D. & Hiscott, J. Vesicular stomatitis virus oncolytic treatment interferes with tumor-associated dendritic cell functions and abrogates tumor antigen presentation. J. Virol. 85, 12160–12169 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lapteva, N. et al. Targeting the intratumoral dendritic cells by the oncolytic adenoviral vaccine expressing RANTES elicits potent antitumor immunity. J. Immunother. 32, 145–156 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Li, J. et al. Chemokine expression from oncolytic vaccinia virus enhances vaccine therapies of cancer. Mol. Ther. 19, 650–657 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Carew, J. F. et al. A novel approach to cancer therapy using an oncolytic herpes virus to package amplicons containing cytokine genes. Mol. Ther. 4, 250–256 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Zhao, H., Janke, M., Fournier, P. & Schirrmacher, V. Recombinant Newcastle disease virus expressing human interleukin-2 serves as a potential candidate for tumor therapy. Virus Res. 136, 75–80 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Post, D. E. et al. Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4. Cancer Res. 67, 6872–6881 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Terada, K., Wakimoto, H., Tyminski, E., Chiocca, E. A. & Saeki, Y. Development of a rapid method to generate multiple oncolytic HSV vectors and their in vivo evaluation using syngeneic mouse tumor models. Gene Ther. 13, 705–714 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Choi, I. K. et al. Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα. Gene Ther. 18, 898–909 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lee, Y. S. et al. Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model. Clin. Cancer Res. 12, 5859–5868 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Derubertis, B. G. et al. Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms. Cancer Gene Ther. 14, 590–597 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Varghese, S. et al. Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther. 13, 253–265 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Shin, E. J. et al. Interleukin-12 expression enhances vesicular stomatitis virus oncolytic therapy in murine squamous cell carcinoma. Laryngoscope 117, 210–214 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Gaston, D. C. et al. Production of bioactive soluble interleukin-15 in complex with interleukin-15 receptor alpha from a conditionally-replicating oncolytic HSV-1. PLoS ONE 8, e81768 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Stephenson, K. B., Barra, N. G., Davies, E., Ashkar, A. A. & Lichty, B. D. Expressing human interleukin-15 from oncolytic vesicular stomatitis virus improves survival in a murine metastatic colon adenocarcinoma model through the enhancement of anti-tumor immunity. Cancer Gene Ther. 19, 238–246 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. van Rikxoort, M. et al. Oncolytic effects of a novel influenza A virus expressing interleukin-15 from the NS reading frame. PLoS ONE 7, e36506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fukuhara, H., Ino, Y., Kuroda, T., Martuza, R. L. & Todo, T. Triple gene-deleted oncolytic herpes simplex virus vector double-armed with interleukin 18 and soluble B7-1 constructed by bacterial artificial chromosome-mediated system. Cancer Res. 65, 10663–10668 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Ino, Y., Saeki, Y., Fukuhara, H. & Todo, T. Triple combination of oncolytic herpes simplex virus-1 vectors armed with interleukin-12, interleukin-18, or soluble B7-1 results in enhanced antitumor efficacy. Clin. Cancer Res. 12, 643–652 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Kirn, D. H., Wang, Y., Le Boeuf, F., Bell, J. & Thorne, S. H. Targeting of interferon-beta to produce a specific, multi-mechanistic oncolytic vaccinia virus. PLoS Med. 4, e353 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Li, H., Peng, K. W., Dingli, D., Kratzke, R. A. & Russell, S. J. Oncolytic measles viruses encoding interferon β and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy. Cancer Gene Ther. 17, 550–558 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shashkova, E. V., Spencer, J. F., Wold, W. S. & Doronin, K. Targeting interferon-α increases antitumor efficacy and reduces hepatotoxicity of E1A-mutated spread-enhanced oncolytic adenovirus. Mol. Ther. 15, 598–607 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Shashkova, E. V., Kuppuswamy, M. N., Wold, W. S. & Doronin, K. Anticancer activity of oncolytic adenovirus vector armed with IFN-α and ADP is enhanced by pharmacologically controlled expression of TRAIL. Cancer Gene Ther. 15, 61–72 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Willmon, C. L. et al. Expression of IFN-β enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma. Cancer Res. 69, 7713–7720 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Su, C. et al. Immune gene-viral therapy with triplex efficacy mediated by oncolytic adenovirus carrying an interferon-γ gene yields efficient antitumor activity in immunodeficient and immunocompetent mice. Mol. Ther. 13, 918–927 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Choi, K. J. et al. Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect. Gene Ther. 13, 1010–1020 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Todo, T., Martuza, R. L., Dallman, M. J. & Rabkin, S. D. In situ expression of soluble B7-1 in the context of oncolytic herpes simplex virus induces potent antitumor immunity. Cancer Res. 61, 153–161 (2001).

    CAS  PubMed  Google Scholar 

  125. Huang, J. H. et al. Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4-1BBL. Mol. Ther. 18, 264–274 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Kim, H. S., Kim-Schulze, S., Kim, D. W. & Kaufman, H. L. Host lymphodepletion enhances the therapeutic activity of an oncolytic vaccinia virus expressing 4-1BB ligand. Cancer Res. 69, 8516–8525 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Li, J. L. et al. A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients. Gene Ther. 16, 376–382 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Yoo, J. Y. et al. Tumor suppression by apoptotic and anti-angiogenic effects of mortalin-targeting adeno-oncolytic virus. J. Gene Med. 12, 586–595 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Hu, Z. B. et al. A simplified system for generating oncolytic adenovirus vector carrying one or two transgenes. Cancer Gene Ther. 15, 173–182 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

B.D.L., D.F.S. and J.C.B. are supported by Ontario Institute for Cancer Research, Terry Fox Foundation. D.F.S. and J.C.B. are supported by the Canadian Institutes of Health Research (CIHR), and the Canadian Cancer Society Research Institute (CCSRI). B.D.L. is supported by the Canadian Breast Cancer Foundation (CBCF).

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Authors and Affiliations

  1. Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, L8S4K1, Ontario, Canada

    Brian D. Lichty

  2. SillaJen Biotherapeutics, San Francisco, 94111, California, USA

    Caroline J. Breitbach

  3. Apoptosis Research Centre, Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, K1H 8L1, Ontario, Canada

    David F. Stojdl

  4. Canada; and the Department of Biochemistry, Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.,

    John C. Bell

  5. and the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.,

    John C. Bell

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  1. Brian D. Lichty
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Correspondence to John C. Bell.

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Employment: SillaJen Biotherapeutics (C.J.B.). B.D.L., D.F.S. and J.C.B. declare no competing interests.

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Lichty, B., Breitbach, C., Stojdl, D. et al. Going viral with cancer immunotherapy. Nat Rev Cancer 14, 559–567 (2014). https://doi.org/10.1038/nrc3770

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