Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible.
Subscribe to Journal
Get full journal access for 1 year
only $20.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Russell, S.J. & Peng, K.W. Viruses as anticancer drugs. Trends Pharmacol. Sci. 28, 326–333 (2007).
Virgin, S. Pathogenesis of viral infection. in Fields Virology, 5th edn, vol. 1 (eds. Knipe, D.M. & Howley, P.M. (Lippincott Williams & Wilkins, Philadelphia, 2007).
Cattaneo, R., Miest, T., Shashkova, E.V. & Barry, M.A. Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded. Nat. Rev. Microbiol. 6, 529–540 (2008).
Dorer, D.E. & Nettelbeck, D.M. Targeting cancer by transcriptional control in cancer gene therapy and viral oncolysis. Adv. Drug Deliv. Rev. 61, 554–571 (2009).
Naik, S. & Russell, S.J. Engineering oncolytic viruses to exploit tumor specific defects in innate immune signaling pathways. Expert Opin. Biol. Ther. 9, 1163–1176 (2009).
Kelly, E.J. & Russell, S.J. MicroRNAs and the regulation of vector tropism. Mol. Ther. 17, 409–416 (2009).
Kelly, E. & Russell, S.J. History of oncolytic viruses: genesis to genetic engineering. Mol. Ther. 15, 651–659 (2007).
Southam, C.M. Present status of oncolytic virus studies. Trans. N.Y. Acad. Sci. 22, 657–673 (1960).
Asada, T. Treatment of human cancer with mumps virus. Cancer 34, 1907–1928 (1974).
Martuza, R.L., Malick, A., Markert, J.M., Ruffner, K.L. & Coen, D.M. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252, 854–856 (1991).
Au, G.G., Lindberg, A.M., Barry, R.D. & Shafren, D.R. Oncolysis of vascular malignant human melanoma tumors by coxsackievirus A21. Int. J. Oncol. 26, 1471–1476 (2005).
Rudin, C.M. et al. Phase I clinical study of Seneca Valley virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features. Clin. Cancer Res. 17, 888–895 (2011).
Tai, C.K. & Kasahara, N. Replication-competent retrovirus vectors for cancer gene therapy. Front. Biosci. 13, 3083–3095 (2008).
Liu, T.C., Galanis, E. & Kirn, D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat. Clin. Pract. Oncol. 4, 101–117 (2007).
Schoofs, G. et al. A high-yielding serum-free, suspension cell culture process to manufacture recombinant adenoviral vectors for gene therapy. Cytotechnology 28, 81–89 (1998).
Knop, D.R. & Harrell, H. Bioreactor production of recombinant herpes simplex virus vectors. Biotechnol. Prog. 23, 715–721 (2007).
Lewis, J.A., Brown, E.L. & Duncan, P.A. Approaches to the release of a master cell bank of PER.C6 cells; a novel cell substrate for the manufacture of human vaccines. Dev. Biol. (Basel) 123, 165–176, discussion 183–197 (2006).
Russell, S.J. Replicating vectors for cancer therapy: a question of strategy. Semin. Cancer Biol. 5, 437–443 (1994).
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).
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).
Eager, R.M. & Nemunaitis, J. Clinical development directions in oncolytic viral therapy. Cancer Gene Ther. 18, 305–317 (2011).
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).
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).
Harrington, K.J., Vile, R.G., Melcher, A., Chester, J. & Pandha, H.S. Clinical trials with oncolytic reovirus: moving beyond phase I into combinations with standard therapeutics. Cytokine Growth Factor Rev. 21, 91–98 (2010).
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).
Peng, K.W., Facteau, S., Wegman, T., O'Kane, D. & Russell, S.J. Non-invasive in vivo monitoring of trackable viruses expressing soluble marker peptides. Nat. Med. 8, 527–531 (2002).
Kelly, E.J., Hadac, E.M., Greiner, S. & Russell, S.J. Engineering microRNA responsiveness to decrease virus pathogenicity. Nat. Med. 14, 1278–1283 (2008).
Naik, S. et al. Curative one-shot systemic virotherapy in murine myeloma. Leukemia published online, 10.1038/leu.2012.70 (19 March 2012).
Breitbach, C.J. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011).
Serganova, I., Ponomarev, V. & Blasberg, R. Human reporter genes: potential use in clinical studies. Nucl. Med. Biol. 34, 791–807 (2007).
Galanis, E. et al. Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer. Cancer Res. 70, 875–882 (2010).
Jacobs, A. et al. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 358, 727–729 (2001).
Dingli, D., Russell, S.J. & Morris, J.C. III. In vivo imaging and tumor therapy with the sodium iodide symporter. J. Cell. Biochem. 90, 1079–1086 (2003).
Barton, K.N. et al. Phase I study of noninvasive imaging of adenovirus-mediated gene expression in the human prostate. Mol. Ther. 16, 1761–1769 (2008).
Dingli, D. et al. Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. Blood 103, 1641–1646 (2004).
Underhill, D.M. & Ozinsky, A. Phagocytosis of microbes: complexity in action. Annu. Rev. Immunol. 20, 825–852 (2002).
Haisma, H.J. et al. Scavenger receptor A: a new route for adenovirus 5. Mol. Pharm. 6, 366–374 (2009).
Bessis, N., GarciaCozar, F.J. & Boissier, M.C. Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene Ther. 11 (suppl. 1), S10–S17 (2004).
Fisher, K.D. & Seymour, L.W. HPMA copolymers for masking and retargeting of therapeutic viruses. Adv. Drug Deliv. Rev. 62, 240–245 (2010).
Eto, Y., Yoshioka, Y., Mukai, Y., Okada, N. & Nakagawa, S. Development of PEGylated adenovirus vector with targeting ligand. Int. J. Pharm. 354, 3–8 (2008).
Duncan, R. Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer 6, 688–701 (2006).
Morrison, J. et al. Virotherapy of ovarian cancer with polymer-cloaked adenovirus retargeted to the epidermal growth factor receptor. Mol. Ther. 16, 244–251 (2008).
Croyle, M.A. et al. PEGylation of a vesicular stomatitis virus G pseudotyped lentivirus vector prevents inactivation in serum. J. Virol. 78, 912–921 (2004).
Alemany, R., Suzuki, K. & Curiel, D.T. Blood clearance rates of adenovirus type 5 in mice. J. Gen. Virol. 81, 2605–2609 (2000).
Doronin, K., Shashkova, E.V., May, S.M., Hofherr, S.E. & Barry, M.A. Chemical modification with high molecular weight polyethylene glycol reduces transduction of hepatocytes and increases efficacy of intravenously delivered oncolytic adenovirus. Hum. Gene Ther. 20, 975–988 (2009).
Green, N.K. et al. Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus. Gene Ther. 11, 1256–1263 (2004).
Ikeda, K. et al. Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses. Nat. Med. 5, 881–887 (1999).
Ikeda, K. et al. Complement depletion facilitates the infection of multiple brain tumors by an intravascular, replication-conditional herpes simplex virus mutant. J. Virol. 74, 4765–4775 (2000).
Wakimoto, H. et al. The complement response against an oncolytic virus is species-specific in its activation pathways. Mol. Ther. 5, 275–282 (2002).
Haisma, H.J. & Bellu, A.R. Pharmacological interventions for improving adenovirus usage in gene therapy. Mol. Pharm. 8, 50–55 (2011).
Shashkova, E.V., Doronin, K., Senac, J.S. & Barry, M.A. Macrophage depletion combined with anticoagulant therapy increases therapeutic window of systemic treatment with oncolytic adenovirus. Cancer Res. 68, 5896–5904 (2008).
Koski, A. et al. Systemic adenoviral gene delivery to orthotopic murine breast tumors with ablation of coagulation factors, thrombocytes and Kupffer cells. J. Gene Med. 11, 966–977 (2009).
Ziegler, R.J. et al. Correction of the nonlinear dose response improves the viability of adenoviral vectors for gene therapy of Fabry disease. Hum. Gene Ther. 13, 935–945 (2002).
Manickan, E. et al. Rapid Kupffer cell death after intravenous injection of adenovirus vectors. Mol. Ther. 13, 108–117 (2006).
Tao, N. et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol. Ther. 3, 28–35 (2001).
Power, A.T. & Bell, J.C. Taming the Trojan horse: optimizing dynamic carrier cell/oncolytic virus systems for cancer biotherapy. Gene Ther. 15, 772–779 (2008).
Ilett, E.J. et al. Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity. Gene Ther. 16, 689–699 (2009).
Liu, C., Russell, S.J. & Peng, K.W. Systemic therapy of disseminated myeloma in passively immunized mice using measles virus-infected cell carriers. Mol. Ther. 18, 1155–1164 (2010).
Dwyer, R.M., Khan, S., Barry, F.P., O'Brien, T. & Kerin, M.J. Advances in mesenchymal stem cell-mediated gene therapy for cancer. Stem Cell Res. Ther. 1, 25 (2010).
García-Castro, J. et al. Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study. Cancer Gene Ther. 17, 476–483 (2010).
Ling, X. et al. Mesenchymal stem cells overexpressing IFN-β inhibit breast cancer growth and metastases through Stat3 signaling in a syngeneic tumor model. Cancer Microenviron. 3, 83–95 (2010).
Mader, E.K. et al. Mesenchymal stem cell carriers protect oncolytic measles viruses from antibody neutralization in an orthotopic ovarian cancer therapy model. Clin. Cancer Res. 15, 7246–7255 (2009).
Ilett, E.J. et al. Internalization of oncolytic reovirus by human dendritic cell carriers protects the virus from neutralization. Clin. Cancer Res. 17, 2767–2776 (2011).
Qiao, J. et al. Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors. Gene Ther. 15, 604–616 (2008).
Ong, H.T., Hasegawa, K., Dietz, A.B., Russell, S.J. & Peng, K.W. Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies. Gene Ther. 14, 324–333 (2007).
Matsumura, Y. & Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986).
Fang, J., Nakamura, H. & Maeda, H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev. 63, 136–151 (2011).
Hobbs, S.K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA 95, 4607–4612 (1998).
Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).
Jain, R.K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).
Fox, M.E., Szoka, F.C. & Frechet, J.M. Soluble polymer carriers for the treatment of cancer: the importance of molecular architecture. Acc. Chem. Res. 42, 1141–1151 (2009).
Barnett, F.H. et al. Selective delivery of herpes virus vectors to experimental brain tumors using RMP-7. Cancer Gene Ther. 6, 14–20 (1999).
Tseng, J.C., Granot, T., DiGiacomo, V., Levin, B. & Meruelo, D. Enhanced specific delivery and targeting of oncolytic Sindbis viral vectors by modulating vascular leakiness in tumor. Cancer Gene Ther. 17, 244–255 (2010).
Kottke, T. et al. Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice. J. Clin. Invest. 120, 1551–1560 (2010).
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).
Driessen, W.H., Ozawa, M.G., Arap, W. & Pasqualini, R. Ligand-directed cancer gene therapy to angiogenic vasculature. Adv. Genet. 67, 103–121 (2009).
Thorne, S.H. et al. Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. J. Clin. Invest. 117, 3350–3358 (2007).
Neri, D. & Bicknell, R. Tumour vascular targeting. Nat. Rev. Cancer 5, 436–446 (2005).
Sanz, L. et al. Single-chain antibody-based gene therapy: inhibition of tumor growth by in situ production of phage-derived human antibody fragments blocking functionally active sites of cell-associated matrices. Gene Ther. 9, 1049–1053 (2002).
Palumbo, A. et al. A chemically modified antibody mediates complete eradication of tumours by selective disruption of tumour blood vessels. Br. J. Cancer 104, 1106–1115 (2011).
Nakamura, T. et al. Rescue and propagation of fully retargeted oncolytic measles viruses. Nat. Biotechnol. 23, 209–214 (2005).
Morrison, J. et al. Cetuximab retargeting of adenovirus via the epidermal growth factor receptor for treatment of intraperitoneal ovarian cancer. Hum. Gene Ther. 20, 239–251 (2009).
Bachtarzi, H. et al. Targeting adenovirus gene delivery to activated tumour-associated vasculature via endothelial selectins. J. Control. Release 150, 196–203 (2011).
Ong, H.T. et al. Intravascularly administered RGD-displaying measles viruses bind to and infect neovessel endothelial cells in vivo. Mol. Ther. 17, 1012–1021 (2009).
Jing, Y. et al. Tumor and vascular targeting of a novel oncolytic measles virus retargeted against the urokinase receptor. Cancer Res. 69, 1459–1468 (2009).
Kumar, C.C. et al. Biochemical characterization of the binding of echistatin to integrin αvβ3 receptor. J. Pharmacol. Exp. Ther. 283, 843–853 (1997).
Breitbach, C.J. et al. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19, 886–894 (2011).
Chen, H.H. et al. Active adenoviral vascular penetration by targeted formation of heterocellular endothelial-epithelial syncytia. Mol. Ther. 19, 67–75 (2011).
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).
Schoggins, J.W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011).
Haller, O., Kochs, G. & Weber, F. Interferon, Mx, and viral countermeasures. Cytokine Growth Factor Rev. 18, 425–433 (2007).
Vandevenne, P., Sadzot-Delvaux, C. & Piette, J. Innate immune response and viral interference strategies developed by human herpesviruses. Biochem. Pharmacol. 80, 1955–1972 (2010).
Lu, M.Y. & Liao, F. Interferon-stimulated gene ISG12b2 is localized to the inner mitochondrial membrane and mediates virus-induced cell death. Cell Death Differ. 18, 925–936 (2011).
Stojdl, D.F. et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat. Med. 6, 821–825 (2000).
Haralambieva, I. et al. Engineering oncolytic measles virus to circumvent the intracellular innate immune response. Mol. Ther. 15, 588–597 (2007).
Altomonte, J. et al. Exponential enhancement of oncolytic vesicular stomatitis virus potency by vector-mediated suppression of inflammatory responses in vivo. Mol. Ther. 16, 146–153 (2008).
Le Boeuf, F. et al. Synergistic interaction between oncolytic viruses augments tumor killing. Mol. Ther. 18, 888–895 (2010).
Kirn, D.H. & Thorne, S.H. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat. Rev. Cancer 9, 64–71 (2009).
Chang, H.M. et al. Induction of interferon-stimulated gene expression and antiviral responses require protein deacetylase activity. Proc. Natl. Acad. Sci. USA 101, 9578–9583 (2004).
Nguyên, 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).
Otsuki, A. et al. Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses. Mol. Ther. 16, 1546–1555 (2008).
MacTavish, H. et al. Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors. PLoS ONE 5, e14462 (2010).
Diallo, J.S. et al. A high-throughput pharmacoviral approach identifies novel oncolytic virus sensitizers. Mol. Ther. 18, 1123–1129 (2010).
Passer, B.J. et al. Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication. Cancer Res. 70, 3890–3895 (2010).
Alain, T. et al. Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production. Proc. Natl. Acad. Sci. USA 107, 1576–1581 (2010).
Lun, X. et al. Myxoma virus virotherapy for glioma in immunocompetent animal models: optimizing administration routes and synergy with rapamycin. Cancer Res. 70, 598–608 (2010).
Lun, X.Q. et al. Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin. Cancer Res. 67, 8818–8827 (2007).
Qiao, J. et al. Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus. Clin. Cancer Res. 14, 259–269 (2008).
Kottke, T. et al. Improved systemic delivery of oncolytic reovirus to established tumors using preconditioning with cyclophosphamide-mediated Treg modulation and interleukin-2. Clin. Cancer Res. 15, 561–569 (2009).
Kurozumi, K. et al. Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy. J. Natl. Cancer Inst. 99, 1768–1781 (2007).
Kirn, D.H., Wang, Y., Liang, W., Contag, C.H. & Thorne, S.H. Enhancing poxvirus oncolytic effects through increased spread and immune evasion. Cancer Res. 68, 2071–2075 (2008).
Reeves, P.M. et al. Variola and monkeypox viruses utilize conserved mechanisms of virion motility and release that depend on abl and SRC family tyrosine kinases. J. Virol. 85, 21–31 (2011).
Hoffmann, D. & Wildner, O. Enhanced killing of pancreatic cancer cells by expression of fusogenic membrane glycoproteins in combination with chemotherapy. Mol. Cancer Ther. 5, 2013–2022 (2006).
Patel, B. et al. Differential cytopathology and kinetics of measles oncolysis in two primary B-cell malignancies provides mechanistic insights. Mol. Ther. 19, 1034–1040 (2011).
Israyelyan, A. et al. Herpes simplex virus type-1(HSV-1) oncolytic and highly fusogenic mutants carrying the NV1020 genomic deletion effectively inhibit primary and metastatic tumors in mice. Virol. J. 5, 68 (2008).
Brown, C.W. et al. The p14 FAST protein of reptilian reovirus increases vesicular stomatitis virus neuropathogenesis. J. Virol. 83, 552–561 (2009).
Sauthoff, H. et al. Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: virus persists and spreads systemically at late time points. Hum. Gene Ther. 14, 425–433 (2003).
Yun, C.O. Overcoming the extracellular matrix barrier to improve intratumoral spread and therapeutic potential of oncolytic virotherapy. Curr. Opin. Mol. Ther. 10, 356–361 (2008).
Diop-Frimpong, B., Chauhan, V.P., Krane, S., Boucher, Y. & Jain, R.K. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl. Acad. Sci. USA 108, 2909–2914 (2011).
Ganesh, S., Gonzalez-Edick, M., Gibbons, D., Van Roey, M. & Jooss, K. Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models. Clin. Cancer Res. 14, 3933–3941 (2008).
Guedan, S. et al. Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. Mol. Ther. 18, 1275–1283 (2010).
Toth, K., Dhar, D. & Wold, W.S. Oncolytic (replication-competent) adenoviruses as anticancer agents. Expert Opin. Biol. Ther. 10, 353–368 (2010).
Muthana, M. et al. Use of macrophages to target therapeutic adenovirus to human prostate tumors. Cancer Res. 71, 1805–1815 (2011).
Lee, C.Y.F. et al. Transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 for targeting prostate tumors. Mol. Ther. 18, 929–935 (2010).
Foka, P. et al. Novel tumour-specific promoters for transcriptional targeting of hepatocellular carcinoma by herpes simplex virus vectors. J. Gene Med. 12, 956–967 (2010).
Muik, A. et al. Pseudotyping vesicular stomatitis virus with lymphocytic choriomeningitis virus glycoproteins enhances infectivity for glioma cells and minimizes neurotropism. J. Virol. 85, 5679–5684 (2011).
Ayala Breton, C., Barber, G.N., Russell, S. & Peng, K.W. Retargeting vesicular stomatitis virus using measles virus envelope glycoproteins. Hum. Gene Ther. 23, 484–491 (2012).
Shashkova, E.V., May, S.M., Doronin, K. & Barry, M.A. Expanded anticancer therapeutic window of hexon-modified oncolytic adenovirus. Mol. Ther. 17, 2121–2130 (2009).
Leber, M.F. et al. MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism. Mol. Ther. 19, 1097–1106 (2011).
Cawood, R., Wong, S.L., Di, Y., Baban, D.F. & Seymour, L.W. MicroRNA controlled adenovirus mediates anti-cancer efficacy without affecting endogenous microRNA activity. PLoS ONE 6, e16152 (2011).
Cawood, R. et al. Use of tissue-specific microRNA to control pathology of wild-type adenovirus without attenuation of its ability to kill cancer cells. PLoS Pathog. 5, e1000440 (2009).
Kelly, E.J., Nace, R., Barber, G.N. & Russell, S.J. Attenuation of vesicular stomatitis virus encephalitis through microRNA targeting. J. Virol. 84, 1550–1562 (2010).
Edge, R.E. et al. A let-7 microRNA-sensitive vesicular stomatitis virus demonstrates tumor-specific replication. Mol. Ther. 16, 1437–1443 (2008).
Sugio, K. et al. Enhanced safety profiles of the telomerase-specific replication-competent adenovirus by incorporation of normal cell-specific microRNA-targeted sequences. Clin. Cancer Res. 17, 2807–2818 (2011).
Yang, X. et al. Evaluation of IRES-mediated, cell-type-specific cytotoxicity of poliovirus using a colorimetric cell proliferation assay. J. Virol. Methods 155, 44–54 (2009).
Roos, F.C. et al. Oncolytic targeting of renal cell carcinoma via encephalomyocarditis virus. EMBO Mol. Med. 2, 275–288 (2010).
Oliere, S. et al. Vesicular stomatitis virus oncolysis of T lymphocytes requires cell cycle entry and translation initiation. J. Virol. 82, 5735–5749 (2008).
Stoff-Khalili, M.A. et al. Cancer-specific targeting of a conditionally replicative adenovirus using mRNA translational control. Breast Cancer Res. Treat. 108, 43–55 (2008).
Banaszynski, L.A., Sellmyer, M.A., Contag, C.H., Wandless, T.J. & Thorne, S.H. Chemical control of protein stability and function in living mice. Nat. Med. 14, 1123–1127 (2008).
Glass, M., Busche, A., Wagner, K., Messerle, M. & Borst, E.M. Conditional and reversible disruption of essential herpesvirus proteins. Nat. Methods 6, 577–579 (2009).
Banaszynski, L.A., Chen, L.C., Maynard-Smith, L.A., Ooi, A.G. & Wandless, T.J. A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules. Cell 126, 995–1004 (2006).
Stepkowski, S.M. Molecular targets for existing and novel immunosuppressive drugs. Expert Rev. Mol. Med. 2, 1–23 (2000).
Chiocca, E.A. The host response to cancer virotherapy. Curr. Opin. Mol. Ther. 10, 38–45 (2008).
Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Yang, L., Pang, Y. & Moses, H.L. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 31, 220–227 (2010).
Melcher, A., Parato, K., Rooney, C.M. & Bell, J.C. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol. Ther. 6, 1008–1016 (2011).
Mastrangelo, M.J., Maguire, H.C. & Lattime, E.C. Intralesional vaccinia/GM-CSF recombinant virus in the treatment of metastatic melanoma. Adv. Exp. Med. Biol. 465, 391–400 (2000).
Diaz, R.M. et al. Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res. 67, 2840–2848 (2007).
Bridle, B.W., Hanson, S. & Lichty, B.D. Combining oncolytic virotherapy and tumour vaccination. Cytokine Growth Factor Rev. 21, 143–148 (2010).
Kottke, T. et al. Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. Nat. Med. 17, 854–859 (2011).
Pulido, J. et al. Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat. Biotechnol. 30, 337–343 (2012).
Kottke, T. et al. Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer. Mol. Ther. 16, 1910–1918 (2008).
Senac, J.S. et al. Infection and killing of multiple myeloma by adenoviruses. Hum. Gene Ther. 21, 179–190 (2010).
Zhang, X., Zhao, L., Hang, Z., Guo, H. & Zhang, M. Evaluation of HSV-1 and adenovirus vector-mediated infection, replication and cytotoxicity in lymphoma cell lines. Oncol. Rep. 26, 637–644 (2011).
Kanai, R., Wakimoto, H., Cheema, T. & Rabkin, S.D. Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer? Future Oncol. 6, 619–634 (2010).
Russell, S.J. & Peng, K.W. Measles virus for cancer therapy. Curr. Top. Microbiol. Immunol. 330, 213–241 (2009).
Byrnes, A.P. & Griffin, D.E. Large-plaque mutants of Sindbis virus show reduced binding to heparan sulfate, heightened viremia, and slower clearance from the circulation. J. Virol. 74, 644–651 (2000).
Lee, P., Knight, R., Smit, J.M., Wilschut, J. & Griffin, D.E. A single mutation in the E2 glycoprotein important for neurovirulence influences binding of sindbis virus to neuroblastoma cells. J. Virol. 76, 6302–6310 (2002).
Chen, N. et al. Poxvirus interleukin-4 expression overcomes inherent resistance and vaccine-induced immunity: pathogenesis, prophylaxis, and antiviral therapy. Virology 409, 328–337 (2011).
Peng, K.W. et al. Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses. Gene Ther. published, online doi:10.1038/gt.2012.31 (5 April 2012).
Miyatake, S., Iyer, A., Martuza, R.L. & Rabkin, S.D. Transcriptional targeting of herpes simplex virus for cell-specific replication. J. Virol. 71, 5124–5132 (1997).
Rodriguez, R. et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res. 57, 2559–2563 (1997).
Kuhn, I. et al. Directed evolution generates a novel oncolytic virus for the treatment of colon cancer. PLoS ONE 3, e2409 (2008).
Doronin, K. et al. Tumor-specific, replication-competent adenovirus vectors overexpressing the adenovirus death protein. J. Virol. 74, 6147–6155 (2000).
Wong, R.J. et al. Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma. Hum. Gene Ther. 12, 253–265 (2001).
Kim, J.H. et al. Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J. Natl. Cancer Inst. 98, 1482–1493 (2006).
Thorne, S.H., Negrin, R.S. & Contag, C.H. Synergistic antitumor effects of immune cell-viral biotherapy. Science 311, 1780–1784 (2006).
S.J.R. and K.-W.P. acknowledge funding support from the Mayo Foundation, Mayo Clinic Comprehensive Cancer Center (CA15083), US National Institutes of Health and National Cancer Institute (CA100634, CA129966, CA118488, CA129193, CA136547 and CA136393), Richard M. Schulze Family Foundation, Al and Mary Agnes McQuinn and Minnesota Partnership for Biotechnology. J.C.B. is supported by the Ontario Institute for Cancer Research, the Terry Fox Foundation and the Ottawa Regional Cancer Foundation.
J.C.B. is the chief scientific officer of Jennerex Biotherapeutics.
About this article
Journal of Theoretical Biology (2020)
Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies
Pediatric Blood & Cancer (2020)
Oncolytic virotherapy, alone or in combination with immune checkpoint inhibitors, for advanced melanoma: A systematic review and meta-analysis
International Immunopharmacology (2020)
Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy
Molecular Therapy (2019)
Dual-Isotope SPECT Imaging with NIS Reporter Gene and Duramycin to Visualize Tumor Susceptibility to Oncolytic Virus Infection
Molecular Therapy - Oncolytics (2019)