The discovery and development of oncolytic viruses: are they the future of cancer immunotherapy?

References

• Miller JAP, Sadelain M. The journey from discoveries in fundamental immunology to cancer immunotherapy. Cancer Cell. 2015;27(4):439–449.
   PubMed Web of Science ®Google Scholar
• Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8:1069–1086.
   PubMed Web of Science ®Google Scholar
• Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–1355.
   PubMed Web of Science ®Google Scholar
• Waldmann TA. Cytokines in cancer immunotherapy. Cold Spring Harb Perspect Biol. 2018;10:a028472.
   PubMed Web of Science ®Google Scholar
• Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014;2:295–300.
   PubMed Web of Science ®Google Scholar
• Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019;18:197–218.
   PubMed Web of Science ®Google Scholar
• Harrington K, Freeman DJ, Kelly B, et al. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov. 2019;18:689–706.
   PubMed Web of Science ®Google Scholar
• Dock G. The influence of complicating diseases upon leukaemia. The Am J Med Sci (1827-1924). 1904;127:563.
   Google Scholar
• Southam CM, Moore AE. West Nile, Ilheus, and Bunyamwera virus infections in man. Am J Trop Med Hyg. 1951;31:724–741.
   PubMed Web of Science ®Google Scholar
• Southam CM. Division of microbiology: present status of oncolytic virus studies. Trans N Y Acad Sci. 1960;22(8 Series II):657–673.
   PubMedGoogle Scholar
• Southam CM, Moore AE. Clinical studies of viruses as antineoplastic agents with particular reference to Egypt 101 virus. Cancer. 1952;5:1025–1034.
   PubMed Web of Science ®Google Scholar
• Higgins GK, Pack GT. Virus therapy in the treatment of tumors. Bull Hosp Joint Dis. 1951;12:379–382.
   PubMedGoogle Scholar
• Smith RR, Huebner RJ, Rowe WP, et al. Studies on the use of viruses in the treatment of carcinoma of the cervix. Cancer. 1956;9:1211–1218.
   PubMed Web of Science ®Google Scholar
• Liu TC, Galanis E, Kirn D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pract Oncol. 2007;4:101–117.
   PubMedGoogle Scholar
• Asada T. Treatment of human cancer with mumps virus. Cancer. 1974;34:1907–1928.
   PubMed Web of Science ®Google Scholar
• Martuza RL, Malick A, Markert JM, et al. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science. 1991;252:854–856.
   PubMed Web of Science ®Google Scholar
• Zheng M, Huang J, Tong A, et al. Oncolytic viruses for cancer therapy: barriers and recent advances. Mol Ther Oncolytics. 2019;15:234–247.
   PubMed Web of Science ®Google Scholar
• Bommareddy PK, Peters C, Saha D, et al. Oncolytic herpes simplex viruses as a paradigm for the treatment of cancer. Ann Revi Cancer Biol. 2018;2:155–173.
   Google Scholar
• Guo ZS, Liu Z, Bartlett DL. Oncolytic immunotherapy: dying the right way is a key to eliciting potent antitumor immunity. Front Oncol. 2014;4:74.
   PubMedGoogle Scholar
• Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642–662.
   PubMed Web of Science ®Google Scholar
• Toda M, Rabkin SD, Kojima H, et al. Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity. Hum Gene Ther. 1999;10:385–393.
   PubMed Web of Science ®Google Scholar
• Russell SJ, Barber GN. Oncolytic viruses as antigen-agnostic cancer vaccines. Cancer Cell. 2018;33:599–605.
   PubMed Web of Science ®Google Scholar
• Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170:1109–1119.e10.
   PubMed Web of Science ®Google Scholar
• Zamarin D, Holmgaard RB, Subudhi SK, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med. 2014;6:226ra32.
   PubMed Web of Science ®Google Scholar
• Gujar S, Pol JG, Kim Y, et al. Antitumor benefits of antiviral immunity: an underappreciated aspect of oncolytic virotherapies. Trends Immunol. 2018;39:209–221.
   PubMed Web of Science ®Google Scholar
• Breitbach CJ, De Silva NS, Falls TJ, et al. Targeting tumor vasculature with an oncolytic virus. Mol Ther. 2011;19:886–894.
   PubMed Web of Science ®Google Scholar
• Breitbach CJ, Arulanandam R, De Silva N, et al. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res. 2013;73:1265–1275.
   PubMed Web of Science ®Google Scholar
• Matuszewska K, Santry LA, van Vloten JP, et al. Combining vascular normalization with an oncolytic virus enhances immunotherapy in a preclinical model of advanced-stage ovarian cancer. Clin Cancer Res. 2019;25:1624–1638.
   PubMed Web of Science ®Google Scholar
• Ilkow CS, Marguerie M, Batenchuk C, et al. Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity. Nat Med. 2015;21:530–536.
   PubMed Web of Science ®Google Scholar
• de Graaf JF, de Vor L, Fouchier RAM, et al. Armed oncolytic viruses: A kick-start for anti-tumor immunity. Cytokine Growth Factor Rev. 2018;41:28–39.
   PubMed Web of Science ®Google Scholar
• Rahman MM, McFadden G. Oncolytic virotherapy with myxoma virus. J Clin Med. 2020;9:171.
   Web of Science ®Google Scholar
• Bretscher C, Marchini A. H-1 parvovirus as a cancer-killing agent: past, present, and future. Viruses. 2019;11:562.
   Web of Science ®Google Scholar
• Stojdl DF, Lichty B, Knowles S, et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med. 2000;6:821–825.
   PubMed Web of Science ®Google Scholar
• Zeh HJ, Bartlett DL. Development of a replication-selective, oncolytic poxvirus for the treatment of human cancers. Cancer Gene Ther. 2002;9:1001–1012.
   PubMed Web of Science ®Google Scholar
• Chaurasiya S, Chen NG, Lu J, et al. A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models. Cancer Gene Ther. 2020;27:125–135.
   PubMed Web of Science ®Google Scholar
• Peters C, Rabkin SD. Designing herpes viruses as oncolytics. Mol Ther Oncolytics. 2015;2:15010.
   PubMed Web of Science ®Google Scholar
• Liu TC, Kirn D. Viruses with deletions in antiapoptotic genes as potential oncolytic agents. Oncogene. 2005;24:6069–6079.
   PubMed Web of Science ®Google Scholar
• Liu TC, Wakimoto H, Martuza RL, et al. Herpes simplex virus Us3(-) mutant as oncolytic strategy and synergizes with phosphatidylinositol 3-kinase-Akt targeting molecular therapeutics. Clin Cancer Res. 2007;13:5897–5902.
   PubMed Web of Science ®Google Scholar
• Pisklakova A, McKenzie B, Zemp F, et al. M011L-deficient oncolytic myxoma virus induces apoptosis in brain tumor-initiating cells and enhances survival in a novel immunocompetent mouse model of glioblastoma. Neuro Oncol. 2016;18:1088–1098.
   PubMed Web of Science ®Google Scholar
• Pelin A, Foloppe J, Petryk J, et al. Deletion of apoptosis inhibitor F1L in vaccinia virus increases safety and oncolysis for cancer therapy. Mol Ther Oncolytics. 2019;14:246–252.
   PubMed Web of Science ®Google Scholar
• Guo ZS, Naik A, O’Malley ME, et al. The enhanced tumor selectivity of an oncolytic vaccinia lacking the host range and antiapoptosis genes SPI-1 and SPI-2. Cancer Res. 2005;65:9991–9998.
   PubMed Web of Science ®Google Scholar
• Mansour M, Palese P, Zamarin D. Oncolytic specificity of Newcastle disease virus is mediated by selectivity for apoptosis-resistant cells. J Virol. 2011;85:6015–6023.
   PubMed Web of Science ®Google Scholar
• Matveeva OV, Chumakov PM. Defects in interferon pathways as potential biomarkers of sensitivity to oncolytic viruses. Rev Med Virol. 2018;28:e2008.
   PubMed Web of Science ®Google Scholar
• Stojdl DF, Lichty BD, tenOever BR, et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell. 2003;4:263–275.
   PubMed Web of Science ®Google Scholar
• Willmon CL, Saloura V, Fridlender ZG, et al. Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma. Cancer Res. 2009;69:7713–7720.
   PubMed Web of Science ®Google Scholar
• Zamarin D, Martínez-Sobrido L, Kelly K, et al. Enhancement of oncolytic properties of recombinant newcastle disease virus through antagonism of cellular innate immune responses. Mol Ther. 2009;17:697–706.
   PubMed Web of Science ®Google Scholar
• Peters C, Paget M, Tshilenge KT, et al. Restriction of replication of oncolytic herpes simplex virus with a deletion of gamma34.5 in glioblastoma stem-like cells. J Virol. 2018;92:e00246–18.
   PubMed Web of Science ®Google Scholar
• Chiocca EA, Nakashima H, Kasai K, et al. Preclinical toxicology of rQNestin34.5v.2: an oncolytic herpes virus with transcriptional regulation of the ICP34.5 neurovirulence gene. Mol Ther Methods Clin Dev. 2020;17:871–893.
   PubMed Web of Science ®Google Scholar
• Cassady KA. Human cytomegalovirus TRS1 and IRS1 gene products block the double-stranded-RNA-activated host protein shutoff response induced by herpes simplex virus type 1 infection. J Virol. 2005;79:8707–8715.
   PubMed Web of Science ®Google Scholar
• Baker AT, Aguirre-Hernández C, Halldén G, et al. Designer oncolytic adenovirus: coming of age. Cancers (Basel). 2018;10:201.
   Web of Science ®Google Scholar
• McCart JA, Ward JM, Lee J, et al. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res. 2001;61:8751–8757.
   PubMed Web of Science ®Google Scholar
• Cattaneo R, Miest T, Shashkova EV, et al. Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded. Nat Rev Microbiol. 2008;6:529–540.
   PubMed Web of Science ®Google Scholar
• Goins WF, Hall B, Cohen JB, et al. Retargeting of herpes simplex virus (HSV) vectors. Curr Opin Virol. 2016;21:93–101.
   PubMed Web of Science ®Google Scholar
• Aref S, Bailey K, Fielding A. Measles to the rescue: a review of oncolytic measles virus. Viruses. 2016;8:294.
   Web of Science ®Google Scholar
• Liu XQ, Xin HY, Lyu YN, et al. Oncolytic herpes simplex virus tumor targeting and neutralization escape by engineering viral envelope glycoproteins. Drug Deliv. 2018;25:1950–1962.
   PubMed Web of Science ®Google Scholar
• Miyatake S, Iyer A, Martuza RL, et al. Transcriptional targeting of herpes simplex virus for cell-specific replication. J Virol. 1997;71:5124–5132.
   PubMed Web of Science ®Google Scholar
• Rodriguez R, Schuur ER, Lim HY, et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res. 1997;57:2559–2563.
   PubMed Web of Science ®Google Scholar
• Nemunaitis J, Tong AW, Nemunaitis M, et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. 2010;18:429–434.
   PubMed Web of Science ®Google Scholar
• Zhang W, Ge K, Zhao Q, et al. A novel oHSV-1 targeting telomerase reverse transcriptase-positive cancer cells via tumor-specific promoters regulating the expression of ICP4. Oncotarget. 2015;6:20345–20355.
   PubMedGoogle Scholar
• Lee CY, Bu LX, DeBenedetti A, et al. Transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 for targeting prostate tumors. Mol Ther. 2010;18:929–935.
   PubMed Web of Science ®Google Scholar
• Sasso E, Froechlich G, Cotugno G, et al. Replicative conditioning of Herpes simplex type 1 virus by Survivin promoter, combined to ERBB2 retargeting, improves tumour cell-restricted oncolysis. Sci Rep. 2020;10:4307.
   PubMed Web of Science ®Google Scholar
• Mazzacurati L, Marzulli M, Reinhart B, et al. Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. Mol Ther. 2015;23:99–107.
   PubMed Web of Science ®Google Scholar
• Ruiz AJ, Russell SJ. MicroRNAs and oncolytic viruses. Curr Opin Virol. 2015;13:40–48.
   PubMed Web of Science ®Google Scholar
• Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18:498–513.
   PubMed Web of Science ®Google Scholar
• Russell L, Peng KW, Russell SJ, et al. Oncolytic viruses: priming time for cancer immunotherapy. BioDrugs. 2019;33:485–501.
   PubMed Web of Science ®Google Scholar
• Alvarez-Breckenridge CA, Choi BD, Suryadevara CM, et al. Potentiating oncolytic viral therapy through an understanding of the initial immune responses to oncolytic viral infection. Curr Opin Virol. 2015;13:25–32.
   PubMed Web of Science ®Google Scholar
• Chahlavi A, Rabkin S, Todo T, et al. Effect of prior exposure to herpes simplex virus 1 on viral vector-mediated tumor therapy in immunocompetent mice. Gene Ther. 1999;6:1751–1758.
   PubMed Web of Science ®Google Scholar
• Lambright ES, Kang EH, Force S, et al. Effect of preexisting anti-herpes immunity on the efficacy of herpes simplex viral therapy in a murine intraperitoneal tumor model. Mol Ther. 2000;2:387–393.
   PubMed Web of Science ®Google Scholar
• Dhar D, Spencer JF, Toth K, et al. Effect of preexisting immunity on oncolytic adenovirus vector INGN 007 antitumor efficacy in immunocompetent and immunosuppressed Syrian hamsters. J Virol. 2009;83:2130–2139.
   PubMed Web of Science ®Google Scholar
• Ricca JM, Oseledchyk A, Walther T, et al. Pre-existing immunity to oncolytic virus potentiates its immunotherapeutic efficacy. Mol Ther. 2018;26:1008–1019.
   PubMed Web of Science ®Google Scholar
• Delman KA, Bennett JJ, Zager JS, et al. Effects of preexisting immunity on the response to herpes simplex-based oncolytic viral therapy. Hum Gene Ther. 2000;11:2465–2472.
   PubMed Web of Science ®Google Scholar
• Dispenzieri A, Tong C, LaPlant B, et al. Phase I trial of systemic administration of Edmonston strain of measles virus genetically engineered to express the sodium iodide symporter in patients with recurrent or refractory multiple myeloma. Leukemia. 2017;31:2791–2798.
   PubMed Web of Science ®Google Scholar
• Adair RA, Roulstone V, Scott KJ, et al. Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients. Sci Transl Med. 2012;4:138ra77.
   PubMed Web of Science ®Google Scholar
• Geevarghese SK, Geller DA, de Haan HA, et al. Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver. Hum Gene Ther. 2010;21:1119–1128.
   PubMed Web of Science ®Google Scholar
• Zeh HJ, Downs-Canner S, McCart JA, et al. First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity. Mol Ther. 2015;23:202–214.
   PubMed Web of Science ®Google Scholar
• Desjardins A, Gromeier M, Herndon JE 2nd, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med. 2018;379:150–161.
   PubMed Web of Science ®Google Scholar
• Hu JC, Coffin RS, Davis CJ, 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. 2006;12:6737–6747.
   PubMed Web of Science ®Google Scholar
• Chaurasiya S, Fong Y, Warner SG. Optimizing oncolytic viral design to enhance antitumor efficacy: progress and challenges. Cancers (Basel). 2020;12:1699.
   Web of Science ®Google Scholar
• Haddad D, Fong Y. Molecular imaging of oncolytic viral therapy. Mol Ther Oncolytics. 2015;1:14007.
   PubMedGoogle Scholar
• Markert JM, Medlock MD, Rabkin SD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 2000;7:867–874.
   PubMed Web of Science ®Google Scholar
• Kelly KJ, Wong J, Gönen M, et al. Human trial of a genetically modified herpes simplex virus for rapid detection of positive peritoneal cytology in the staging of pancreatic cancer. EBioMedicine. 2016;7:94–99.
   PubMed Web of Science ®Google Scholar
• Kelly KJ, Brader P, Woo Y, et al. Real-time intraoperative detection of melanoma lymph node metastases using recombinant vaccinia virus GLV-1h68 in an immunocompetent animal model. Int J Cancer. 2009;124:911–918.
   PubMed Web of Science ®Google Scholar
• Yano S, Takehara K, Miwa S, et al. Improved resection and outcome of colon-cancer liver metastasis with fluorescence-guided surgery using in situ GFP labeling with a telomerase-dependent adenovirus in an orthotopic mouse model. PLoS One. 2016;11:e0148760.
   PubMed Web of Science ®Google Scholar
• Miller A, Russell SJ. The use of the NIS reporter gene for optimizing oncolytic virotherapy. Expert Opin Biol Ther. 2016;16:15–32.
   PubMed Web of Science ®Google Scholar
• Dingli D, Peng KW, Harvey ME, et al. Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. Blood. 2004;103:1641–1646.
   PubMed Web of Science ®Google Scholar
• Conlon KC, Miljkovic MD, Waldmann TA. Cytokines in the treatment of cancer. J Interferon Cytokine Res. 2019;39:6–21.
   PubMed Web of Science ®Google Scholar
• Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993;90:3539–3543.
   PubMed Web of Science ®Google Scholar
• Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003;10:292–303.
   PubMed Web of Science ®Google Scholar
• Varghese S, Rabkin SD, Liu R, 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. 2006;13:253–265.
   PubMed Web of Science ®Google Scholar
• Andtbacka RHI, Collichio F, Harrington KJ, et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019;7:145.
   PubMed Web of Science ®Google Scholar
• Andtbacka RH, Ross M, Puzanov I, et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol. 2016;23:4169–4177.
   PubMed Web of Science ®Google Scholar
• Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: interim results. Urol Oncol. 2018;36:440–447.
   PubMed Web of Science ®Google Scholar
• Ranki T, Pesonen S, Hemminki A, et al. Phase I study with ONCOS-102 for the treatment of solid tumors - an evaluation of clinical response and exploratory analyses of immune markers. J Immunother Cancer. 2016;4:17.
   PubMed Web of Science ®Google Scholar
• Nguyen HM, Guz-Montgomery K, Saha D. Oncolytic virus encoding a master pro-inflammatory cytokine interleukin 12 in cancer immunotherapy. Cells. 2020;9:400.
   Web of Science ®Google Scholar
• Liu R, Varghese S, Rabkin SD. Oncolytic herpes simplex virus vector therapy of breast cancer in C3(1)/SV40 T-antigen transgenic mice. Cancer Res. 2005;65:1532–1540.
   PubMed Web of Science ®Google Scholar
• Varghese S, Rabkin SD, Nielsen GP, et al. Systemic therapy of spontaneous prostate cancer in transgenic mice with oncolytic herpes simplex viruses. Cancer Res. 2007;67:9371–9379.
   PubMed Web of Science ®Google Scholar
• Cheema TA, Wakimoto H, Fecci PE, et al. Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc Natl Acad Sci U S A. 2013;110:12006–12011.
   PubMed Web of Science ®Google Scholar
• Wang P, Li X, Wang J, et al. Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. Nat Commun. 2017;8:1395.
   PubMed Web of Science ®Google Scholar
• Ge Y, Wang H, Ren J, et al. Oncolytic vaccinia virus delivering tethered IL-12 enhances antitumor effects with improved safety. J Immunother Cancer. 2020;8:e000710.
   PubMed Web of Science ®Google Scholar
• Liu Z, Ge Y, Wang H, et al. Modifying the cancer-immune set point using vaccinia virus expressing re-designed interleukin-2. Nat Commun. 2018;9(1):4682.
   PubMedGoogle Scholar
• Bai F, Niu Z, Tian H, et al. Genetically engineered Newcastle disease virus expressing interleukin 2 is a potential drug candidate for cancer immunotherapy. Immunol Lett. 2014;159(1–2):36–46.
   PubMed Web of Science ®Google Scholar
• Santos JM, Cervera-Carrascon V, Havunen R, et al. Adenovirus coding for Interleukin-2 and tumor necrosis factor alpha replaces lymphodepleting chemotherapy in adoptive T Cell therapy. Mol Ther. 2018;26:2243–2254.
   PubMed Web of Science ®Google Scholar
• Buijs P, van Nieuwkoop S, Vaes V, et al. Recombinant immunomodulating lentogenic or mesogenic oncolytic newcastle disease virus for treatment of pancreatic adenocarcinoma. Viruses. 2015;7:2980–2998.
   PubMed Web of Science ®Google Scholar
• Shashkova EV, Spencer JF, Wold WS, et al. Targeting interferon-alpha increases antitumor efficacy and reduces hepatotoxicity of E1A-mutated spread-enhanced oncolytic adenovirus. Mol Ther. 2007;15:598–607.
   PubMed Web of Science ®Google Scholar
• Kirn DH, Wang Y, Le Boeuf F, et al. Targeting of interferon-beta to produce a specific, multi-mechanistic oncolytic vaccinia virus. PLoS Med. 2007;4:e353.
   PubMed Web of Science ®Google Scholar
• Strazza M, Mor A. The complexity of targeting chemokines to promote a tumor immune response. Inflammation. 2020;43:1201–1208.
   PubMed Web of Science ®Google Scholar
• Lapteva N, Aldrich M, Weksberg D, et al. Targeting the intratumoral dendritic cells by the oncolytic adenoviral vaccine expressing RANTES elicits potent antitumor immunity. J Immunother. 2009;32:145–156.
   PubMed Web of Science ®Google Scholar
• Li J, O’Malley M, Urban J, et al. Chemokine expression from oncolytic vaccinia virus enhances vaccine therapies of cancer. Mol Ther. 2011;19:650–657.
   PubMed Web of Science ®Google Scholar
• Li J, O’Malley M, Sampath P, et al. Expression of CCL19 from oncolytic vaccinia enhances immunotherapeutic potential while maintaining oncolytic activity. Neoplasia. 2012;14:1115.
   PubMed Web of Science ®Google Scholar
• Moon EK, Wang LS, Bekdache K, et al. Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines. Oncoimmunology. 2018;7:e1395997.
   PubMed Web of Science ®Google Scholar
• Liu Z, Ravindranathan R, Li J, et al. CXCL11-Armed oncolytic poxvirus elicits potent antitumor immunity and shows enhanced therapeutic efficacy. Oncoimmunology. 2016;5:e1091554.
   PubMed Web of Science ®Google Scholar
• Eckert EC, Nace RA, Tonne JM, et al. Generation of a tumor-specific chemokine gradient using oncolytic vesicular stomatitis virus encoding CXCL9. Mol Ther Oncolytics. 2020;16:63–74.
   PubMed Web of Science ®Google Scholar
• Chiu M, Armstrong EJL, Jennings V, et al. Combination therapy with oncolytic viruses and immune checkpoint inhibitors. Expert Opin Biol Ther. 2020;20:635–652.
   PubMed Web of Science ®Google Scholar
• Wu C, Wu M, Liang M, et al. A novel oncolytic virus engineered with PD-L1 scFv effectively inhibits tumor growth in a mouse model. Cell Mol Immunol. 2019;16:780–782.
   PubMed Web of Science ®Google Scholar
• Kleinpeter P, Fend L, Thioudellet C, et al. Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death −1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition. Oncoimmunology. 2016;5:e1220467.
   PubMed Web of Science ®Google Scholar
• Lin C, Ren W, Luo Y, et al. Intratumoral delivery of a PD-1-blocking scFv encoded in oncolytic HSV-1 promotes antitumor immunity and synergizes with TIGIT blockade. Cancer Immunol Res. 2020;8:632–647.
   PubMed Web of Science ®Google Scholar
• Engeland CE, Grossardt C, Veinalde R, et al. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol Ther. 2014;22:1949–1959.
   PubMed Web of Science ®Google Scholar
• Zhu Y, Hu X, Feng L, et al. Enhanced therapeutic efficacy of a novel oncolytic herpes simplex virus type 2 encoding an antibody against programmed cell death 1. Mol Ther Oncolytics. 2019;15:201–213.
   PubMed Web of Science ®Google Scholar
• Schiza A, Wenthe J, Mangsbo S, et al. Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients. J Transl Med. 2017;15:79.
   PubMed Web of Science ®Google Scholar
• Jiang H, Rivera-Molina Y, Gomez-Manzano C, et al. Oncolytic adenovirus and tumor-targeting immune modulatory therapy improve autologous cancer vaccination. Cancer Res. 2017;77:3894–3907.
   PubMed Web of Science ®Google Scholar
• Jiang H, Shin DH, Nguyen TT, et al. Localized treatment with oncolytic adenovirus delta-24-RGDOX induces systemic immunity against disseminated subcutaneous and intracranial melanomas. Clin Cancer Res. 2019;25:6801–6814.
   PubMed Web of Science ®Google Scholar
• Rivera-Molina Y, Jiang H, Fueyo J, et al. GITRL-armed Delta-24-RGD oncolytic adenovirus prolongs survival and induces anti-glioma immune memory. Neurooncol Adv. 2019;1:vdz009.
   PubMedGoogle Scholar
• Wenthe J, Naseri S, Hellström AC, et al. Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40. Cancer Gene Ther. 2020 May 1.DOI:10.1038/s41417-020-0176-9
   PubMed Web of Science ®Google Scholar
• Eriksson E, Milenova I, Wenthe J, et al. Shaping the tumor stroma and sparking immune activation by CD40 and 4-1BB signaling induced by an armed oncolytic virus. Clin Cancer Res. 2017;23:5846–5857.
   PubMed Web of Science ®Google Scholar
• Zamarin D, Holmgaard RB, Ricca J, et al. Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity. Nat Commun. 2017;8:14340.
   PubMed Web of Science ®Google Scholar
• Vijayakumar G, McCroskery S, Palese P. Engineering newcastle disease virus as an oncolytic vector for intratumoral delivery of immune checkpoint inhibitors and immunocytokines. J Virol. 2020;94:e016677–19.
   Web of Science ®Google Scholar
• Thomas S, Kuncheria L, Roulstone V, et al. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. J Immunother Cancer. 2019;7:214.
   PubMed Web of Science ®Google Scholar
• Guo ZS, Lotze MT, Zhu Z, et al. Bi- and tri-specific T cell engager-armed oncolytic viruses: next-generation cancer immunotherapy. Biomedicines. 2020;8:204.
   Web of Science ®Google Scholar
• Yu F, Wang X, Guo ZS, et al. T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol Ther. 2014;22:102–111.
   PubMed Web of Science ®Google Scholar
• Speck T, Heidbuechel JPW, Veinalde R, et al. Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors. Clin Cancer Res. 2018;24:2128–2137.
   PubMed Web of Science ®Google Scholar
• de Sostoa J, Fajardo CA, Moreno R, et al. Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager. J Immunother Cancer. 2019;7:19.
   PubMed Web of Science ®Google Scholar
• Freedman JD, Duffy MR, Lei-Rossmann J, et al. An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells. Cancer Res. 2018;78:6852–6865.
   PubMed Web of Science ®Google Scholar
• Scott EM, Jacobus EJ, Lyons B, et al. Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples. J Immunother Cancer. 2019;7:320.
   PubMed Web of Science ®Google Scholar
• Wing A, Fajardo CA, Posey AD Jr., et al. Improving CART-cell therapy of solid tumors with oncolytic virus-driven production of a bispecific T-cell engager. Cancer Immunol Res. 2018;6:605–616.
   PubMed Web of Science ®Google Scholar
• Bridle BW, Stephenson KB, Boudreau JE, et al. Potentiating cancer immunotherapy using an oncolytic virus. Mol Ther. 2010;18:1430–1439.
   PubMed Web of Science ®Google Scholar
• Pol JG, Zhang L, Bridle BW, et al. Maraba virus as a potent oncolytic vaccine vector. Mol Ther. 2014;22:420–429.
   PubMed Web of Science ®Google Scholar
• Pulido J, Kottke T, Thompson J, et al. Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat Biotechnol. 2012;30:337–343.
   PubMed Web of Science ®Google Scholar
• Castelo-Branco P, Passer BJ, Buhrman JS, et al. Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancer. Gene Ther. 2010;17:805–810.
   PubMed Web of Science ®Google Scholar
• Kennedy EM, Farkaly T, Behera P, et al. Abstract 1455: design of ONCR-177 base vector, a next generation oncolytic herpes simplex virus type-1, optimized for robust oncolysis, transgene expression and tumor-selective replication. Cancer Res. 2019;79(13 Supplement):1455.
   Web of Science ®Google Scholar
• Santos JM, Heiniö C, Cervera-Carrascon V, et al. Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity. J Immunother Cancer. 2020;8:e000188.
   PubMed Web of Science ®Google Scholar
• Champion BR, Besneux M, Patsalidou M, et al. Abstract 5013: NG-641: an oncolytic T-SIGn virus targeting cancer-associated fibroblasts in the stromal microenvironment of human carcinomas. Cancer Res. 2019;79(13 Supplement):5013.
   Web of Science ®Google Scholar
• Saha D, Martuza RL, Rabkin SD. Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell. 2017;32:253–267.
   PubMed Web of Science ®Google Scholar
• Malfitano AM, Di Somma S, Iannuzzi CA, et al. Virotherapy: from single agents to combinatorial treatments. Biochem Pharmacol. 2020;177:113986.
   PubMed Web of Science ®Google Scholar
• Phan M, Watson MF, Alain T, et al. Oncolytic viruses on drugs: achieving higher therapeutic efficacy. ACS Infect Dis. 2018;4:1448–1467.
   PubMed Web of Science ®Google Scholar
• Peng KW, Myers R, Greenslade A, et al. Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses. Gene Ther. 2013;20:255–261.
   PubMed Web of Science ®Google Scholar
• Zemp FJ, McKenzie BA, Lun X, et al. Cellular factors promoting resistance to effective treatment of glioma with oncolytic myxoma virus. Cancer Res. 2014;74:7260–7273.
   PubMed Web of Science ®Google Scholar
• Roulstone V, Khan K, Pandha HS, et al. Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors. Clin Cancer Res. 2015;21:1305–1312.
   PubMed Web of Science ®Google Scholar
• Burke MJ, Ahern C, Weigel BJ, et al. Phase I trial of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors: a report of the Children’s Oncology Group. Pediatr Blood Cancer. 2015;62:743–750.
   PubMed Web of Science ®Google Scholar
• Cerullo V, Diaconu I, Kangasniemi L, et al. Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus. Mol Ther. 2011;19:1737–1746.
   PubMed Web of Science ®Google Scholar
• Kanai R, Rabkin SD, Yip S, et al. Oncolytic virus-mediated manipulation of DNA damage responses: synergy with chemotherapy in killing glioblastoma stem cells. J Natl Cancer Inst. 2012;104:42–55.
   PubMedGoogle Scholar
• Saha D, Rabkin SD, Martuza RL. Temozolomide antagonizes oncolytic immunovirotherapy in glioblastoma. J Immunother Cancer. 2020;8:e000345.
   PubMed Web of Science ®Google Scholar
• Kleijn A, van den Bossche W, Haefner ES, et al. The sequence of Delta24-RGD and TMZ administration in malignant glioma affects the role of CD8(+)T cell anti-tumor activity. Mol Ther Oncolytics. 2017;5:11–19.
   PubMed Web of Science ®Google Scholar
• Conte M, De Palma R, Altucci L. HDAC inhibitors as epigenetic regulators for cancer immunotherapy. Int J Biochem Cell Biol. 2018;98:65–74.
   PubMed Web of Science ®Google Scholar
• Jennings VA, Scott GB, Rose AMS, et al. Potentiating oncolytic virus-induced immune-mediated tumor cell killing using histone deacetylase inhibition. Mol Ther. 2019;27:1139–1152.
   PubMed Web of Science ®Google Scholar
• Nguyên TL, Abdelbary H, Arguello M, et al. Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis. Proc Natl Acad Sci U S A. 2008;105:14981–14986.
   PubMed Web of Science ®Google Scholar
• Bridle BW, Chen L, Lemay CG, et al. HDAC inhibition suppresses primary immune responses, enhances secondary immune responses, and abrogates autoimmunity during tumor immunotherapy. Mol Ther. 2013;21:887–894.
   PubMed Web of Science ®Google Scholar
• Nguyen A, Ho L, Workenhe ST, et al. HDACi delivery reprograms tumor-infiltrating myeloid cells to eliminate antigen-loss variants. Cell Rep. 2018;24:642–654.
   PubMed Web of Science ®Google Scholar
• Chesney J, Puzanov I, Collichio F, et al. Randomized, open-label Phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol. 2018;36:1658–1667.
   PubMed Web of Science ®Google Scholar
• Samson A, Scott KJ, Taggart D, et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med. 2018;10:eaam7577.
   PubMed Web of Science ®Google Scholar
• Zamarin D, Ricca JM, Sadekova S, et al. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J Clin Invest. 2018;128:1413–1428.
   PubMed Web of Science ®Google Scholar
• Rojas JJ, Sampath P, Hou W, et al. Defining effective combinations of immune checkpoint blockade and oncolytic virotherapy. Clin Cancer Res. 2015;21:5543–5551.
   PubMed Web of Science ®Google Scholar
• Liu Z, Ravindranathan R, Kalinski P, et al. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat Commun. 2017;8:14754.
   PubMed Web of Science ®Google Scholar
• Chon HJ, Lee WS, Yang H, et al. Tumor microenvironment remodeling by intratumoral oncolytic vaccinia virus enhances the efficacy of immune-checkpoint blockade. Clin Cancer Res. 2019;25:1612–1623.
   PubMed Web of Science ®Google Scholar
• Durham NM, Mulgrew K, McGlinchey K, et al. Oncolytic VSV primes differential responses to immuno-oncology therapy. Mol Ther. 2017;25:1917–1932.
   PubMed Web of Science ®Google Scholar
• John LB, Howland LJ, Flynn JK, et al. Oncolytic virus and anti-4-1BB combination therapy elicits strong antitumor immunity against established cancer. Cancer Res. 2012;72:1651–1660.
   PubMed Web of Science ®Google Scholar
• Weichselbaum RR, Liang H, Deng L, et al. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14:365–379.
   PubMed Web of Science ®Google Scholar
• Touchefeu Y, Vassaux G, Harrington KJ. Oncolytic viruses in radiation oncology. Radiother Oncol. 2011;99:262–270.
   PubMed Web of Science ®Google Scholar
• Twigger K, Vidal L, White CL, et al. Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy. Clin Cancer Res. 2008;14:912–923.
   PubMed Web of Science ®Google Scholar
• Wilkinson MJ, Smith HG, McEntee G, et al. Oncolytic vaccinia virus combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis. Oncotarget. 2016;7:81208–81222.
   PubMedGoogle Scholar
• Salzwedel AO, Han J, LaRocca CJ, et al. Combination of interferon-expressing oncolytic adenovirus with chemotherapy and radiation is highly synergistic in hamster model of pancreatic cancer. Oncotarget. 2018;9:18041–18052.
   PubMedGoogle Scholar
• Kim W, Seong J, Oh HJ, et al. A novel combination treatment of armed oncolytic adenovirus expressing IL-12 and GM-CSF with radiotherapy in murine hepatocarcinoma. J Radiat Res. 2011;52:646–654.
   PubMed Web of Science ®Google Scholar
• Udayakumar TS, Betancourt DM, Ahmad A, et al. Radiation attenuates prostate tumor antiviral responses to vesicular stomatitis virus containing IFNβ, resulting in pronounced antitumor systemic immune responses. Mol Cancer Res. 2020;18:1232–1243.
   PubMed Web of Science ®Google Scholar
• Vijayakumar G, Palese P, Goff PH. Oncolytic Newcastle disease virus expressing a checkpoint inhibitor as a radioenhancing agent for murine melanoma. EBioMedicine. 2019;49:96–105.
   PubMed Web of Science ®Google Scholar
• Harrington KJ, Vile RG, Melcher A, et al. Clinical trials with oncolytic reovirus: moving beyond phase I into combinations with standard therapeutics. Cytokine Growth Factor Rev. 2010;21:91–98.
   PubMed Web of Science ®Google Scholar
• Sarén T, Ramachandran M, Martikainen M, et al. Insertion of the Type-I IFN decoy receptor B18R in a miRNA-tagged Semliki forest virus improves oncolytic capacity but results in neurotoxicity. Mol Ther Oncolytics. 2017;7:67–75.
   PubMed Web of Science ®Google Scholar
• Nosaki K, Hamada K, Takashima Y, et al. A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity. Mol Ther Oncolytics. 2016;3:16022.
   PubMed Web of Science ®Google Scholar
• Kowalsky SJ, Liu Z, Feist M, et al. Superagonist IL-15-armed oncolytic virus elicits potent antitumor immunity and therapy that are enhanced with PD-1 blockade. Mol Ther. 2018;26:2476–2486.
   PubMed Web of Science ®Google Scholar
• Tosic V, Thomas DL, Kranz DM, et al. Myxoma virus expressing a fusion protein of Interleukin-15 (IL15) and IL15 receptor alpha has enhanced antitumor activity. Plos One. 2014;9:e109801.
   PubMed Web of Science ®Google Scholar
• LaRocca CJ, Han J, Gavrikova T, et al. Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer. Surgery. 2015;157:888–898.
   PubMed Web of Science ®Google Scholar
• Oh E, Hong J, Kwon OJ, et al. A hypoxia- and telomerase-responsive oncolytic adenovirus expressing secretable trimeric TRAIL triggers tumour-specific apoptosis and promotes viral dispersion in TRAIL-resistant glioblastoma. Sci Rep. 2018;8:1420.
   PubMedGoogle Scholar
• Jahan N, Lee JM, Shah K, et al. Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus. Int J Cancer. 2017;141:1671–1681.
   PubMed Web of Science ®Google Scholar
• Wu Y, He J, Geng J, et al. Recombinant Newcastle disease virus expressing human TRAIL as a potential candidate for hepatoma therapy. Eur J Pharmacol. 2017;802:85–92.
   PubMed Web of Science ®Google Scholar