Development of oncolytic virotherapy: from genetic modification to combination therapy

Abstract

Oncolytic virotherapy (OVT) is a novel form of immunotherapy using natural or genetically modified viruses to selectively replicate in and kill malignant cells. Many genetically modified oncolytic viruses (OVs) with enhanced tumor targeting, antitumor efficacy, and safety have been generated, and some of which have been assessed in clinical trials. Combining OVT with other immunotherapies can remarkably enhance the antitumor efficacy. In this work, we review the use of wild-type viruses in OVT and the strategies for OV genetic modification. We also review and discuss the combinations of OVT with other immunotherapies.

Keywords

immunotherapy / oncolytic virus / genetic modification / immune checkpoint blockade / chimeric antigen receptor T cell

References

[1] Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 2016; 13(5): 273–290

[2] Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 2015; 125(9): 3335–3337

[3] Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov 2015; 14(9): 642–662

[4] Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res 2014; 2(4): 295–300

[5] Yu F, Wang X, Guo ZS, Bartlett DL, Gottschalk SM, Song XT. T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol Ther 2014; 22(1): 102–111

[6] Wang P, Li X, Wang J, Gao D, Li Y, Li H, Chu Y, Zhang Z, Liu H, Jiang G, Cheng Z, Wang S, Dong J, Feng B, Chard LS, Lemoine NR, Wang Y. Re-designing interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. Nat Commun 2017; 8(1): 1395

[7] Samson A, Scott KJ, Taggart D, West EJ, Wilson E, Nuovo GJ, Thomson S, Corns R, Mathew RK, Fuller MJ, Kottke TJ, Thompson JM, Ilett EJ, Cockle JV, van Hille P, Sivakumar G, Polson ES, Turnbull SJ, Appleton ES, Migneco G, Rose AS, Coffey MC, Beirne DA, Collinson FJ, Ralph C, Alan Anthoney D, Twelves CJ, Furness AJ, Quezada SA, Wurdak H, Errington-Mais F, Pandha H, Harrington KJ, Selby PJ, Vile RG, Griffin SD, Stead LF, Short SC, Melcher AA. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med 2018; 10(422): eaam7577

[8] Geletneky K, Hajda J, Angelova AL, Leuchs B, Capper D, Bartsch AJ, Neumann J-O, Schöning T, Hüsing J, Beelte B, Kiprianova I, Roscher M, Bhat R, von Deimling A, Brück W, Just A, Frehtman V, Löbhard S, Terletskaia-Ladwig E, Fry J, Jochims K, Daniel V, Krebs O, Dahm M, Huber B, Unterberg A, Rommelaere J. Oncolytic H-1 parvovirus shows safety and signs of immunogenic activity in a first phase I/IIa glioblastoma trial. Mol Ther 2017; 25(12): 2620–2634

[9] Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, Merghoub T, Wolchok JD, Allison JP. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 2014; 6(226): 226ra32

[10] Bourgeois-Daigneault MC, Roy DG, Aitken AS, El Sayes N, Martin NT, Varette O, Falls T, St-Germain LE, Pelin A, Lichty BD, Stojdl DF, Ungerechts G, Diallo JS, Bell JC. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci Transl Med 2018; 10(422): eaao1641

[11] Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, Prabhu SS, Rao G, Fuller GN, Aldape KD, Gumin J, Vence LM, Wistuba I, Rodriguez-Canales J, Villalobos PA, Dirven CMF, Tejada S, Valle RD, Alonso MM, Ewald B, Peterkin JJ, Tufaro F, Fueyo J. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol 2018; 36(14): 1419–1427

[12] Packiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL 3rd, Clark W, Kroeger M, Dumbadze I, Chamie K, Kader AK, Curran D, Gutheil J, Kuan A, Yeung AW, Steinberg GD. 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(10): 440–447

[13] Mell LK, Brumund KT, Daniels GA, Advani SJ, Zakeri K, Wright ME, Onyeama SJ, Weisman RA, Sanghvi PR, Martin PJ, Szalay AA. Phase I trial of intravenous oncolytic vaccinia virus (GL-ONC1) with cisplatin and radiotherapy in patients with locoregionally advanced head and neck carcinoma. Clin Cancer Res 2017; 23(19): 5696–5702

[14] Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim HY, Chung HC, Kim CW, Burke J, Lencioni R, Hickman T, Moon A, Lee YS, Kim MK, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney C, Bell JC, Rhee BG, Patt R, Hwang TH, Kirn DH. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 2013; 19(3): 329–336

[15] Kaufman HL, Bines SD. OPTIM trial: a phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol 2010; 6(6): 941–949

[16] Kasuya H, Kodera Y, Nakao A, Yamamura K, Gewen T, Zhiwen W, Hotta Y, Yamada S, Fujii T, Fukuda S, Tsurumaru N, Kuwahara T, Kikumori T, Koide Y, Fujimoto Y, Nakashima T, Hirooka Y, Shiku H, Tanaka M, Takesako K, Kondo T, Aleksic B, Kawashima H, Goto H, Nishiyama Y. Phase I dose-escalation clinical trial of HF10 oncolytic herpes virus in 17 Japanese patients with advanced cancer. Hepatogastroenterology 2014; 61(131): 599–605

[17] Nüesch JP, Lacroix J, Marchini A, Rommelaere J. Molecular pathways: rodent parvoviruses--mechanisms of oncolysis and prospects for clinical cancer treatment. Clin Cancer Res 2012; 18(13): 3516–3523

[18] Noonan AM, Farren MR, Geyer SM, Huang Y, Tahiri S, Ahn D, Mikhail S, Ciombor KK, Pant S, Aparo S, Sexton J, Marshall JL, Mace TA, Wu CS, El-Rayes B, Timmers CD, Zwiebel J, Lesinski GB, Villalona-Calero MA, Bekaii-Saab TS. Randomized phase 2 trial of the oncolytic virus Pelareorep (Reolysin) in upfront treatment of metastatic pancreatic adenocarcinoma. Mol Ther 2016; 24(6): 1150–1158

[19] Mahalingam D, Fountzilas C, Moseley J, Noronha N, Tran H, Chakrabarty R, Selvaggi G, Coffey M, Thompson B, Sarantopoulos J. A phase II study of REOLYSIN^® (pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma. Cancer Chemother Pharmacol 2017; 79(4): 697–703

[20] Tayeb S, Zakay-Rones Z, Panet A. Therapeutic potential of oncolytic Newcastle disease virus: a critical review. Oncolytic Virother 2015; 4: 49–62

[21] Dispenzieri A, Tong C, LaPlant B, Lacy MQ, Laumann K, Dingli D, Zhou Y, Federspiel MJ, Gertz MA, Hayman S, Buadi F, O’Connor M, Lowe VJ, Peng KW, Russell SJ. 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(12): 2791–2798

[22] Niemann J, Kühnel F. Oncolytic viruses: adenoviruses. Virus Genes 2017; 53(5): 700–706

[23] Torres-Domínguez LE, McFadden G. Poxvirus oncolytic virotherapy. Expert Opin Biol Ther 2019; 19(6): 561–573

[24] Watanabe D, Goshima F. Oncolytic virotherapy by HSV. Adv Exp Med Biol 2018; 1045: 63–84

[25] Angelova AL, Barf M, Geletneky K, Unterberg A, Rommelaere J. Immunotherapeutic potential of oncolytic H-1 parvovirus: hints of glioblastoma microenvironment conversion towards immunogenicity. Viruses 2017; 9(12): 382

[26] Msaouel P, Opyrchal M, Dispenzieri A, Peng KW, Federspiel MJ, Russell SJ, Galanis E. Clinical trials with oncolytic measles virus: current status and future prospects. Curr Cancer Drug Targets 2018; 18(2): 177–187

[27] Schirrmacher V. Fifty years of clinical application of Newcastle disease virus: time to celebrate! Biomedicines 2016; 4(3): 16

[28] Durham NM, Mulgrew K, McGlinchey K, Monks NR, Ji H, Herbst R, Suzich J, Hammond SA, Kelly EJ. Oncolytic VSV primes differential responses to immuno-oncology therapy. Mol Ther 2017; 25(8): 1917–1932

[29] Brown MC, Dobrikova EY, Dobrikov MI, Walton RW, Gemberling SL, Nair SK, Desjardins A, Sampson JH, Friedman HS, Friedman AH, Tyler DS, Bigner DD, Gromeier M. Oncolytic polio virotherapy of cancer. Cancer 2014; 120(21): 3277–3286

[30] Bradley S, Jakes AD, Harrington K, Pandha H, Melcher A, Errington-Mais F. Applications of coxsackievirus A21 in oncology. Oncolytic Virother 2014; 3: 47–55

[31] Bourhill T, Mori Y, Rancourt DE, Shmulevitz M, Johnston RN. Going (Reo)Viral: factors promoting successful reoviral oncolytic infection. Viruses 2018; 10(8): 421

[32] Wheelock EF, Dingle JH. Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 1964; 271(13): 645–651

[33] Zygiert Z. Hodgkin’s disease: remissions after measles. Lancet 1971; 297(7699): 593

[34] Toolan HW, Saunders EL, Southam CM, Moore AE, Levin AG. H-1 virus viremia in the human. Proc Soc Exp Biol Med 1965; 119(3): 711–715

[35] Howells A, Marelli G, Lemoine NR, Wang Y. Oncolytic viruses-interaction of virus and tumor cells in the battle to eliminate cancer. Front Oncol 2017; 7(195): 195

[36] Aghi M, Martuza RL. Oncolytic viral therapies—the clinical experience. Oncogene 2005; 24(52): 7802–7816

[37] Eissa IR, Bustos-Villalobos I, Ichinose T, Matsumura S, Naoe Y, Miyajima N, Morimoto D, Mukoyama N, Zhiwen W, Tanaka M, Hasegawa H, Sumigama S, Aleksic B, Kodera Y, Kasuya H. The current status and future prospects of oncolytic viruses in clinical trials against melanoma, glioma, pancreatic, and breast cancers. Cancers (Basel) 2018; 10(10): 356

[38] Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991; 252(5007): 854–856

[39] Liang M. Oncorine, the world first oncolytic virus medicine and its update in China. Curr Cancer Drug Targets 2018; 18(2): 171–176

[40] Wei D, Xu J, Liu XY, Chen ZN, Bian H. Fighting cancer with viruses: oncolytic virus therapy in China. Hum Gene Ther 2018; 29(2): 151–159

[41] Kohlhapp FJ, Zloza A, Kaufman HL. Talimogene laherparepvec (T-VEC) as cancer immunotherapy. Drugs Today (Barc) 2015; 51(9): 549–558

[42] Conry RM, Westbrook B, McKee S, Norwood TG. Talimogene laherparepvec: first in class oncolytic virotherapy. Hum Vaccin Immunother 2018; 14(4): 839–846

[43] Bourgeois-Daigneault MC, St-Germain LE, Roy DG, Pelin A, Aitken AS, Arulanandam R, Falls T, Garcia V, Diallo JS, Bell JC. Combination of paclitaxel and MG1 oncolytic virus as a successful strategy for breast cancer treatment. Breast Cancer Res 2016; 18(1): 83

[44] Garofalo M, Saari H, Somersalo P, Crescenti D, Kuryk L, Aksela L, Capasso C, Madetoja M, Koskinen K, Oksanen T, Mäkitie A, Jalasvuori M, Cerullo V, Ciana P, Yliperttula M. Antitumor effect of oncolytic virus and paclitaxel encapsulated in extracellular vesicles for lung cancer treatment. J Control Release 2018; 283: 223–234

[45] Binz E, Berchtold S, Beil J, Schell M, Geisler C, Smirnow I, Lauer UM. Chemovirotherapy of pancreatic adenocarcinoma by combining oncolytic vaccinia virus GLV-1h68 with nab-paclitaxel plus gemcitabine. Mol Ther Oncolytics 2017; 6: 10–21

[46] Wilkinson MJ, Smith HG, McEntee G, Kyula-Currie J, Pencavel TD, Mansfield DC, Khan AA, Roulstone V, Hayes AJ, Harrington KJ. Oncolytic vaccinia virus combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis. Oncotarget 2016; 7(49): 81208–81222

[47] O’Cathail SM, Pokrovska TD, Maughan TS, Fisher KD, Seymour LW, Hawkins MA. Combining oncolytic adenovirus with radiation—a paradigm for the future of radiosensitization. Front Oncol 2017; 7: 153

[48] McKenzie BA, Zemp FJ, Pisklakova A, Narendran A, McFadden G, Lun X, Kenchappa RS, Kurz EU, Forsyth PA. In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells. Neuro-oncol 2015; 17(8): 1086–1094

[49] Dornan MH, Krishnan R, Macklin AM, Selman M, El Sayes N, Son HH, Davis C, Chen A, Keillor K, Le PJ, Moi C, Ou P, Pardin C, Canez CR, Le Boeuf F, Bell JC, Smith JC, Diallo JS, Boddy CN. First-in-class small molecule potentiators of cancer virotherapy. Sci Rep 2016; 6(1): 26786

[50] Ajina A, Maher J. Prospects for combined use of oncolytic viruses and CAR T-cells. J Immunother Cancer 2017; 5(1): 90

[51] Chen CY, Hutzen B, Wedekind MF, Cripe TP. Oncolytic virus and PD-1/PD-L1 blockade combination therapy. Oncolytic Virother 2018; 7: 65–77

[52] Russell L, Peng KW, Russell SJ, Diaz RM. Oncolytic viruses: priming time for cancer immunotherapy. BioDrugs 2019; 33(5): 485–501

[53] Kelly KR, Espitia CM, Zhao W, Wu K, Visconte V, Anwer F, Calton CM, Carew JS, Nawrocki ST. Oncolytic reovirus sensitizes multiple myeloma cells to anti-PD-L1 therapy. Leukemia 2018; 32(1): 230–233

[54] Achard C, Surendran A, Wedge ME, Ungerechts G, Bell J, Ilkow CS. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy. EBioMedicine 2018; 31: 17–24

[55] Au GG, Lincz LF, Enno A, Shafren DR. Oncolytic coxsackievirus A21 as a novel therapy for multiple myeloma. Br J Haematol 2007; 137(2): 133–141

[56] Geiss C, Kis Z, Leuchs B, Frank-Stöhr M, Schlehofer JR, Rommelaere J, Dinsart C, Lacroix J. Preclinical testing of an oncolytic parvovirus: standard protoparvovirus H-1PV efficiently induces osteosarcoma cell lysis in vitro. Viruses 2017; 9(10): 301

[57] Vidal L, Pandha HS, Yap TA, White CL, Twigger K, Vile RG, Melcher A, Coffey M, Harrington KJ, DeBono JS. A phase I study of intravenous oncolytic reovirus type 3 Dearing in patients with advanced cancer. Clin Cancer Res 2008; 14(21): 7127–7137

[58] Annels NE, Mansfield D, Arif M, Ballesteros-Merino C, Simpson GR, Denyer M, Sandhu SS, Melcher AA, Harrington KJ, Davies B, Au G, Grose M, Bagwan I, Fox B, Vile R, Mostafid H, Shafren D, Pandha HS. Phase I trial of an ICAM-1-targeted immunotherapeutic-coxsackievirus A21 (CVA21) as an oncolytic agent against non muscle-invasive bladder cancer. Clin Cancer Res 2019; 25(19): 5818–5831

[59] Annels NE, Mansfield D, Arif M, Ballesteros-Merino C, Simpson GR, Denyer M, Sandhu SS, Melcher AA, Harrington KJ, Davies B, Au G, Grose M, Bagwan I, Fox B, Vile R, Mostafid H, Shafren D, Pandha HS. Viral targeting of non-muscle-invasive bladder cancer and priming of antitumor immunity following intravesical coxsackievirus A21. Clin Cancer Res 2019 Aug. 14. [Epub ahead of print] doi: 10.1158/1078-0432.CCR-18-4022

[60] Andtbacka RHI, Curti BD, Kaufman H, Daniels GA, Nemunaitis JJ, Spitler LE, Hallmeyer S, Lutzky J, Schultz SM, Whitman ED, Zhou K, Karpathy R, Weisberg JI, Grose M, Shafren D. Final data from CALM: a phase II study of coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma. J Clin Oncol 2015; 33(15_suppl): 9030

[61] Angelova AL, Witzens-Harig M, Galabov AS, Rommelaere J. The oncolytic virotherapy era in cancer management: prospects of applying H-1 parvovirus to treat blood and solid cancers. Front Oncol 2017; 7: 93

[62] Garant KA, Shmulevitz M, Pan L, Daigle RM, Ahn DG, Gujar SA, Lee PWK. Oncolytic reovirus induces intracellular redistribution of Ras to promote apoptosis and progeny virus release. Oncogene 2016; 35(6): 771–782

[63] Sborov DW, Nuovo GJ, Stiff A, Mace T, Lesinski GB, Benson DM Jr, Efebera YA, Rosko AE, Pichiorri F, Grever MR, Hofmeister CC. A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma. Clin Cancer Res 2014; 20(23): 5946–5955

[64] Mahalingam D, Goel S, Aparo S, Patel Arora S, Noronha N, Tran H, Chakrabarty R, Selvaggi G, Gutierrez A, Coffey M, Nawrocki ST, Nuovo G, Mita MM. A phase II study of Pelareorep (REOLYSIN^®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. Cancers (Basel) 2018; 10(6): 160

[65] Galanis E, Markovic SN, Suman VJ, Nuovo GJ, Vile RG, Kottke TJ, Nevala WK, Thompson MA, Lewis JE, Rumilla KM, Roulstone V, Harrington K, Linette GP, Maples WJ, Coffey M, Zwiebel J, Kendra K. Phase II trial of intravenous administration of Reolysin(®) (Reovirus Serotype-3-dearing Strain) in patients with metastatic melanoma. Mol Ther 2012; 20(10): 1998–2003

[66] Stiff A, Caserta E, Sborov DW, Nuovo GJ, Mo X, Schlotter SY, Canella A, Smith E, Badway J, Old M, Jaime-Ramirez AC, Yan P, Benson DM, Byrd JC, Baiocchi R, Kaur B, Hofmeister CC, Pichiorri F. Histone deacetylase inhibitors enhance the therapeutic potential of reovirus in multiple myeloma. Mol Cancer Ther 2016; 15(5):830–841

[67] Ramachandran M, Yu D, Dyczynski M, Baskaran S, Zhang L, Lulla A, Lulla V, Saul S, Nelander S, Dimberg A, Merits A, Leja-Jarblad J, Essand M. Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically delivered triple microRNA-detargeted oncolytic Semliki Forest Virus. Clin Cancer Res 2017; 23(6): 1519–1530

[68] Quetglas JI, Labiano S, Aznar MA, Bolaños E, Azpilikueta A, Rodriguez I, Casales E, Sánchez-Paulete AR, Segura V, Smerdou C, Melero I. Virotherapy with a Semliki Forest virus-based vector encoding IL12 synergizes with PD-1/PD-L1 blockade. Cancer Immunol Res 2015; 3(5): 449–454

[69] Huang PY, Guo JH, Hwang LH. Oncolytic Sindbis virus targets tumors defective in the interferon response and induces significant bystander antitumor immunity in vivo. Mol Ther 2012; 20(2): 298–305

[70] Lin Y, Zhang H, Liang J, Li K, Zhu W, Fu L, Wang F, Zheng X, Shi H, Wu S, Xiao X, Chen L, Tang L, Yan M, Yang X, Tan Y, Qiu P, Huang Y, Yin W, Su X, Hu H, Hu J, Yan G. Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers. Proc Natl Acad Sci U S A 2014; 111(42): E4504–E4512

[71] Hu C, Liu Y, Lin Y, Liang JK, Zhong WW, Li K, Huang WT, Wang DJ, Yan GM, Zhu WB, Qiu JG, Gao X. Intravenous injections of the oncolytic virus M1 as a novel therapy for muscle-invasive bladder cancer. Cell Death Dis 2018; 9(3): 274

[72] Liang J, Guo L, Li K, Xiao X, Zhu W, Zheng X, Hu J, Zhang H, Cai J, Yu Y, Tan Y, Li C, Liu X, Hu C, Liu Y, Qiu P, Su X, He S, Lin Y, Yan G. Inhibition of the mevalonate pathway enhances cancer cell oncolysis mediated by M1 virus. Nat Commun 2018; 9(1): 1524

[73] Zhang H, Lin Y, Li K, Liang J, Xiao X, Cai J, Tan Y, Xing F, Mai J, Li Y, Chen W, Sheng L, Gu J, Zhu W, Yin W, Qiu P, Su X, Lu B, Tian X, Liu J, Lu W, Dou Y, Huang Y, Hu B, Kang Z, Gao G, Mao Z, Cheng SY, Lu L, Bai XT, Gong S, Yan G, Hu J. Naturally existing oncolytic virus M1 is nonpathogenic for the nonhuman primates after multiple rounds of repeated intravenous injections. Hum Gene Ther 2016; 27(9): 700–711

[74] Zhang H, Li K, Lin Y, Xing F, Xiao X, Cai J, Zhu W, Liang J, Tan Y, Fu L, Wang F, Yin W, Lu B, Qiu P, Su X, Gong S, Bai X, Hu J, Yan G. Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma. Sci Transl Med 2017; 9(404): eaam7996

[75] Xiao X, Liang J, Huang C, Li K, Xing F, Zhu W, Lin Z, Xu W, Wu G, Zhang J, Lin X, Tan Y, Cai J, Hu J, Chen X, Huang Y, Qin Z, Qiu P, Su X, Chen L, Lin Y, Zhang H, Yan G. DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage. Nat Commun 2018; 9(1): 4342

[76] Choi AH, O’Leary MP, Fong Y, Chen NG. From benchtop to bedside: a review of oncolytic virotherapy. Biomedicines 2016; 4(3): 18

[77] Maroun J, Muñoz-Alía M, Ammayappan A, Schulze A, Peng KW, Russell S. Designing and building oncolytic viruses. Future Virol 2017; 12(4):193–213

[78] Jhawar SR, Thandoni A, Bommareddy PK, Hassan S, Kohlhapp FJ, Goyal S, Schenkel JM, Silk AW, Zloza A. Oncolytic viruses-natural and genetically engineered cancer immunotherapies. Front Oncol 2017; 7: 202

[79] Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol 2018; 18(8): 498–513

[80] Miest TS, Cattaneo R. New viruses for cancer therapy: meeting clinical needs. Nat Rev Microbiol 2014; 12(1): 23–34

[81] Stepanenko AA, Chekhonin VP. Tropism and transduction of oncolytic adenovirus 5 vectors in cancer therapy: focus on fiber chimerism and mosaicism, hexon and pIX. Virus Res 2018; 257: 40–51

[82] Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics 2017; 14(2): 333–344

[83] Betancourt D, Ramos JC, Barber GN. Retargeting oncolytic vesicular stomatitis virus to human T-cell lymphotropic virus type 1-associated adult T-cell leukemia. J Virol 2015; 89(23): 11786–11800

[84] Leoni V, Vannini A, Gatta V, Rambaldi J, Sanapo M, Barboni C, Zaghini A, Nanni P, Lollini PL, Casiraghi C, Campadelli-Fiume G. A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors. PLoS Pathog 2018; 14(8): e1007209

[85] Menotti L, Cerretani A, Hengel H, Campadelli-Fiume G. Construction of a fully retargeted herpes simplex virus 1 recombinant capable of entering cells solely via human epidermal growth factor receptor 2. J Virol 2008; 82(20): 10153–10161

[86] Alessandrini F, Menotti L, Avitabile E, Appolloni I, Ceresa D, Marubbi D, Campadelli-Fiume G, Malatesta P. Eradication of glioblastoma by immuno-virotherapy with a retargeted oncolytic HSV in a preclinical model. Oncogene 2019; 38(23): 4467–4479

[87] Shibata T, Uchida H, Shiroyama T, Okubo Y, Suzuki T, Ikeda H, Yamaguchi M, Miyagawa Y, Fukuhara T, Cohen JB, Glorioso JC, Watabe T, Hamada H, Tahara H. Development of an oncolytic HSV vector fully retargeted specifically to cellular EpCAM for virus entry and cell-to-cell spread. Gene Ther 2016; 23(6): 479–488

[88] Uchida H, Marzulli M, Nakano K, Goins WF, Chan J, Hong CS, Mazzacurati L, Yoo JY, Haseley A, Nakashima H, Baek H, Kwon H, Kumagai I, Kuroki M, Kaur B, Chiocca EA, Grandi P, Cohen JB, Glorioso JC. Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Mol Ther 2013; 21(3): 561–569

[89] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646–674

[90] Pikor LA, Bell JC, Diallo JS. Oncolytic viruses: exploiting cancer’s deal with the devil. Trends Cancer 2015; 1(4): 266–277

[91] Kohlhapp FJ, Kaufman HL. Molecular pathways: mechanism of action for Talimogene Laherparepvec, a new oncolytic virus immunotherapy. Clin Cancer Res 2016; 22(5): 1048–1054

[92] Martínez-Vélez N, Xipell E, Vera B, Acanda de la Rocha A, Zalacain M, Marrodán L, Gonzalez-Huarriz M, Toledo G, Cascallo M, Alemany R, Patiño A, Alonso MM. The oncolytic adenovirus VCN-01 as therapeutic approach against pediatric osteosarcoma. Clin Cancer Res 2016; 22(9): 2217–2225

[93] Garant KA, Shmulevitz M, Pan L, Daigle RM, Ahn DG, Gujar SA, Lee PW. Oncolytic reovirus induces intracellular redistribution of Ras to promote apoptosis and progeny virus release. Oncogene 2016; 35(6): 771–782

[94] Lin WH, Yeh SH, Yang WJ, Yeh KH, Fujiwara T, Nii A, Chang SS, Chen PJ. Telomerase-specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice. Int J Cancer 2013; 132(6): 1451–1462

[95] Li JM, Kao KC, Li LF, Yang TM, Wu CP, Horng YM, Jia WW, Yang CT. MicroRNA-145 regulates oncolytic herpes simplex virus-1 for selective killing of human non-small cell lung cancer cells. Virol J 2013; 10(1): 241

[96] Fujiwara T, Shirakawa Y, Kagawa S. Telomerase-specific oncolytic virotherapy for human gastrointestinal cancer. Expert Rev Anticancer Ther 2011; 11(4): 525–532

[97] Hardcastle J, Kurozumi K, Chiocca EA, Kaur B. Oncolytic viruses driven by tumor-specific promoters. Curr Cancer Drug Targets 2007; 7(2): 181–189

[98] Zhang W, Ge K, Zhao Q, Zhuang X, Deng Z, Liu L, Li J, Zhang Y, Dong Y, Zhang Y, Zhang S, Liu B. A novel oHSV-1 targeting telomerase reverse transcriptase-positive cancer cells via tumor-specific promoters regulating the expression of ICP4. Oncotarget 2015; 6(24): 20345–20355

[99] Taki M, Kagawa S, Nishizaki M, Mizuguchi H, Hayakawa T, Kyo S, Nagai K, Urata Y, Tanaka N, Fujiwara T. Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 (‘Telomelysin-RGD’). Oncogene 2005; 24(19): 3130–3140

[100] Huang P, Kaku H, Chen J, Kashiwakura Y, Saika T, Nasu Y, Urata Y, Fujiwara T, Watanabe M, Kumon H. Potent antitumor effects of combined therapy with a telomerase-specific, replication-competent adenovirus (OBP-301) and IL-2 in a mouse model of renal cell carcinoma. Cancer Gene Ther 2010; 17(7): 484–491

[101] Shayestehpour M, Moghim S, Salimi V, Jalilvand S, Yavarian J, Romani B, Mokhtari-Azad T. Targeting human breast cancer cells by an oncolytic adenovirus using microRNA-targeting strategy. Virus Res 2017; 240: 207–214

[102] Leber MF, Baertsch MA, Anker SC, Henkel L, Singh HM, Bossow S, Engeland CE, Barkley R, Hoyler B, Albert J, Springfeld C, Jäger D, von Kalle C, Ungerechts G. Enhanced control of oncolytic measles virus using microRNA target sites. Mol Ther Oncolytics 2018; 9: 30–40

[103] Leber MF, Bossow S, Leonard VH, Zaoui K, Grossardt C, Frenzke M, Miest T, Sawall S, Cattaneo R, von Kalle C, Ungerechts G. MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism. Mol Ther 2011; 19(6): 1097–1106

[104] McCart JA, Ward JM, Lee J, Hu Y, Alexander HR, Libutti SK, Moss B, Bartlett DL. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res 2001; 61(24): 8751–8757

[105] Badrinath N, Heo J, Yoo SY. Viruses as nanomedicine for cancer. Int J Nanomedicine 2016; 11: 4835–4847

[106] Kanai R, Zaupa C, Sgubin D, Antoszczyk SJ, Martuza RL, Wakimoto H, Rabkin SD. Effect of g34.5 deletions on oncolytic herpes simplex virus activity in brain tumors. J Virol 2012; 86(8): 4420–4431

[107] McKie EA, MacLean AR, Lewis AD, Cruickshank G, Rampling R, Barnett SC, Kennedy PGE, Brown SM. Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours—evaluation of a potentially effective clinical therapy. Br J Cancer 1996; 74(5): 745–752

[108] Kirn DH, Thorne SH. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat Rev Cancer 2009; 9(1): 64–71

[109] Pease DF, Kratzke RA. Oncolytic viral therapy for mesothelioma. Front Oncol 2017; 7: 179

[110] Jefferson A, Cadet VE, Hielscher A. The mechanisms of genetically modified vaccinia viruses for the treatment of cancer. Crit Rev Oncol Hematol 2015; 95(3): 407–416

[111] Lauer UM, Schell M, Beil J, Berchtold S, Koppenhöfer U, Glatzle J, Königsrainer A, Möhle R, Nann D, Fend F, Pfannenberg C, Bitzer M, Malek NP. Phase I study of oncolytic vaccinia virus GL-ONC1 in patients with peritoneal carcinomatosis. Clin Cancer Res 2018; 24(18): 4388–4398

[112] Johnson DB, Puzanov I, Kelley MC. Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma. Immunotherapy 2015; 7(6): 611–619

[113] Grigg C, Blake Z, Gartrell R, Sacher A, Taback B, Saenger Y. Talimogene laherparepvec (T-Vec) for the treatment of melanoma and other cancers. Semin Oncol 2016; 43(6): 638–646

[114] Masoud SJ, Hu JB, Beasley GM, Stewart JH 4th, Mosca PJ. Efficacy of Talimogene Laherparepvec (T-VEC) therapy in patients with in-transit melanoma metastasis decreases with increasing lesion size. Ann Surg Oncol 2019; 26(13): 4633–4641

[115] Zhu Z, Gorman MJ, McKenzie LD, Chai JN, Hubert CG, Prager BC, Fernandez E, Richner JM, Zhang R, Shan C, Tycksen E, Wang X, Shi PY, Diamond MS, Rich JN, Chheda MG. Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med 2017; 214(10): 2843–2857

[116] Wikan N, Smith DR. Zika virus: history of a newly emerging arbovirus. Lancet Infect Dis 2016; 16(7): e119–e126

[117] Yun SI, Lee YM. Zika virus: an emerging flavivirus. J Microbiol 2017; 55(3): 204–219

[118] Shan C, Muruato AE, Nunes BTD, Luo H, Xie X, Medeiros DBA, Wakamiya M, Tesh RB, Barrett AD, Wang T, Weaver SC, Vasconcelos PFC, Rossi SL, Shi PY. A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models. Nat Med 2017; 23(6): 763–767

[119] Chen Q, Wu J, Ye Q, Ma F, Zhu Q, Wu Y, Shan C, Xie X, Li D, Zhan X, Li C, Li XF, Qin X, Zhao T, Wu H, Shi PY, Man J, Qin CF. Treatment of human glioblastoma with a live attenuated Zika virus vaccine candidate. MBio 2018; 9(5): e01683–18

[120] Shan C, Xie X, Shi PY. Zika virus vaccine: progress and challenges. Cell Host Microbe 2018; 24(1): 12–17

[121] Zeh HJ, Downs-Canner S, McCart JA, Guo ZS, Rao UN, Ramalingam L, Thorne SH, Jones HL, Kalinski P, Wieckowski E, O’Malley ME, Daneshmand M, Hu K, Bell JC, Hwang TH, Moon A, Breitbach CJ, Kirn DH, Bartlett DL. First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity. Mol Ther 2015; 23(1): 202–214

[122] Breitbach CJ, De Silva NS, Falls TJ, Aladl U, Evgin L, Paterson J, Sun YY, Roy DG, Rintoul JL, Daneshmand M, Parato K, Stanford MM, Lichty BD, Fenster A, Kirn D, Atkins H, Bell JC. Targeting tumor vasculature with an oncolytic virus. Mol Ther 2011; 19(5): 886–894

[123] Breitbach CJ, Arulanandam R, De Silva N, Thorne SH, Patt R, Daneshmand M, Moon A, Ilkow C, Burke J, Hwang TH, Heo J, Cho M, Chen H, Angarita FA, Addison C, McCart JA, Bell JC, Kirn DH. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res 2013; 73(4): 1265–1275

[124] Hamid O, Hoffner B, Gasal E, Hong J, Carvajal RD. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother 2017; 66(10): 1249–1264

[125] Cody JJ, Hurst DR. Promising oncolytic agents for metastatic breast cancer treatment. Oncolytic Virother 2015; 4: 63–73

[126] Pearl TM, Markert JM, Cassady KA, Ghonime MG. Oncolytic virus-based cytokine expression to improve immune activity in brain and solid tumors. Mol Ther Oncolytics 2019; 13: 14–21

[127] Roth JC, Cassady KA, Cody JJ, Parker JN, Price KH, Coleman JM, Peggins JO, Noker PE, Powers NW, Grimes SD, Carroll SL, Gillespie GY, Whitley RJ, Markert JM. Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to aotus nonhuman primates. Hum Gene Ther Clin Dev 2014; 25(1): 16–27

[128] Patel DM, Foreman PM, Nabors LB, Riley KO, Gillespie GY, Markert JM. Design of a phase I clinical trial to evaluate M032, a genetically engineered HSV-1 expressing IL-12, in patients with recurrent/progressive glioblastoma multiforme, anaplastic astrocytoma, or gliosarcoma. Hum Gene Ther Clin Dev 2016; 27(2): 69–78

[129] Wu Y, He J, An Y, Wang X, Liu Y, Yan S, Ye X, Qi J, Zhu S, Yu Q, Yin J, Li D, Wang W. Recombinant Newcastle disease virus (NDV/Anh-IL-2) expressing human IL-2 as a potential candidate for suppresses growth of hepatoma therapy. J Pharmacol Sci 2016; 132(1): 24–30

[130] Hock K, Laengle J, Kuznetsova I, Egorov A, Hegedus B, Dome B, Wekerle T, Sachet M, Bergmann M. Oncolytic influenza A virus expressing interleukin-15 decreases tumor growth in vivo. Surgery 2017; 161(3): 735–746

[131] Puskas J, Skrombolas D, Sedlacek A, Lord E, Sullivan M, Frelinger J. Development of an attenuated interleukin-2 fusion protein that can be activated by tumour-expressed proteases. Immunology 2011; 133(2): 206–220

[132] Liu Z, Ge Y, Wang H, Ma C, Feist M, Ju S, Guo ZS, Bartlett DL. Modifying the cancer-immune set point using vaccinia virus expressing re-designed interleukin-2. Nat Commun 2018; 9(1): 4682

[133] Autio K, Knuuttila A, Kipar A, Pesonen S, Guse K, Parviainen S, Rajamäki M, Laitinen-Vapaavuori O, Vähä-Koskela M, Kanerva A, Hemminki A. Safety and biodistribution of a double-deleted oncolytic vaccinia virus encoding CD40 ligand in laboratory Beagles. Mol Ther Oncolytics 2014; 1: 14002

[134] Huang JH, Zhang SN, Choi KJ, Choi IK, Kim JH, Lee MG, Kim H, Yun CO. Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4-1BBL. Mol Ther 2010; 18(2): 264–274

[135] Moran AE, Kovacsovics-Bankowski M, Weinberg AD. The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol 2013; 25(2): 230–237

[136] Eriksson E, Milenova I, Wenthe J, Stahle M, Leja-Jarblad J, Ullenhag G, Dimberg A, Moreno R, Alemany R, Loskog A.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(19): 5846–5857

[137] Rosewell Shaw A, Suzuki M. Recent advances in oncolytic adenovirus therapies for cancer. Curr Opin Virol 2016; 21: 9–15

[138] Navarro SA, Carrillo E, Griñán-Lisón C, Martín A, Perán M, Marchal JA, Boulaiz H. Cancer suicide gene therapy: a patent review. Expert Opin Ther Pat 2016; 26(9): 1095–1104

[139] Zhu W, Zhang H, Shi Y, Song M, Zhu B, Wei L. Oncolytic adenovirus encoding tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits the growth and metastasis of triple-negative breast cancer. Cancer Biol Ther 2013; 14(11): 1016–1023

[140] Hu J, Wang H, Gu J, Liu X, Zhou X. Trail armed oncolytic poxvirus suppresses lung cancer cell by inducing apoptosis. Acta Biochim Biophys Sin (Shanghai) 2018; 50(10): 1018–1027

[141] Chen S, Li YQ, Yin XZ, Li SZ, Zhu YL, Fan YY, Li WJ, Cui YL, Zhao J, Li X, Zhang QG, Jin NY. Recombinant adenoviruses expressing apoptin suppress the growth of MCF7 breast cancer cells and affect cell autophagy. Oncol Rep 2019; 41(5): 2818–2832

[142] Zhou W, Dai S, Zhu H, Song Z, Cai Y, Lee JB, Li Z, Hu X, Fang B, He C, Huang X. Telomerase-specific oncolytic adenovirus expressing TRAIL suppresses peritoneal dissemination of gastric cancer. Gene Ther 2017; 24(4): 199–207

[143] Liu L, Wu W, Zhu G, Liu L, Guan G, Li X, Jin N, Chi B. Therapeutic efficacy of an hTERT promoter-driven oncolytic adenovirus that expresses apoptin in gastric carcinoma. Int J Mol Med 2012; 30(4): 747–754

[144] Schepelmann S, Springer CJ. Viral vectors for gene-directed enzyme prodrug therapy. Curr Gene Ther 2006; 6(6): 647–670

[145] Zhang J, Kale V, Chen M. Gene-directed enzyme prodrug therapy. AAPS J 2015; 17(1): 102–110

[146] Chalikonda S, Kivlen MH, O’Malley ME, Eric Dong XD, McCart JA, Gorry MC, Yin XY, Brown CK, Zeh HJ 3rd, Guo ZS, Bartlett DL. Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene. Cancer Gene Ther 2008; 15(2): 115–125

[147] Dias JD, Liikanen I, Guse K, Foloppe J, Sloniecka M, Diaconu I, Rantanen V, Eriksson M, Hakkarainen T, Lusky M, Erbs P, Escutenaire S, Kanerva A, Pesonen S, Cerullo V, Hemminki A. Targeted chemotherapy for head and neck cancer with a chimeric oncolytic adenovirus coding for bifunctional suicide protein FCU1. Clin Cancer Res 2010; 16(9): 2540–2549

[148] Foloppe J, Kempf J, Futin N, Kintz J, Cordier P, Pichon C, Findeli A, Vorburger F, Quemeneur E, Erbs P. The enhanced tumor specificity of TG6002, an armed oncolytic vaccinia virus deleted in two genes involved in nucleotide metabolism. Mol Ther Oncolytics 2019; 14: 1–14

[149] Erbs P, Regulier E, Kintz J, Leroy P, Poitevin Y, Exinger F, Jund R, Mehtali M. In vivo cancer gene therapy by adenovirus-mediated transfer of a bifunctional yeast cytosine deaminase/uracil phosphoribosyltransferase fusion gene. Cancer Res 2000; 60(14): 3813–3822

[150] Smith E, Breznik J, Lichty BD. Strategies to enhance viral penetration of solid tumors. Hum Gene Ther 2011; 22(9): 1053–1060

[151] Kim JH, Lee YS, Kim H, Huang JH, Yoon AR, Yun CO. Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J Natl Cancer Inst 2006; 98(20): 1482–1493

[152] Schäfer S, Weibel S, Donat U, Zhang Q, Aguilar RJ, Chen NG, Szalay AA. Vaccinia virus-mediated intra-tumoral expression of matrix metalloproteinase 9 enhances oncolysis of PC-3 xenograft tumors. BMC Cancer 2012; 12(1): 366

[153] Dmitrieva N, Yu L, Viapiano M, Cripe TP, Chiocca EA, Glorioso JC, Kaur B. Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy. Clin Cancer Res 2011; 17(6): 1362–1372

[154] Guedan S, Rojas JJ, Gros A, Mercade E, Cascallo M, Alemany R. Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. Mol Ther 2010; 18(7): 1275–1283

[155] Rodríguez-García A, Giménez-Alejandre M, Rojas JJ, Moreno R, Bazan-Peregrino M, Cascalló M, Alemany R. Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res 2015; 21(6): 1406–1418

[156] Pascual-Pasto G, Bazan-Peregrino M, Olaciregui NG, Restrepo-Perdomo CA, Mato-Berciano A, Ottaviani D, Weber K, Correa G, Paco S, Vila-Ubach M, Cuadrado-Vilanova M, Castillo-Ecija H, Botteri G, Garcia-Gerique L, Moreno-Gilabert H, Gimenez-Alejandre M, Alonso-Lopez P, Farrera-Sal M, Torres-Manjon S, Ramos-Lozano D, Moreno R, Aerts I, Doz F, Cassoux N, Chapeaublanc E, Torrebadell M, Roldan M, König A, Suñol M, Claverol J, Lavarino C, Carmen de T, Fu L, Radvanyi F, Munier FL, Catalá-Mora J, Mora J, Alemany R, Cascalló M, Chantada GL, Carcaboso AM. Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01. Sci Transl Med 2019; 11(476): eaat9321

[157] Viallard C, Larrivée B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 2017; 20(4): 409–426

[158] Siveen KS, Prabhu K, Krishnankutty R, Kuttikrishnan S, Tsakou M, Alali FQ, Dermime S, Mohammad RM, Uddin S. Vascular endothelial growth factor (VEGF) signaling in tumour vascularization: potential and challenges. Curr Vasc Pharmacol 2017; 15(4): 339–351

[159] Frentzen A, Yu YA, Chen N, Zhang Q, Weibel S, Raab V, Szalay AA. Anti-VEGF single-chain antibody GLAF-1 encoded by oncolytic vaccinia virus significantly enhances antitumor therapy. Proc Natl Acad Sci USA 2009; 106(31): 12915–12920

[160] Goodwin JM, Schmitt AD, McGinn CM, Fuchs BC, Kuruppu D, Tanabe KK, Lanuti M. Angiogenesis inhibition using an oncolytic herpes simplex virus expressing endostatin in a murine lung cancer model. Cancer Invest 2012; 30(3): 243–250

[161] Hutzen B, Bid HK, Houghton PJ, Pierson CR, Powell K, Bratasz A, Raffel C, Studebaker AW. Treatment of medulloblastoma with oncolytic measles viruses expressing the angiogenesis inhibitors endostatin and angiostatin. BMC Cancer 2014; 14(1): 206

[162] Tsuji T, Nakamori M, Iwahashi M, Nakamura M, Ojima T, Iida T, Katsuda M, Hayata K, Ino Y, Todo T, Yamaue H. An armed oncolytic herpes simplex virus expressing thrombospondin-1 has an enhanced in vivo antitumor effect against human gastric cancer. Int J Cancer 2013; 132(2): 485–494

[163] Miller A, Russell SJ. The use of the NIS reporter gene for optimizing oncolytic virotherapy. Expert Opin Biol Ther 2016; 16(1): 15–32

[164] Haddad D. Genetically engineered vaccinia viruses as agents for cancer treatment, imaging, and transgene delivery. Front Oncol 2017; 7: 96

[165] Domingo-Musibay E, Allen C, Kurokawa C, Hardcastle JJ, Aderca I, Msaouel P, Bansal A, Jiang H, DeGrado TR, Galanis E. Measles Edmonston vaccine strain derivatives have potent oncolytic activity against osteosarcoma. Cancer Gene Ther 2014; 21(11): 483–490

[166] Jiang K, Song C, Kong L, Hu L, Lin G, Ye T, Yao G, Wang Y, Chen H, Cheng W, Barr MP, Liu Q, Zhang G, Ding C, Meng S. Recombinant oncolytic Newcastle disease virus displays antitumor activities in anaplastic thyroid cancer cells. BMC Cancer 2018; 18(1): 746

[167] Aref S, Bailey K, Fielding A. Measles to the rescue: a review of oncolytic measles virus. Viruses 2016; 8(10): 294

[168] Peng KW, Facteau S, Wegman T, O’Kane D, Russell SJ. Non-invasive in vivo monitoring of trackable viruses expressing soluble marker peptides. Nat Med 2002; 8(5): 527–531

[169] Robinson S, Galanis E. Potential and clinical translation of oncolytic measles viruses. Expert Opin Biol Ther 2017; 17(3): 353–363

[170] Johnson DB, Puzanov I, Kelley MC. Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma. Immunotherapy 2015; 7(6): 611–619

[171] Bell J, McFadden G. Viruses for tumor therapy. Cell Host Microbe 2014; 15(3): 260–265

[172] Andtbacka RH, Agarwala SS, Ollila DW, Hallmeyer S, Milhem M, Amatruda T, Nemunaitis JJ, Harrington KJ, Chen L, Shilkrut M, Ross M, Kaufman HL. Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma. Head Neck 2016; 38(12): 1752–1758

[173] Eissa IR, Naoe Y, Bustos-Villalobos I, Ichinose T, Tanaka M, Zhiwen W, Mukoyama N, Morimoto T, Miyajima N, Hitoki H, Sumigama S, Aleksic B, Kodera Y, Kasuya H. Genomic signature of the natural oncolytic herpes simplex virus HF10 and its therapeutic role in preclinical and clinical trials. Front Oncol 2017; 7: 149

[174] Martínez-Vélez N, Garcia-Moure M, Marigil M, González-Huarriz M, Puigdelloses M, Gallego Pérez-Larraya J, Zalacaín M, Marrodán L, Varela-Guruceaga M, Laspidea V, Aristu JJ, Ramos LI, Tejada-Solís S, Díez-Valle R, Jones C, Mackay A, Martínez-Climent JA, García-Barchino MJ, Raabe E, Monje M, Becher OJ, Junier MP, El-Habr EA, Chneiweiss H, Aldave G, Jiang H, Fueyo J, Patiño-García A, Gomez-Manzano C, Alonso MM. The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Nat Commun 2019; 10(1): 2235

[175] Nakajima O, Ichimaru D, Urata Y, Fujiwara T, Horibe T, Kohno M, Kawakami K. Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer. Oncol Rep 2009; 22(5): 1039–1043

[176] Breitbach CJ, Parato K, Burke J, Hwang TH, Bell JC, Kirn DH. Pexa-Vec double agent engineered vaccinia: oncolytic and active immunotherapeutic. Curr Opin Virol 2015; 13: 49–54

[177] Singh P, Pal SK, Alex A, Agarwal N. Development of PROSTVAC immunotherapy in prostate cancer. Future Oncol 2015; 11(15): 2137–2148

[178] Felt SA, Grdzelishvili VZ. Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update. J Gen Virol 2017; 98(12): 2895–2911

[179] Brown MC, Gromeier M. Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus. Curr Opin Virol 2015; 13: 81–85

[180] Desjardins A, Gromeier M, Herndon JE 2nd, Beaubier N, Bolognesi DP, Friedman AH, Friedman HS, McSherry F, Muscat AM, Nair S, Peters KB, Randazzo D, Sampson JH, Vlahovic G, Harrison WT, McLendon RE, Ashley D, Bigner DD. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med 2018; 379(2): 150–161

[181] Atherton MJ, Stephenson KB, Nikota JK, Hu QN, Nguyen A, Wan Y, Lichty BD. Preclinical development of peptide vaccination combined with oncolytic MG1-E6E7 for HPV-associated cancer. Vaccine 2018; 36(16): 2181–2192

[182] Gong J, Sachdev E, Mita AC, Mita MM. Clinical development of reovirus for cancer therapy: an oncolytic virus with immune-mediated antitumor activity. World J Methodol 2016; 6(1):25–42

[183] Geletneky K, Nüesch JPF, Angelova A, Kiprianova I, Rommelaere J. Double-faceted mechanism of parvoviral oncosuppression. Curr Opin Virol 2015; 13: 17–24

[184] Hajda J, Lehmann M, Krebs O, Kieser M, Geletneky K, Jäger D, Dahm M, Huber B, Schöning T, Sedlaczek O, Stenzinger A, Halama N, Daniel V, Leuchs B, Angelova A, Rommelaere J, Engeland CE, Springfeld C, Ungerechts G. A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol. BMC Cancer 2017; 17(1): 576

[185] Lorence RM, Roberts MS, O’Neil JD, Groene WS, Miller JA, Mueller SN, Bamat MK. Phase 1 clinical experience using intravenous administration of PV701, an oncolytic Newcastle disease virus. Curr Cancer Drug Targets 2007; 7(2): 157–167

[186] Bauzon M, Hermiston T. Armed therapeutic viruses — a disruptive therapy on the horizon of cancer immunotherapy. Front Immunol 2014; 5: 74

[187] Nguyen A, Ho L, Wan Y. Chemotherapy and oncolytic virotherapy: advanced tactics in the war against cancer. Front Oncol 2014; 4: 145

[188] Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27(4): 450–461

[189] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252–264

[190] Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387(10031): 1909–1920

[191] Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, Iyer AK. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol 2017; 8: 561

[192] Wang Q, Wu X. Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment. Int Immunopharmacol 2017; 46: 210–219

[193] Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol 2020; 20(1): 25–39

[194] Liu Z, Ravindranathan R, Kalinski P, Guo ZS, Bartlett DL. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat Commun 2017; 8(1): 14754

[195] Chen CY, Wang PY, Hutzen B, Sprague L, Swain HM, Love JK, Stanek JR, Boon L, Conner J, Cripe TP. Cooperation of oncolytic herpes virotherapy and PD-1 blockade in murine rhabdomyosarcoma models. Sci Rep 2017; 7(1): 2396

[196] Hardcastle J, Mills L, Malo CS, Jin F, Kurokawa C, Geekiyanage H, Schroeder M, Sarkaria J, Johnson AJ, Galanis E. Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment. Neuro Oncol 2017; 19(4): 493–502

[197] Shen W, Patnaik MM, Ruiz A, Russell SJ, Peng KW. Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia. Blood 2016; 127(11): 1449–1458

[198] Saha D, Martuza RL, Rabkin SD. Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell 2017; 32(2): 253–267.e5

[199] Fend L, Yamazaki T, Remy C, Fahrner C, Gantzer M, Nourtier V, Préville X, Quéméneur E, Kepp O, Adam J, Marabelle A, Pitt JM, Kroemer G, Zitvogel L. Immune checkpoint blockade, immunogenic chemotherapy or IFN-a blockade boost the local and abscopal effects of oncolytic virotherapy. Cancer Res 2017; 77(15): 4146–4157

[200] Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 2017; 170(6): 1109–1119.e10

[201] Sun L, Funchain P, Song JM, Rayman P, Tannenbaum C, Ko J, Mcnamara M, Marcela Diaz-Montero C, Gastman B. Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series. J Immunother Cancer 2018; 6(1): 36

[202] Puzanov I, Milhem MM, Minor D, Hamid O, Li A, Chen L, Chastain M, Gorski KS, Anderson A, Chou J, Kaufman HL, Andtbacka RH. Talimogene Laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol 2016; 34(22): 2619–2626

[203] Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, Hamid O, Ross M, Friedlander P, Garbe C, Logan TF, Hauschild A, Lebbé C, Chen L, Kim JJ, Gansert J, Andtbacka RHI, Kaufman HL. 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(17): 1658–1667

[204] Wing A, Fajardo CA, Posey AD, Shaw C, Da T, Young RM, Alemany R, June CH, Guedan S. Improving CART-cell therapy of solid tumors with oncolytic virus–driven production of a bispecific T-cell engager. Cancer Immunol Res 2018; 6(5): 605–616

[205] Watanabe K, Luo Y, Da T, Guedan S, Ruella M, Scholler J, Keith B, Young RM, Engels B, Sorsa S, Siurala M, Havunen R, Tähtinen S, Hemminki A, June CH. Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight 2018; 3(7): e99573

[206] Nishio N, Diaconu I, Liu H, Cerullo V, Caruana I, Hoyos V, Bouchier-Hayes L, Savoldo B, Dotti G. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res 2014; 74(18): 5195–5205

[207] Rosewell Shaw A, Porter CE, Watanabe N, Tanoue K, Sikora A, Gottschalk S, Brenner MK, Suzuki M. Adenovirotherapy delivering cytokine and checkpoint inhibitor augments CAR T cells against metastatic head and neck cancer. Mol Ther 2017; 25(11): 2440–2451

[208] Tanoue K, Rosewell Shaw A, Watanabe N, Porter C, Rana B, Gottschalk S, Brenner M, Suzuki M. Armed oncolytic adenovirus-expressing PD-L1 mini-body enhances antitumor effects of chimeric antigen receptor T cells in solid tumors. Cancer Res 2017; 77(8): 2040–2051

[209] Pento JT. Monoclonal antibodies for the treatment of cancer. Anticancer Res 2017; 37(11): 5935–5939

[210] [No authors listed] Cemiplimab approved for treatment of CSCC. Cancer Discov 2018; 8(12): OF2

[211] Syed YY. Durvalumab: first global approval. Drugs 2017; 77(12): 1369–1376

[212] Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515(7528): 568–571

[213] Taipale K, Liikanen I, Juhila J, Karioja-Kallio A, Oksanen M, Turkki R, Linder N, Lundin J, Ristimäki A, Kanerva A, Koski A, Joensuu T, Vähä-Koskela M, Hemminki A. T-cell subsets in peripheral blood and tumors of patients treated with oncolytic adenoviruses. Mol Ther 2015; 23(5): 964–973

[214] Pesonen S, Diaconu I, Kangasniemi L, Ranki T, Kanerva A, Pesonen SK, Gerdemann U, Leen AM, Kairemo K, Oksanen M, Haavisto E, Holm SL, Karioja-Kallio A, Kauppinen S, Partanen KP, Laasonen L, Joensuu T, Alanko T, Cerullo V, Hemminki A. Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients. Cancer Res 2012; 72(7): 1621–1631

[215] Letendre P, Monga V, Milhem M, Zakharia Y. Ipilimumab: from preclinical development to future clinical perspectives in melanoma. Future Oncol 2017; 13(7): 625–636

[216] Pagel JM, West HJ. Chimeric antigen receptor (CAR) T-cell therapy. JAMA Oncol 2017; 3(11): 1595

[217] Anderson JK, Mehta A. A review of chimeric antigen receptor T-cells in lymphoma. Expert Rev Hematol 2019; 12(7): 551–561

[218] Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood 2017; 130(24): 2594–2602

[219] Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol 2016; 13(6): 370–383

[220] Long KB, Young RM, Boesteanu AC, Davis MM, Melenhorst JJ, Lacey SF, DeGaramo DA, Levine BL, Fraietta JA. CAR T cell therapy of non-hematopoietic malignancies: detours on the road to clinical success. Front Immunol 2018; 9: 2740

[221] Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattini M, Sadelain M. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5(177): 177ra38

[222] Li J, Li W, Huang K, Zhang Y, Kupfer G, Zhao Q. Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward. J Hematol Oncol 2018; 11(1): 22

[223] Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, Spranger S. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 2013; 25(2): 268–276

[224] Lavin Y, Kobayashi S, Leader A, Amir ED, Elefant N, Bigenwald C, Remark R, Sweeney R, Becker CD, Levine JH, Meinhof K, Chow A, Kim-Shulze S, Wolf A, Medaglia C, Li H, Rytlewski JA, Emerson RO, Solovyov A, Greenbaum BD, Sanders C, Vignali M, Beasley MB, Flores R, Gnjatic S, Pe’er D, Rahman A, Amit I, Merad M. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 2017; 169(4): 750–765.e17

[225] Salter AI, Riddell SR. A BiTE from cancer’s intracellular menu. Nat Biotechnol 2015; 33(10): 1040–1041

[226] Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol 2015; 93(3): 290–296

[227] Stieglmaier J, Benjamin J, Nagorsen D. Utilizing the BiTE (bispecific T-cell engager) platform for immunotherapy of cancer. Expert Opin Biol Ther 2015; 15(8): 1093–1099

[228] Scott EM, Duffy MR, Freedman JD, Fisher KD, Seymour LW. Solid tumor immunotherapy with T cell engager-armed oncolytic viruses. Macromol Biosci 2018; 18(1): 1700187

[229] Cheung A, Bax HJ, Josephs DH, Ilieva KM, Pellizzari G, Opzoomer J, Bloomfield J, Fittall M, Grigoriadis A, Figini M, Canevari S, Spicer JF, Tutt AN, Karagiannis SN. Targeting folate receptor alpha for cancer treatment. Oncotarget 2016; 7(32): 52553–52574

[230] Zolov SN, Rietberg SP, Bonifant CL. Programmed cell death protein 1 activation preferentially inhibits CD28.CAR-T cells. Cytotherapy 2018; 20(10): 1259–1266

[231] Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest 2016; 126(8): 3130–3144

[232] Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 2015; 14(8): 561–584

[233] Serganova I, Moroz E, Cohen I, Moroz M, Mane M, Zurita J, Shenker L, Ponomarev V, Blasberg R. Enhancement of PSMA-directed CAR adoptive immunotherapy by PD-1/PD-L1 blockade. Mol Ther Oncolytics 2017; 4: 41–54

[234] Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018; 378(2): 158–168

[235] Svane IM, Verdegaal EM. Achievements and challenges of adoptive T cell therapy with tumor-infiltrating or blood-derived lymphocytes for metastatic melanoma: what is needed to achieve standard of care? Cancer Immunol Immunother 2014; 63(10): 1081–1091

[236] Besser MJ, Shapira-Frommer R, Itzhaki O, Treves AJ, Zippel DB, Levy D, Kubi A, Shoshani N, Zikich D, Ohayon Y, Ohayon D, Shalmon B, Markel G, Yerushalmi R, Apter S, Ben-Nun A, Ben-Ami E, Shimoni A, Nagler A, Schachter J. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res 2013; 19(17): 4792–4800

[237] Santos JM, Havunen R, Siurala M, Cervera-Carrascon V, Tähtinen S, Sorsa S, Anttila M, Karell P, Kanerva A, Hemminki A. Adenoviral production of interleukin-2 at the tumor site removes the need for systemic postconditioning in adoptive cell therapy. Int J Cancer 2017; 141(7): 1458–1468

[238] Hamano S, Mori Y, Aoyama M, Kataoka H, Tanaka M, Ebi M, Kubota E, Mizoshita T, Tanida S, Johnston RN, Asai K, Joh T. Oncolytic reovirus combined with trastuzumab enhances antitumor efficacy through TRAIL signaling in human HER2-positive gastric cancer cells. Cancer Lett 2015; 356(2 Pt B): 846–854

[239] Tan G, Kasuya H, Sahin TT, Yamamura K, Wu Z, Koide Y, Hotta Y, Shikano T, Yamada S, Kanzaki A, Fujii T, Sugimoto H, Nomoto S, Nishikawa Y, Tanaka M, Tsurumaru N, Kuwahara T, Fukuda S, Ichinose T, Kikumori T, Takeda S, Nakao A, Kodera Y. Combination therapy of oncolytic herpes simplex virus HF10 and bevacizumab against experimental model of human breast carcinoma xenograft. Int J Cancer 2015; 136(7): 1718–1730

[240] Bommareddy PK, Aspromonte S, Zloza A, Rabkin SD, Kaufman HL. MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation. Sci Transl Med 2018; 10(471): eaau0417

[241] Abdullahi S, Jäkel M, Behrend SJ, Steiger K, Topping G, Krabbe T, Colombo A, Sandig V, Schiergens TS, Thasler WE, Werner J, Lichtenthaler SF, Schmid RM, Ebert O, Altomonte J. A novel chimeric oncolytic virus vector for improved safety and efficacy as a platform for the treatment of hepatocellular carcinoma. J Virol 2018; 92(23): e01386-18

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