Oncolytic viruses are designed to replicate in and kill cancer cells, and have shown tremendous promise in preclinical and clinical studies. Indeed, several oncolytic viruses are available to patients in a number of different countries around the world. However, most oncolytic viruses show a poor ability to spread throughout the tumor mass, frequently leading to only a partial response and regrowth of the tumor. One approach to improve spread of the viral effect throughout the tumor mass is to arm the oncolytic virus with a fusogenic protein. In this manner, a single infected cell can fuse with many adjacent uninfected cells, essentially amplifying the anti-tumor effects. In this review, we discuss the development and use of fusogenic proteins to enhance the efficacy of human adenovirus-based vectors for cancer therapy.
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Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends–an update. Cancer Epidemiol Biomarkers Prev. 2016;25:16–27.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642.
Keller BA, Bell JC. Oncolytic viruses—immunotherapeutics on the rise. J Mol Med. 2016;94:979–91.
Russell SJ, Peng K-W, Bell JC. Oncolytic virotherapy. Nat Biotechnol 2012;30:658–70.
Dock G. The influence of complicating diseases upon leukemia. Am J Med Sci. 1904;127:563–92.
Kelly E, Russell SJ. History of oncolytic viruses: genesis to genetic engineering. Mol Ther 2007;15:651–9.
Liu TC, Galanis E, Kirn D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pr Oncol. 2007;4:101–17.
Asada T. Treatment of human cancer with mumps virus. Cancer 1974;34:1907–28.
Hoster HA, Zanes RP Jr., Von Haam E. Studies in Hodgkin’s syndrome; the association of viral hepatitis and Hodgkin’s disease; a preliminary report. Cancer Res 1949;9:473–80.
Southam CM, Moore AE. Clinical studies of viruses as antineoplastic agents with particular reference to Egypt 101 virus. Cancer 1952;5:1025–34.
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;252:854–6.
Aghi MK, Chiocca EA. Phase Ib trial of oncolytic herpes virus G207 shows safety of multiple injections and documents viral replication. Mol Ther 2009;17:8–9.
Annels NE, Mansfield D, Arif M, Ballesteros-Merino C, Simpson GR, Denyer M, et al. 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;25:5818–31.
Comins C, Spicer J, Protheroe A, Roulstone V, Twigger K, White CM, et al. REO-10: a phase I study of intravenous reovirus and docetaxel in patients with advanced cancer. Clin Cancer Res. 2010;16:5564–72.
Downs-Canner S, Guo ZS, Ravindranathan R, Breitbach CJ, O’malley ME, Jones HL, et al. Phase 1 study of intravenous oncolytic poxvirus (vvDD) in patients with advanced solid cancers. Mol Ther 2016;24:1492–501.
Geletneky K, Hajda J, Angelova AL, Leuchs B, Capper D, Bartsch AJ, et al. Oncolytic H-1 parvovirus shows safety and signs of immunogenic activity in a first phase I/IIa glioblastoma trial. Mol Ther 2017;25:2620–34.
Heinzerling L, Künzi V, Oberholzer PA, Kündig T, Naim H, Dummer R. Oncolytic measles virus in cutaneous T-cell lymphomas mounts antitumor immune responses in vivo and targets interferon-resistant tumor cells. Blood 2005;106:2287–94.
Kirn D. Oncolytic virotherapy for cancer with the adenovirus dl1520 (Onyx-015): results of phase I and II trials. Expert Opin Biol Ther. 2001;1:525–38.
Babiker HM, Riaz IB, Husnain M, Borad MJ. Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma. Oncolytic Virother 2017;6:11–8.
Garber K. China approves world’s first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst. 2006;98:298–300.
Rehman H, Silk AW, Kane MP, Kaufman HL. Into the clinic: talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. J Immunother Cancer. 2016;4:53.
Greig SL. Talimogene laherparepvec: first global approval. Drugs 2016;76:147–54.
Vasey PA, Shulman LN, Campos S, Davis J, Gore M, Johnston S, et al. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol. 2002;20:1562–9.
Vidal L, Pandha HS, Yap TA, White CL, Twigger K, Vile RG, et al. A phase I study of intravenous oncolytic reovirus type 3 dearing in patients with advanced cancer. Clin Cancer Res. 2008;14:7127–37.
Patel MR, Kratzke RA. Oncolytic virus therapy for cancer: the first wave of translational clinical trials. Transl Res 2013;161:355–64.
Pol J, Buqué A, Aranda F, Bloy N, Cremer I, Eggermont A, et al. Trial watch—oncolytic viruses and cancer therapy. Oncoimmunology 2016;5:e1117740.
Bai FL, Yu YH, Tian H, Ren GP, Wang H, Zhou B, et al. Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy. Cancer Biol Ther. 2014;15:1226–38.
Grossardt C, Engeland CE, Bossow S, Halama N, Zaoui K, Leber MF, et al. Granulocyte-macrophage colony-stimulating factor-armed oncolytic measles virus is an effective therapeutic cancer vaccine. Hum Gene Ther. 2013;24:644–54.
Lee YS, Kim JH, Choi KJ, Choi IK, Kim H, Cho S, et al. Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model. Clin cancer Res. 2006;12:5859–68.
Maroun J, Muñoz-Alía M, Ammayappan A, Schulze A, Peng K-W, Russell S. Designing and building oncolytic viruses. Future Virol 2017;12:193–213.
Martin NT, Bell JC. Oncolytic virus combination therapy: killing one bird with two stones. Mol Ther 2018;26:1414–22.
de Graaf JF, de Vor L, Fouchier RAM, van den Hoogen BG. Armed oncolytic viruses: a kick-start for anti-tumor immunity. Cytokine Growth Factor Rev. 2018;41:28–39.
Meyers DE, Wang AA, Thirukkumaran CM, Morris DG. Current immunotherapeutic strategies to enhance oncolytic virotherapy. Front Oncol 2017;7:114.
Sampath P, Thorne SH. Arming viruses in multi-mechanistic oncolytic viral therapy: current research and future developments, with emphasis on poxviruses. Oncolytic Virother. 2014;3:1–9.
Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–8.
Ranki T, Pesonen S, Hemminki A, Partanen K, Kairemo K, Alanko T, 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.
Vassilev L, Ranki T, Joensuu T, Jager E, Karbach J, Wahle C, et al. Repeated intratumoral administration of ONCOS-102 leads to systemic antitumor CD8(+) T-cell response and robust cellular and transcriptional immune activation at tumor site in a patient with ovarian cancer. Oncoimmunology 2015;4:e1017702.
Nash LA, Parks RJ. Adenovirus Biology and Development as a Gene Delivery Vector. In: Ng P, Brunetti-Pierri N, editors. Gene Therapy with Adenoviral Based Vectors. New York: Taylor and Francis; 2016.
Rowe WP, Huebner RJ, Gilmore LK, Parrott RH, Ward TG. Isolation of a cytopathogenic agent from human adenoids undergoing spontaneous degeneration in tissue culture. Proc Soc Exp Biol Med. 1953;84:570–3.
Ghebremedhin B. Human adenovirus: Viral pathogen with increasing importance. Eur J Microbiol Immunol. 2014;4:26–33.
Chroboczek J, Bieber F, Jacrot B. The sequence of the genome of adenovirus type 5 and its comparison with the genome of adenovirus type 2. Virology 1992;186:280–5.
Wold WS, Ison MG Adenovirus. Fields Virology 6th Edition: Lippincott, Williams & Wilkins; 2013.
Choi J-W, Lee J-S, Kim SW, Yun C-O. Evolution of oncolytic adenovirus for cancer treatment. Adv Drug Deliv Rev. 2012;64:720–9.
Kirn D. Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer. Oncogene 2000;19:6660–9.
Whyte P, Williamson NM, Harlow E. Cellular targets for transformation by the adenovirus E1A proteins. Cell 1989;56:67–75.
Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997;57:2559–63.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74.
Seymour LW, Fisher KD. Oncolytic viruses: finally delivering. Br J Cancer. 2016;114:357–61.
Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996;274:373–6.
Debbas M, White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev 1993;7:546–54.
Sarnow P, Ho YS, Williams J, Levine AJ. Adenovirus E1b-58kd tumor antigen and SV40 large tumor antigen are physically associated with the same 54 kd cellular protein in transformed cells. Cell 1982;28:387–94.
Ries S, Korn WM. ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus. Br J Cancer. 2002;86:5–11.
Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene 2000;19:2–12.
Whyte P, Ruley H, Harlow E. Two regions of the adenovirus early region 1A proteins are required for transformation. J Virol. 1988;62:257–65.
Zamanian M, La Thangue NB. Adenovirus E1a prevents the retinoblastoma gene product from repressing the activity of a cellular transcription factor. EMBO J 1992;11:2603–10.
Mast TC, Kierstead L, Gupta SB, Nikas AA, Kallas EG, Novitsky V, et al. International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: correlates of high Ad5 titers and implications for potential HIV vaccine trials. Vaccine 2010;28:950–7.
Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D, et al. Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States. Clin Diagn Lab Immunol. 2004;11:351–7.
Tsai V, Johnson DE, Rahman A, Wen SF, LaFace D, Philopena J, et al. Impact of human neutralizing antibodies on antitumor efficacy of an oncolytic adenovirus in a murine model. Clin Cancer Res. 2004;10:7199–206.
Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L, et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000;6:879–85.
DeWeese TL, van der Poel H, Li S, Mikhak B, Drew R, Goemann M, et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res 2001;61:7464–72.
Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science 2015;348:74–80.
Bernt KM, Ni S, Li ZY, Shayakhmetov DM, Lieber A. The effect of sequestration by nontarget tissues on anti-tumor efficacy of systemically applied, conditionally replicating adenovirus vectors. Mol Ther 2003;8:746–55.
Ross PJ, Parks RJ. Oncolytic adenovirus: getting there is half the battle. Mol Ther 2003;8:705–6.
Sauthoff H, Hu J, Maca C, Goldman M, Heitner S, Yee H, et al. Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: virus persists and spreads systemically at late time points. Hum Gene Ther. 2003;14:425–33.
Heise CC, Williams A, Olesch J, Kirn DH. Efficacy of a replication-competent adenovirus (ONYX-015) following intratumoral injection: intratumoral spread and distribution effects. Cancer Gene Ther. 1999;6:499–504.
Wang Y, Hu JK, Krol A, Li YP, Li CY, Yuan F. Systemic dissemination of viral vectors during intratumoral injection. Mol Cancer Ther. 2003;2:1233–42.
Shaw AR, Suzuki M. Recent advances in oncolytic adenovirus therapies for cancer. Curr Opin Virol. 2016;21:9–15.
Reeh M, Bockhorn M, Gorgens D, Vieth M, Hoffmann T, Simon R, et al. Presence of the coxsackievirus and adenovirus receptor (CAR) in human neoplasms: a multitumour array analysis. Br J Cancer. 2013;109:1848–58.
Thaci B, Ulasov IV, Wainwright DA, Lesniak MS. The challenge for gene therapy: innate immune response to adenoviruses. Oncotarget 2011;2:113–21.
Tamanini A, Nicolis E, Bonizzato A, Bezzerri V, Melotti P, Assael BM, et al. Interaction of adenovirus type 5 fiber with the coxsackievirus and adenovirus receptor activates inflammatory response in human respiratory cells. J Virol. 2006;80:11241–54.
Di Paolo NC, Miao EA, Iwakura Y, Murali-Krishna K, Aderem A, Flavell RA, et al. Virus binding to a plasma membrane receptor triggers interleukin-1 alpha-mediated proinflammatory macrophage response in vivo. Immunity 2009;31:110–21.
Stein SC, Falck-Pedersen E. Sensing adenovirus infection: activation of interferon regulatory factor 3 in RAW 264.7 cells. J Virol 2012;86:4527–37.
Stein SC, Lam E, Falck-Pedersen E. Cell-specific regulation of nucleic acid sensor cascades: a controlling interest in the antiviral response. J Virol 2012;86:13303–12.
Ahtiainen L, Mirantes C, Jahkola T, Escutenaire S, Diaconu I, Osterlund P, et al. Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus. PLoS ONE 2010;5:e13859.
Naik S, Russell SJ. Engineering oncolytic viruses to exploit tumor specific defects in innate immune signaling pathways. Expert Opin Biol Ther. 2009;9:1163–76.
Tollefson AE, Scaria A, Hermiston TW, Ryerse JS, Wold LJ, Wold W. The adenovirus death protein (E3-11.6 K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells. J Virol. 1996;70:2296–306.
Cody JJ, Douglas JT. Armed replicating adenoviruses for cancer virotherapy. Cancer Gene Ther. 2009;16:473–88.
Thomas GP, Mathews MB. DNA replication and the early to late transition in adenovirus infection. Cell 1980;22:523–33.
Carette JE, Graat HC, Schagen FH, El Hassan MAA, Gerritsen WR, van Beusechem VW. Replication‐dependent transgene expression from a conditionally replicating adenovirus via alternative splicing to a heterologous splice‐acceptor site. J Gene Med. 2005;7:1053–62.
Jin F, Kretschmer PJ, Hermiston TW. Identification of novel insertion sites in the Ad5 genome that utilize the Ad splicing machinery for therapeutic gene expression. Mol Ther 2005;12:1052–63.
Rivera AA, Wang M, Suzuki K, Uil TG, Krasnykh V, Curiel DT, et al. Mode of transgene expression after fusion to early or late viral genes of a conditionally replicating adenovirus via an optimized internal ribosome entry site in vitro and in vivo. Virology 2004;320:121–34.
Sauthoff H, Pipiya T, Heitner S, Chen S, Norman RG, Rom WN, et al. Late expression of p53 from a replicating adenovirus improves tumor cell killing and is more tumor cell specific than expression of the adenoviral death protein. Hum Gene Ther. 2002;13:1859–71.
Funston GM, Kallioinen SE, de Felipe P, Ryan MD, Iggo RD. Expression of heterologous genes in oncolytic adenoviruses using picornaviral 2A sequences that trigger ribosome skipping. J Gen Virol. 2008;89:389–96.
Ganesh S, Gonzalez Edick M, Idamakanti N, Abramova M, Vanroey M, Robinson M, et al. Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice. Cancer Res 2007;67:4399–407.
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;98:1482–93.
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;18:1275–83.
Choi IK, Lee YS, Yoo JY, Yoon AR, Kim H, Kim DS, et al. Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy. Gene Ther 2010;17:190–201.
Krabbe T, Altomonte J. Fusogenic Viruses in Oncolytic Immunotherapy. Cancers (Basel). 2018;10:216.
Del Papa J, Parks RJ. Adenoviral vectors armed with cell fusion-inducing proteins as anti-cancer agents. Viruses 2017;9:13.
Bateman AR, Harrington KJ, Kottke T, Ahmed A, Melcher AA, Gough MJ, et al. Viral fusogenic membrane glycoproteins kill solid tumor cells by nonapoptotic mechanisms that promote cross presentation of tumor antigens by dendritic cells. Cancer Res 2002;62:6566–78.
Errington F, Jones J, Merrick A, Bateman A, Harrington K, Gough M, et al. Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming. Gene Ther 2006;13:138–49.
Ebert O, Shinozaki K, Kournioti C, Park M-S, García-Sastre A, Woo SL. Syncytia induction enhances the oncolytic potential of vesicular stomatitis virus in virotherapy for cancer. Cancer Res 2004;64:3265–70.
Fu X, Tao L, Jin A, Vile R, Brenner MK, Zhang X. Expression of a fusogenic membrane glycoprotein by an oncolytic herpes simplex virus potentiates the viral antitumor effect. Mol Ther 2003;7:748–54.
Gainey MD, Manuse MJ, Parks GD. A hyperfusogenic F protein enhances the oncolytic potency of a paramyxovirus simian virus 5 P/V mutant without compromising sensitivity to type I interferon. J Virol. 2008;82:9369–80.
Le Boeuf F, Diallo J-S, McCart JA, Thorne S, Falls T, Stanford M, et al. Synergistic interaction between oncolytic viruses augments tumor killing. Mol Ther 2010;18:888–95.
Li H, Haviv YS, Derdeyn CA, Lam J, Coolidge C, Hunter E, et al. Human immunodeficiency virus type 1-mediated syncytium formation is compatible with adenovirus replication and facilitates efficient dispersion of viral gene products and de novo-synthesized virus particles. Hum Gene Ther. 2001;12:2155–65.
Takaoka H, Takahashi G, Ogawa F, Imai T, Iwai S, Yura Y. A novel fusogenic herpes simplex virus for oncolytic virotherapy of squamous cell carcinoma. Virol J 2011;8:294.
Dewar RL, Natarajan V, Vasudevachari MB, Salzman NP. Synthesis and processing of human immunodeficiency virus type 1 envelope proteins encoded by a recombinant human adenovirus. J Virol. 1989;63:129–36.
Gómez‐Treviño A, Castel S, López‐Iglesias C, Cortadellas N, Comas‐Riu J, Mercade E. Effects of adenovirus‐mediated SV5 fusogenic glycoprotein expression on tumor cells. J Gene Med. 2003;5:483–92.
Guedan S, Grases D, Rojas JJ, Gros A, Vilardell F, Vile R, et al. GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution. Gene Ther 2012;19:1048–57.
Guedan S, Gros A, Cascallo M, Vile R, Mercade E, Alemany R. Syncytia formation affects the yield and cytotoxicity of an adenovirus expressing a fusogenic glycoprotein at a late stage of replication. Gene Ther 2008;15:1240–5.
Hoffmann D, Bayer W, Grunwald T, Wildner O. Intratumoral expression of respiratory syncytial virus fusion protein in combination with cytokines encoded by adenoviral vectors as in situ tumor vaccine for colorectal cancer. Mol Cancer Ther. 2007;6:1942–50.
Hoffmann D, Bayer W, Wildner O. In situ tumor vaccination with adenovirus vectors encoding measles virus fusogenic membrane proteins and cytokines. World J Gastroenterol. 2007;13:3063–70.
Hoffmann D, Bayer W, Wildner O. Therapeutic immune response induced by intratumoral expression of the fusogenic membrane protein of vesicular stomatitis virus and cytokines encoded by adenoviral vectors. Int J Mol Med. 2007;20:673–81.
Horn GP, Vongpunsawad S, Kornmann E, Fritz B, Dittmer DP, Cattaneo R, et al. Enhanced cytotoxicity without internuclear spread of adenovirus upon cell fusion by measles virus glycoproteins. J Virol. 2005;79:1911–7.
Bett A, Prevec L, Graham F. Packaging capacity and stability of human adenovirus type 5 vectors. J Virol. 1993;67:5911–21.
Saha B, Wong CM, Parks RJ. The adenovirus genome contributes to the structural stability of the virion. Viruses 2014;6:3563–83.
Ciechonska M, Duncan R. Reovirus FAST proteins: virus-encoded cellular fusogens. Trends Microbiol 2014;22:715–24.
Duncan R. Fusogenic Reoviruses and Their Fusion-Associated Small Transmembrane (FAST) Proteins. Annu Rev Virol. 2019;6:341–63.
Diller JR, Parrington HM, Patton JT, Ogden KM. Rotavirus species B encodes a functional fusion-associated small transmembrane protein. J Virol. 2019;93:e00813–19.
Margam NN, Duncan R. Myomaker and myomerger: it takes two to make one. Dev Cell 2018;46:676–8.
Nibert ML, Duncan R. Bioinformatics of recent aqua- and orthoreovirus isolates from fish: evolutionary gain or loss of FAST and fiber proteins and taxonomic implications. PLoS ONE 2013;8:e68607.
Corcoran JA, Duncan R. Reptilian reovirus utilizes a small type III protein with an external myristylated amino terminus to mediate cell-cell fusion. J Virol. 2004;78:4342–51.
Parmar HB, Barry C, Kai F, Duncan R. Golgi complex-plasma membrane trafficking directed by an autonomous, tribasic Golgi export signal. Mol Biol Cell. 2014;25:866–78.
Barry C, Duncan R. Multifaceted sequence-dependent and -independent roles for reovirus FAST protein cytoplasmic tails in fusion pore formation and syncytiogenesis. J Virol. 2009;83:12185–95.
Top D, Barry C, Racine T, Ellis CL, Duncan R. Enhanced fusion pore expansion mediated by the trans-acting Endodomain of the reovirus FAST proteins. PLoS Pathog 2009;5:e1000331.
Corcoran JA, Clancy EK, Duncan R. Homomultimerization of the reovirus p14 fusion-associated small transmembrane protein during transit through the ER–Golgi complex secretory pathway. J Gen Virol. 2011;92:162–6.
Corcoran JA, Salsman J, de Antueno R, Touhami A, Jericho MH, Clancy EK, et al. The p14 fusion-associated small transmembrane (FAST) protein effects membrane fusion from a subset of membrane microdomains. J Biol Chem. 2006;281:31778–89.
Salsman J, Top D, Barry C, Duncan R. A virus-encoded cell-cell fusion machine dependent on surrogate adhesins. PLoS Pathog 2008;4:e1000016.
Ciechonska M, Duncan R. Lysophosphatidylcholine reversibly arrests pore expansion during syncytium formation mediated by diverse viral fusogens. J Virol 2014;88:6528–31.
Ciechonska M, Key T, Duncan R. Efficient reovirus- and measles virus-mediated pore expansion during syncytium formation is dependent on annexin A1 and intracellular calcium. J Virol 2014;88:6137–47.
Sampath SC, Sampath SC, Millay DP. Myoblast fusion confusion: the resolution begins. Skelet Muscle 2018;8:3.
Leikina E, Gamage DG, Prasad V, Goykhberg J, Crowe M, Diao J, et al. Myomaker and myomerger work independently to control distinct steps of membrane remodeling during myoblast fusion. Dev Cell 2018;46:767–80. e7
Petrany MJ, Millay DP. Cell fusion: merging membranes and making muscle. Trends Cell Biol. 2019;29:964–73.
Salsman J, Top D, Boutilier J, Duncan R. Extensive syncytium formation mediated by the reovirus FAST proteins triggers apoptosis-induced membrane instability. J Virol 2005;79:8090–100.
Le Boeuf F, Gebremeskel S, McMullen N, He H, Greenshields AL, Hoskin DW, et al. Reovirus FAST protein enhances vesicular stomatitis virus oncolytic virotherapy in primary and metastatic tumor models. Mol Ther-Oncolytics. 2017;6:80–9.
Wong CM, Poulin KL, Tong G, Christou C, Kennedy MA, Falls T, et al. Adenovirus-mediated expression of the p14 fusion-associated small transmembrane protein promotes cancer cell fusion and apoptosis in vitro but does not provide therapeutic efficacy in a xenograft mouse model of cancer. PLoS ONE 2016;11:e0151516.
Wong CM, Nash LA, Del Papa J, Poulin KL, Falls T, Bell JC, et al. Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer. Cancer Gene Ther. 2016;23:355–64.
Del Papa J, Petryk J, Bell JC, Parks RJ. An oncolytic adenovirus vector expressing p14 FAST protein induces widespread syncytium formation and reduces tumor growth rate in vivo. Mol Ther Oncolytics. 2019;14:107–20.
Tollefson AE, Ryerse JS, Scaria A, Hermiston TW, Wold WS. The E3-11.6-kDa adenovirus death protein (ADP) is required for efficient cell death: characterization of cells infected with adp mutants. Virology 1996;220:152–62.
Blair GE, Dixon SC, Griffiths SA, Zajdel ME. Restricted replication of human adenovirus type 5 in mouse cell lines. Virus Res 1989;14:339–46.
Silverstein G, Strohl WA. Restricted replication of adenovirus type 2 in mouse Balb/3T3 cells. Arch Virol 1986;87:241–64.
Prestwich RJ, Errington F, Diaz RM, Pandha HS, Harrington KJ, Melcher AA, et al. The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon. Hum Gene Ther. 2009;20:1119–32.
Marelli G, Howells A, Lemoine NR, Wang Y. Oncolytic viral therapy and the immune system: a double-edged sword against cancer. Front Immunol 2018;9:866.
Zhang Z, Krimmel J, Hu Z, Seth P. Systemic delivery of a novel liver-detargeted oncolytic adenovirus causes reduced liver toxicity but maintains the antitumor response in a breast cancer bone metastasis model. Hum Gene Ther. 2011;22:1137–42.
Hallden G, Hill R, Wang Y, Anand A, Liu TC, Lemoine NR, et al. Novel immunocompetent murine tumor models for the assessment of replication-competent oncolytic adenovirus efficacy. Mol Ther 2003;8:412–24.
Franks LM, Carbonell AW, Hemmings VJ, Riddle PN. Metastasizing tumors from serum-supplemented and serum-free cell lines from a C57BL mouse lung tumor. Cancer Res 1976;36:1049–55.
Rincon E, Cejalvo T, Kanojia D, Alfranca A, Rodriguez-Milla MA, Gil Hoyos RA, et al. Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model. Oncotarget 2017;8:45415–31.
Li X, Wang P, Li H, Du X, Liu M, Huang Q, et al. The efficacy of oncolytic adenovirus is mediated by T-cell responses against virus and tumor in Syrian hamster model. Clin Cancer Res. 2017;23:239–49.
Thomas MA, Spencer JF, Toth K, Sagartz JE, Phillips NJ, Wold WS. Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model. Mol Ther 2008;16:1665–73.
Wold WS, Toth K. Chapter three–Syrian hamster as an animal model to study oncolytic adenoviruses and to evaluate the efficacy of antiviral compounds. Adv Cancer Res. 2012;115:69–92.
Jogler C, Hoffmann D, Theegarten D, Grunwald T, Uberla K, Wildner O. Replication properties of human adenovirus in vivo and in cultures of primary cells from different animal species. J Virol. 2006;80:3549–58.
Schenk M, Matar AJ, Hanekamp I, Hawley RJ, Huang CA, Duran-Struuck R. Development of a transplantable GFP+ B-cell lymphoma tumor cell line from MHC-defined miniature swine: potential for a large animal tumor model. Front Oncol 2019;9:209.
Allen C, McDonald C, Giannini C, Peng KW, Rosales G, Russell SJ, et al. Adenoviral vectors expressing fusogenic membrane glycoproteins activated via matrix metalloproteinase cleavable linkers have significant antitumor potential in the gene therapy of gliomas. J gene Med. 2004;6:1216–27.
Brade AM, Szmitko P, Ngo D, Liu FF, Klamut HJ. Heat-directed tumor cell fusion. Hum Gene Ther. 2003;14:447–61.
Chen HH, Cawood R, El-Sherbini Y, Purdie L, Bazan-Peregrino M, Seymour LW, et al. Active adenoviral vascular penetration by targeted formation of heterocellular endothelial-epithelial syncytia. Mol Ther 2011;19:67–75.
Ahmed A, Jevremovic D, Suzuki K, Kottke T, Thompson J, Emery S, et al. Intratumoral expression of a fusogenic membrane glycoprotein enhances the efficacy of replicating adenovirus therapy. Gene Ther 2003;10:1663–71.
Alkhatib G, Richardson C, Shen SH. Intracellular processing, glycosylation, and cell-surface expression of the measles virus fusion protein (F) encoded by a recombinant adenovirus. Virology 1990;175:262–70.
Galanis E, Bateman A, Johnson K, Diaz RM, James CD, Vile R, et al. Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas. Hum Gene Ther. 2001;12:811–21.
Hoffmann D, Bangen JM, Bayer W, Wildner O. Synergy between expression of fusogenic membrane proteins, chemotherapy and facultative virotherapy in colorectal cancer. Gene Ther. 2006;13:1534–44.
Hoffmann D, Bayer W, Heim A, Potthoff A, Nettelbeck DM, Wildner O. Evaluation of twenty-one human adenovirus types and one infectivity-enhanced adenovirus for the treatment of malignant melanoma. J Invest Dermatol. 2008;128:988–98.
Hoffmann D, Wildner O. Enhanced killing of pancreatic cancer cells by expression of fusogenic membrane glycoproteins in combination with chemotherapy. Mol Cancer Ther. 2006;5:2013–22.
Funding was provided by grants to R.J.P. from the Cancer Research Society (grant number 19363), Canadian Institutes of Health Research (MOP-136898, MOP-142316) and the Natural Sciences and Engineering Research Council (RGPIN-2014-04810, RGPIN-2019-04786). R.C. and J.D.P. were supported by the Ontario Government through a Queen Elizabeth II Graduate Scholarship in Science and Technology and an Ontario Graduate Scholarship.
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The authors declare that they have no conflict of interest.
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Del Papa, J., Clarkin, R.G. & Parks, R.J. Use of cell fusion proteins to enhance adenoviral vector efficacy as an anti-cancer therapeutic. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-0192-9