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For the Success of Oncolytic Viruses: Single Cycle Cures or Repeat Treatments? (One Cycle Should Be Enough)

2018; Elsevier BV; Volume: 26; Issue: 8 Linguagem: Inglês

10.1016/j.ymthe.2018.07.003

1525-0024

Stephen J. Russell,

Viral gastroenteritis research and epidemiology

Oncolytic viruses (OVs) should be aggressively pursued as single cycle therapies to replace the protracted and poorly tolerated cancer treatment regimens currently offered to patients with surgically incurable cancers. Patients want single cycle therapies, clinical proof of concept exists for the efficacy of the approach, and OVs can be further engineered to increase their virulence, at the same time controlling their capacity to cause collateral damage by targeting their tropisms. Long-term repeat dosing regimens give diminishing returns with each successive OV administration, there are no preclinical or clinical studies demonstrating superiority of repeat dosing versus single cycle OV therapy and, even if harmless, it would be wasteful to continue OV therapy once patients are no longer deriving benefit. So what is a "single cycle" of oncolytic virotherapy? The definition adopted for the purpose of the current debate is that a single cycle lasts no longer than 2 weeks, which is the approximate time taken for antiviral antibodies to appear in the bloodstream after the first virus exposure. For clarity, an OV may be administered multiple times during a single cycle. The main value of this "dose fractionation" approach is that it can give more uniform intratumoral distribution of the OV, whatever the route of administration. Closely spaced intratumoral injections deposit virus in different and noncontiguous regions of the injected tumor, whereas temporally spaced intravenous injections allow the virus to extravasate into distinct tumor microregions because the pattern of microvascular tumor perfusion fluxes over time.1Bailey K. Kirk A. Naik S. Nace R. Steele M.B. Suksanpaisan L. Li X. Federspiel M.J. Peng K.W. Kirk D. Russell S.J. Mathematical model for radial expansion and conflation of intratumoral infectious centers predicts curative oncolytic virotherapy parameters.PLoS ONE. 2013; 8: e73759Crossref PubMed Scopus (25) Google Scholar, 2Miller A. Nace R. Ayala-Breton C C. Steele M. Bailey K. Peng K.W. Russell S.J. Perfusion Pressure Is a Critical Determinant of the Intratumoral Extravasation of Oncolytic Viruses.Mol. Ther. 2016; 24: 306-317Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar While the OVs currently approved or being tested in clinical trials were mostly designed to be administered repeatedly and to wage an immunological war of attrition on cancer, the future prospect of a single cycle OV cure offers a far more appealing prospect. A modern day diagnosis of surgically incurable cancer will typically result in the patient being offered a potentially toxic multimodality treatment program lasting months to years. Intensive months of long multi-cycle induction therapies are frequently followed by equally protracted consolidation regimens, which may then be followed by years of maintenance therapy. Nonspecific symptoms such as fatigue or lethargy and nonspecific gastrointestinal (GI) disturbance are common during maintenance therapy and negatively impact overall quality of life. The idea of a single cycle OV therapy that can result in long term disease remission or even cure, without the need for maintenance therapy, is very appealing to most cancer patients. Is it reasonable to imagine that OVs are capable of delivering a single cycle cure? Recent successes with chimeric antigen receptor (CAR)-T cell therapy have taught us the potential power of "living" drugs that self amplify in the body, specifically recognize and attack the tumor, and do not stop killing until there are no cancer cells left.3Perales M.A. Kebriaei P. Kean L.S. Sadelain M. Building a Safer and Faster CAR: Seatbelts, Airbags, and CRISPR.Biol. Blood Marrow Transplant. 2018; 24: 27-31Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Viruses have similar "Terminator"-like properties and have the potential to provide a new and more versatile generation of targeted, self-amplifying cancer therapies capable of delivering a single-shot cure. Since virus targeting is not solely reliant on the availability of unique tumor cell surface markers (which are few and far between), but can also be directed to targets inside the cancer cell, the potential for generating truly tumor-specific viruses far outstrips the potential for generating tumor-specific T cells. Numerous preclinical studies have reported tumor eradication after a single OV administration, not only in immune compromised mice where intratumoral spread and oncolytic destruction remain relatively unopposed due to the lack of an adaptive immune response, but also in immunocompetent syngeneic tumor models where the OV races with the antiviral immune response, destroying as many tumor cells as it can infect before the infection is controlled, after which residual uninfected tumor cells are eliminated by tumor-reactive effector T cells generated and/or amplified in the slip stream of the antiviral immune response. This two-stage mechanism of tumor eradication was notably demonstrated in an immune competent plasmacytoma model using a single intravenous dose of VSV-IFNβ-NIS, a recombinant vesicular stomatitis virus that had been engineered to encode mouse interferon beta to enhance the proinflammatory properties of the virus, and the thyroidal sodium iodide symporter (NIS) to drive radioiodine uptake in virus-infected tissues so that the intratumoral spread of the infection could be noninvasively monitored using single-photon emission computed tomography (SPECT) imaging in living animals.4Naik S. Nace R. Federspiel M.J. Barber G.N. Peng K.W. Russell S.J. Curative one-shot systemic virotherapy in murine myeloma.Leukemia. 2012; 26: 1870-1878Crossref PubMed Scopus (64) Google Scholar Proof of concept for effective single cycle virotherapy has also been obtained in a human clinical setting. In one particularly compelling example, a 49-year-old woman with disseminated, treatment refractory myeloma obtained a durable complete remission after a single, very high dose intravenous infusion of MV-NIS, an oncolytic measles virus.5Russell S.J. Federspiel M.J. Peng K.W. Tong C. Dingli D. Morice W.G. Lowe V. O'Connor M.K. Kyle R.A. Leung N. et al.Remission of disseminated cancer after systemic oncolytic virotherapy.Mayo Clin. Proc. 2014; 89: 926-933Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar The treatment led to rapid oncolytic destruction of her myeloma cells, which was followed by long term immune control, boosted on two occasions by local radiotherapy treatment to recurrent bone lesions, but with no sign of systemic relapse. Today she remains in complete remission having had no systemic antimyeloma therapy in the 5 years following her MV-NIS infusion, and her bone marrow remains negative for minimal residual disease (S.J.R., unpublished data). Importantly, although this patient had been previously vaccinated against measles, she was measles seronegative by the time she received her MV-NIS infusion. While proof of principle for the single shot cure is firmly established, the majority of OV-treated patients (and tumor-bearing mice) have not responded so favorably to the therapy, either because the OVs have been so attenuated that they are unable to overcome the innate immune defenses of the tumor cells and/or because they are neutralized by antiviral antibodies before they reach their target.6Warner S.G. O'Leary M.P. Fong Y. Therapeutic oncolytic viruses: clinical advances and future directions.Curr. Opin. Oncol. 2017; 29: 359-365Crossref PubMed Scopus (14) Google Scholar, 7Robinson S. Galanis E. Potential and clinical translation of oncolytic measles viruses.Expert Opin. Biol. Ther. 2017; 17: 353-363Crossref PubMed Scopus (36) Google Scholar In general, since all currently studied OVs lack critical virulence determinants, when an occasional tumor does respond dramatically to a single OV administration, it is fair to assume not only that the patient was seronegative to the virus being used, but also that the tumor had defective innate antiviral defenses, a common finding that is increasingly recognized as a key driver of intratumoral virus propagation.8Liu Y.P. Suksanpaisan L. Steele M.B. Russell S.J. Peng K.W. Induction of antiviral genes by the tumor microenvironment confers resistance to virotherapy.Sci. Rep. 2013; 3: 2375Crossref PubMed Scopus (44) Google Scholar Thus, if single cycle OV therapy is to be more broadly applied across the cancer spectrum, it will be necessary to use low seroprevalence OVs, rearm them with virulence factors so that they can overcome the innate antiviral defenses of even the most resilient tumors, and then target them to ensure they can be safely deployed.9Maroun J. Muñoz-Alía M. Ammayappan A. Schulze A. Peng K.W. Russell S. Designing and building oncolytic viruses.Future Virol. 2017; 12: 193-213Crossref PubMed Scopus (86) Google Scholar Fortunately, since they are the key to avoiding collateral damage to noncancerous normal tissues, effective virus-targeting technologies are available. Targeting is especially relevant in the single cycle OV scenario where high virulence OVs will be used, doses will be pushed to the limits of feasibility, and immunomodulatory drugs may also be deployed to control the antiviral immune responses, thereby extending the "reach" of the virus. Targeting has been elegantly demonstrated for a number of OV platforms through engineering of their attachment specificities (transductional), and/or promoter-enhancer elements (transcriptional).10Russell S.J. Peng K.W. Bell J.C. Oncolytic virotherapy.Nat. Biotechnol. 2012; 30: 658-670Crossref PubMed Scopus (971) Google Scholar The attachment and subsequent cell entry of enveloped viruses such as measles, herpes simplex virus (HSV), and vesicular stomatitis virus (VSV) has been efficiently and accurately retargeted by ablating their natural receptor tropisms and then displaying cell targeting polypeptides on their surfaces.11Nakamura T. Peng K.W. Harvey M. Greiner S. Lorimer I.A. James C.D. Russell S.J. Rescue and propagation of fully retargeted oncolytic measles viruses.Nat. Biotechnol. 2005; 23: 209-214Crossref PubMed Scopus (222) Google Scholar, 12Petrovic B. Gianni T. Gatta V. Campadelli-Fiume G. Insertion of a ligand to HER2 in gB retargets HSV tropism and obviates the need for activation of the other entry glycoproteins.PLoS Pathog. 2017; 13: e1006352Crossref PubMed Scopus (24) Google Scholar, 13Ammayappan A. Peng K.W. Russell S.J. Characteristics of oncolytic vesicular stomatitis virus displaying tumor-targeting ligands.J. Virol. 2013; 87: 13543-13555Crossref PubMed Scopus (26) Google Scholar, 14Grandi P. Fernandez J. Szentirmai O. Carter R. Gianni D. Sena-Esteves M. Breakefield X.O. Targeting HSV-1 virions for specific binding to epidermal growth factor receptor-vIII-bearing tumor cells.Cancer Gene Ther. 2010; 17: 655-663Crossref PubMed Scopus (20) Google Scholar Exquisite control of the specificity of cell entry has been achieved in this way through the display of growth factors, snake venom peptides, single chain antibodies, darpins, and even single chain T cell receptors to redirect the virus attachment proteins.15Buchholz C.J. Friedel T. Büning H. Surface-Engineered Viral Vectors for Selective and Cell Type-Specific Gene Delivery.Trends Biotechnol. 2015; 33: 777-790Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 16Peng K.W. Holler P.D. Orr B.A. Kranz D.M. Russell S.J. Targeting virus entry and membrane fusion through specific peptide/MHC complexes using a high-affinity T-cell receptor.Gene Ther. 2004; 11: 1234-1239Crossref PubMed Scopus (33) Google Scholar, 17Friedrich K. Hanauer J.R. Prüfer S. Münch R.C. Völker I. Filippis C. Jost C. Hanschmann K.M. Cattaneo R. Peng K.W. et al.DARPin-targeting of measles virus: unique bispecificity, effective oncolysis, and enhanced safety.Mol. Ther. 2013; 21: 849-859Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 18Jing Y. Tong C. Zhang J. Nakamura T. Iankov I. Russell S.J. Merchan J.R. Tumor and vascular targeting of a novel oncolytic measles virus retargeted against the urokinase receptor.Cancer Res. 2009; 69: 1459-1468Crossref PubMed Scopus (57) Google Scholar, 19Ong H.T. Trejo T.R. Pham L.D. Oberg A.L. Russell S.J. Peng K.W. Intravascularly administered RGD-displaying measles viruses bind to and infect neovessel endothelial cells in vivo.Mol. Ther. 2009; 17: 1012-1021Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Likewise, tissue-specific promoter-enhancer elements have been engineered into the genomes of DNA viruses upstream of genes that control their life cycles.20Nakashima H. Nguyen T. Kasai K. Passaro C. Ito H. Goins W.F. Shaikh I. Erdelyi R. Nishihara R. Nakano I. et al.Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma.Clin. Cancer Res. 2018; 24: 2574-2584Crossref PubMed Scopus (29) Google Scholar, 21Yoon A.R. Hong J. Kim S.W. Yun C.O. Redirecting adenovirus tropism by genetic, chemical, and mechanical modification of the adenovirus surface for cancer gene therapy.Expert Opin. Drug Deliv. 2016; 13: 843-858Crossref PubMed Scopus (37) Google Scholar And, in a third targeting strategy, specific unwanted tissue tropisms are eliminated by engineering appropriate microRNA target sequences into the OV genome.22Kelly E.J. Russell S.J. MicroRNAs and the regulation of vector tropism.Mol. Ther. 2009; 17: 409-416Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 23Ruiz A.J. Russell S.J. MicroRNAs and oncolytic viruses.Curr. Opin. Virol. 2015; 13: 40-48Crossref PubMed Scopus (50) Google Scholar This paradigm of microRNA targeting has been demonstrated in Coxsackievirus A21, vaccinia, adenovirus, HSV, and measles OVs used to eliminate toxicities in brain, muscle, or liver.24Kelly E.J. Hadac E.M. Cullen B.R. Russell S.J. MicroRNA antagonism of the picornaviral life cycle: alternative mechanisms of interference.PLoS Pathog. 2010; 6: e1000820Crossref PubMed Scopus (50) Google Scholar, 25Hikichi M. Kidokoro M. Haraguchi T. Iba H. Shida H. Tahara H. Nakamura T. MicroRNA regulation of glycoprotein B5R in oncolytic vaccinia virus reduces viral pathogenicity without impairing its antitumor efficacy.Mol. Ther. 2011; 19: 1107-1115Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 26Ylösmäki E. Hakkarainen T. Hemminki A. Visakorpi T. Andino R. Saksela K. Generation of a conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type-specific MicroRNA.J. Virol. 2008; 82: 11009-11015Crossref PubMed Scopus (111) Google Scholar, 27Lee C.Y. Rennie P.S. Jia W.W. MicroRNA regulation of oncolytic herpes simplex virus-1 for selective killing of prostate cancer cells.Clin. Cancer Res. 2009; 15: 5126-5135Crossref PubMed Scopus (87) Google Scholar, 28Leber M.F. Bossow S. Leonard V.H. 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: 1097-1106Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 29Mazzacurati L. Marzulli M. Reinhart B. Miyagawa Y. Uchida H. Goins W.F. Li A. Kaur B. Caligiuri M. Cripe T. 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: 99-107Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Repeat OV dosing is of questionable value because the tumor cell killing potential of an OV diminishes with each successive dose. Vaccination is predicated on the fact that adaptive antiviral immune responses, especially those leading to the generation of antiviral antibodies and memory T lymphocytes, are powerfully protective and prevent virus-mediated tissue damage upon repeat virus exposure. OVs are no exception to this universal virological principle. OV delivery is severely compromised by antiviral antibodies, whatever route of administration is chosen, and their ability to propagate in neoplastic tissues is further limited by antiviral T cells. These limitations can be partially overcome by deploying OVs inside infected carrier cells to circumvent antibody neutralization,30Russell S.J. Peng K.W. The utility of cells as vehicles for oncolytic virus therapies.Curr. Opin. Mol. Ther. 2008; 10: 380-386PubMed Google Scholar and intratumoral spread may be less important in tumors lacking MHC expression, but nevertheless presents a serious obstacle to the delivery and spread of the vast majority of OV candidates upon repeat administration. While the oncolytic phase of an OV infection is, without doubt, compromised by antiviral immunity, the possibility remains that the diminishing tumor cell kill achieved after each successive OV dose may nonetheless be sufficient to sustain or even progressively boost the cytotoxic lymphocyte (CTL) response to tumor antigens, thereby sustaining the destruction of uninfected tumor cells.31Russell S.J. Barber G.N. Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines.Cancer Cell. 2018; 33: 599-605Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar This is the primary thrust of Melcher's argument in the accompanying Commentary in this issue of Molecular Therapy, which is in favor of repeat dosing and is an important claim for the OV field. In support of the claim, available evidence does strongly support the idea that OV-mediated tumor destruction amplifies the CTL response to tumor antigens.32Shen W. Patnaik M.M. Ruiz A. Russell S.J. Peng K.W. Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia.Blood. 2016; 127: 1449-1458Crossref PubMed Scopus (87) Google Scholar, 33Woller N. Gürlevik E. Fleischmann-Mundt B. Schumacher A. Knocke S. Kloos A.M. Saborowski M. Geffers R. Manns M.P. Wirth T.C. et al.Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses.Mol. Ther. 2015; 23: 1630-1640Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 34Engeland C.E. Grossardt C. Veinalde R. Bossow S. Lutz D. Kaufmann J.K. Shevchenko I. Umansky V. Nettelbeck D.M. Weichert W. et al.CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy.Mol. Ther. 2014; 22: 1949-1959Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar However, at the present time there is little evidence to demonstrate that repeat administration of a single OV species serves to further amplify or even sustain the tumor-reactive CTLs.35Russell S.J. Peng K.W. Oncolytic Virotherapy: A Contest between Apples and Oranges.Mol. Ther. 2017; 25: 1107-1116Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Talimogene laherparevec (TVEC) is often cited as the example that proves the value of repeat OV dosing.35Russell S.J. Peng K.W. Oncolytic Virotherapy: A Contest between Apples and Oranges.Mol. Ther. 2017; 25: 1107-1116Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 36Rehman H. Silk A.W. Kane M.P. Kaufman H.L. Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy.J. Immunother. Cancer. 2016; 4: 53Crossref PubMed Scopus (228) Google Scholar This oncolytic HSV was approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of metastatic melanoma based on a phase 3 clinical trial in which the virus was administered by repeat intratumoral inoculation, initially at a dose of 106 infectious units, followed 3 weeks later by 108 infectious units with repeat dosing every 2 weeks thereafter.37Harrington K.J. Puzanov I. Hecht J.R. Hodi F.S. Szabo Z. Murugappan S. Kaufman H.L. Clinical development of talimogene laherparepvec (T-VEC): a modified herpes simplex virus type-1-derived oncolytic immunotherapy.Expert Rev. Anticancer Ther. 2015; 15: 1389-1403Crossref PubMed Scopus (79) Google Scholar The rationale for the design of this trial was that the first dose renders the patient HSV-immune without risking systemic spread of the primary inoculum and that later doses cause local inflammatory tumor damage to further stimulate antitumor immunity without the risk (or opportunity) of progeny viruses spreading via the bloodstream to normal host tissues or to other sites of tumor growth. Thus, the TVEC premise was that the repeat cycles of intratumoral therapy would serve to progressively boost the antitumor T cell response. However, no published studies demonstrate that antitumor T cell responses are progressively boosted by TVEC or that there is added value afforded by the second, third, and subsequent doses of virus. This concept is very important for the field and should be urgently addressed using both rodent models and correlative studies on blood or biopsy material from human subjects enrolled in TVEC trials. As to the current enthusiasm for combining OVs with immune checkpoint blocking antibodies, phase 1 and randomized phase 2 melanoma trials have recently been published showing that intratumoral TVEC substantially boosts the potency of pembrolizumab (anti-PD1) and ipilumumab (anti-CTLA4).38Ribas A. Dummer R. Puzanov I. VanderWalde A. Andtbacka R.H.I. Michielin O. Olszanski A.J. Malvehy J. Cebon J. Fernandez E. et al.Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy.Cell. 2017; 170: 1109-1119 e1110Abstract Full Text Full Text PDF PubMed Scopus (871) Google Scholar, 39Puzanov I. Milhem M.M. Minor D. Hamid O. Li A. Chen L. Chastain M. Gorski K.S. Anderson A. Chou J. et al.Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma.J. Clin. Oncol. 2016; 34: 2619-2626Crossref PubMed Scopus (376) Google Scholar TVEC was administered on a 2-weekly repeat dosing cycle in these studies, which were therefore uninformative as to whether a single OV injection would have been sufficient. Pertinent to this question, it has recently been shown in preclinical cancer models that a single OV injection can greatly enhance the antitumor efficacy of a subsequent more prolonged course of immune checkpoint inhibitor antibody therapy. However, since OVs are the primary focus of the current debate, combination therapies will not be further discussed. When considering the TVEC case study in relation to the single cycle versus repeat dosing discussion, it is worth pointing out that TVEC was designed for repeat intratumoral administration. If a single high intratumoral dose of TVEC (e.g., 109 infectious units) were administered to an HSV-naive subject, the virus might be expected to propagate extensively in the infected tumor, causing massive local destruction, but with systemic release of granulocyte-macrophage colony-stimulating factor (GM-CSF) potentially causing unacceptable systemic toxicity. Further, in the absence of anti-HSV antibodies, progeny TVEC virions generated in the infected tumor might spread via the bloodstream to normal tissues, causing additional toxicities. Whereas TVEC was not designed to be a single cycle therapy, if the HSV platform were further engineered to fully retarget its tropism by ligand display, promoter insertion and/or microRNA targeting, and if the GM-CSF transgene were removed from its genome, the resulting virus might be much better suited for single cycle high dose therapy without associated toxicities.14Grandi P. Fernandez J. Szentirmai O. Carter R. Gianni D. Sena-Esteves M. Breakefield X.O. Targeting HSV-1 virions for specific binding to epidermal growth factor receptor-vIII-bearing tumor cells.Cancer Gene Ther. 2010; 17: 655-663Crossref PubMed Scopus (20) Google Scholar, 20Nakashima H. Nguyen T. Kasai K. Passaro C. Ito H. Goins W.F. Shaikh I. Erdelyi R. Nishihara R. Nakano I. et al.Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma.Clin. Cancer Res. 2018; 24: 2574-2584Crossref PubMed Scopus (29) Google Scholar, 29Mazzacurati L. Marzulli M. Reinhart B. Miyagawa Y. Uchida H. Goins W.F. Li A. Kaur B. Caligiuri M. Cripe T. 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: 99-107Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar This and similar approaches are currently being pursued for a number of OV platforms and, in the opinion of the author, it is only a matter of time before they will realize their potential to reliably deliver single cycle cures. In this regard, the development of OV therapies can be likened to the evolution of the motor car industry where new, more powerful, more reliable, and safer models are continuously developed and introduced into the marketplace. In parallel with the continuous improvement and honing of OV platforms designed to deliver single cycle cures, it is likely that another avenue will be developed, namely repeat dosing with different OV species. In contrast to the diminishing returns approach of repeat dosing with a single OV species, there are good reasons to believe that sequential administration of OVs belonging to different virus families could result in progressive boosting of the CTL response to tumor antigens.31Russell S.J. Barber G.N. Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines.Cancer Cell. 2018; 33: 599-605Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar The rationale here is that, since the tumor antigens remain constant throughout the treatment schedule, regularly changing the mix of viral antigens with which they are copresented can serve to position the tumor antigens as the dominant targets for the immune response. This is in line with the principle of original antigenic sin, but has yet to be confirmed experimentally in the sequential oncolytic virotherapy setting.40Vatti A. Monsalve D.M. Pacheco Y. Chang C. Anaya J.M. Gershwin M.E. Original antigenic sin: A comprehensive review.J. Autoimmun. 2017; 83: 12-21Crossref PubMed Scopus (103) Google Scholar A final argument against repeat OV dosing is wastefulness. Even though repeat dosing may be associated with diminishing antitumor activity after each dose administered, it could be argued that no harm will come of it, so why not just continue? This might be a good commercial argument but repeat intratumoral dosing does require a great deal of time, effort, and inconvenience for the patient as well significant repetitive resource deployment, especially for those tumors that require CT or MRI guidance to place the needle in a deep-seated tumor for each repeat injection. Most of the OVs currently approved or in clinical testing were developed with a repeat dosing paradigm in mind. To this end, they have been substantially attenuated and engineered to be only modestly tumor selective and are often administered in combination with immune-enhancing checkpoint antibody therapy. Pursuit of the single cycle cure will require a shift of research emphasis toward the use of low seroprevalence viruses to which intended recipients have not been previously exposed, engineered not just for increased virulence but also for exquisite tumor specificity. These new viruses will be administered at the highest doses possible and will be combined with immunomodulatory drugs to slow the kinetics of the antiviral immune response. The age of single cycle OV cures is approaching. Oncolytic Virotherapy: Single Cycle Cures or Repeat Treatments? (Repeat Dosing Is Crucial!)Alan MelcherMolecular TherapyJuly 15, 2018In BriefRepeat dosing is essential for the success of oncolytic virotherapy because it is a form of cancer immunotherapy. Therefore, the focus of optimizing the efficacy of oncolytic viruses (OVs) needs to be maximizing activation of anti-tumor immunity, and this simply cannot be achieved by a "single shot". Full-Text PDF Open Archive