For the Success of Oncolytic Viruses: Single Cycle Cures or Repeat Treatments? (One Cycle Should Be Enough) (2018)

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 adenovirus on destruction of by a cell Virol. 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Oncol. 2016; PubMed Scopus Google Scholar was administered on a repeat dosing cycle in which were as to a single OV would have been to this it has been in preclinical cancer models that a single OV can enhance the antitumor efficacy of a subsequent more of immune therapy. since OVs are the of the current therapies will not be further the in to the single cycle versus repeat dosing it is that was designed for repeat intratumoral administration. a single high intratumoral dose of infectious were administered to an the virus be to in the tumor, local but with systemic of factor potentially systemic in the of antibodies, virions generated in the tumor spread the bloodstream to normal tissues, was not designed to be a single cycle therapy, if the HSV were further engineered to fully its tropism by ligand and/or microRNA and if the were its the virus be for single cycle high dose therapy without P. Fernandez J. Szentirmai O. Carter R. Gianni D. Sena-Esteves M. Breakefield X.O. 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T. et of sequences to and increase the of an oncolytic Ther. 2015; 23: Full Text Full Text PDF PubMed Scopus Google Scholar This and similar are currently being pursued for a number of OV platforms and, in the of the it is only a of time before they will their potential to single cycle In this the of OV therapies can be to the of the where more more and models are and into the In with the and of OV platforms designed to single cycle it is that will be repeat dosing with different OV In to the diminishing returns approach of repeat dosing with a single OV there are to that of OVs to different virus could result in of the to tumor S.J. Barber G.N. Oncolytic Viruses as Cancer 2018; 33: Full Text Full Text PDF PubMed Scopus Google Scholar The is since the tumor remain the treatment the of viral with which they are can to the tumor as the targets for the immune response. This is in with the principle of but has to be in the oncolytic virotherapy A. D.M. Y. C. A 2017; PubMed Scopus Google Scholar A against repeat OV dosing is repeat dosing may be with diminishing antitumor after each dose it could be that no will of so not This be a but repeat intratumoral dosing does a of and for the patient as especially for that or to the in a tumor for each repeat of the OVs currently approved or in clinical were with a repeat dosing paradigm in this they have been attenuated and engineered to be only tumor and are administered in with therapy. of the single cycle cure will a of the use of low seroprevalence viruses to which have not been previously engineered not for virulence but also for tumor new viruses will be administered at the doses and will be with immunomodulatory drugs to the of the antiviral immune response. The of single cycle OV is Oncolytic or Is dosing is for the of oncolytic virotherapy because it is a of cancer the of the efficacy of oncolytic viruses (OVs) to be activation of and this be achieved by a “single PDF