Panorama From the Oncolytic Virotherapy Summit

In June, the historical heart of Quebec City welcomed the 7th International Summit on Oncolytic Viral Therapeutics for an excellent opportunity to witness the growth of the field, in both size and maturity. Efforts are being made to better characterize interactions between oncolytic viruses (OVs) and host components, both inside and outside the tumor bed, with their relative contribution to the overall therapeutic efficacy. New approaches in improving OV delivery, tumor selectivity, spreading, and killing continue to flourish. Clinical evaluations, ongoing and upcoming, have never been this numerous. The present review draws on some of the unpublished and recently published findings reported during the meeting. Oncolytic virotherapy appears to be a promising contender for the treatment of neoplasms that fail to respond to approved therapies. Encouraging responses with minimal side effects have already been reported against cancers considered to be incurable, such as glioblastoma multiforme (GBM). With a 15-month median survival and a 5-year survival rate of <10% under standard care, it is the most aggressive primary brain malignancy. Several OVs have demonstrated a tolerable safety profile in phase I trials against GBM. At this summit, related efficacy data were unveiled. It was reported that 52% of the 24 patients who received a single intratumoral injection of the adenovirus (Ad) DNX-2401 as first-line therapy showed stabilization or partial or complete regression of their disease. Six patients are still alive, one reaching 4 years posttreatment (Frank Tufaro, DNAtrix). Clinical activity and benefits have also been reported in GBM patients treated with the replicating lentivirus Toca511 (in combination with the prodrug TocaFC) (Doug Jolly, Tocagen) or with the poliovirus PVS-RIPO (Matthias Gromeier, Duke University). Both viruses were administered locally, as a first-line treatment or as a second-line therapy in combination with resection, respectively. Results are very promising with many complete responses so far. Impressively, three of the seven patients who received the PVS-RIPO so far have already displayed complete response. Three viral oncolytics have reached phases IIB–III of clinical evaluation, giving hope for a first OV approval in Western countries: the modified vaccinia virus (VACV) Pexa-vec/JX-594 (Caroline Breitbach, Jennerex), the wild-type reovirus Reolysin, and the engineered herpes simplex virus (HSV) T-VEC.1Sheridan C Amgen announces oncolytic virus shrinks tumors.Nat Biotechnol. 2013; 31: 471-472Crossref PubMed Scopus (14) Google Scholar Results from the phase III OPTiM trial, involving T-VEC for the treatment of unresected stages IIIb/c and IV melanoma, were presented. T-VEC, an oncolytic HSV-1 expressing granulocyte–macrophage colony-stimulating factor (GM-CSF), was administered into primary or nodal lesions, while the control arm received subcutaneous injections of GM-CSF. The primary end point was met, with a durable response (objective response lasting 6 months or more) observed in 16.3% of patients treated with T-VEC vs. 2.1% in the GM-CSF cohort. The difference was even more striking when only stage IIIb/c patients were considered: 33% vs. 0%, respectively. Several secondary end points were also met, including overall response (26.4% vs. 5.7%). Overall survival analysis was not finalized but showed a trend in favor of T-VEC. Because of tumor evasion and metastasis, efficient treatment of advanced-stage neoplasms will probably require systemic delivery of the oncolytic agent. Through this route, OVs must overcome numerous barriers to reach the tumor, such as antibody neutralization, macrophage capture, and off-target tissue adsorption. Two years ago, Pexa-Vec/JX-594 first demonstrated anti-tumor activity following a single intravenous injection in 12 of 22 patients with advanced treatment-refractory solid tumors.2Breitbach CJ Burke J Jonker D Stephenson J Haas AR Chow LQ et al.Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans.Nature. 2011; 477: 99-102Crossref PubMed Scopus (405) Google Scholar Ever since, several OVs—including Reolysin, the Ad chimera ColoAd1, the VACV GL-ONC1, and the Seneca valley virus NTX-010—have been reported as being suitable for safe blood infusion in phase I human trials. Their therapeutic efficacy is currently under clinical investigation. The list is rapidly extending as additional candidates are translating into the clinic (e.g., measles virus MV-NIS, parvovirus H-1 ParvOryx, rhabdoviruses VSV-hIFN-β and Maraba MG1-hMAGE-A3). Efficacy of oncolytic virotherapy relies not only on viral oncolysis of infected cells but also on the induction of antitumor immunity. Immune mediators contributing to OV-induced antitumor immunity and their dynamics of action are subject to particular attention. Treatment with oncolytic reovirus typically induces the secretion of proinflammatory cytokines and the recruitment of antigen-presenting cells, natural killer (NK) cells, and T lymphocytes within the tumor environment.3Gujar SA Marcato P Pan D Lee PW Reovirus virotherapy overrides tumor antigen presentation evasion and promotes protective antitumor immunity.Mol Cancer Ther. 2010; 9: 2924-2933Crossref PubMed Scopus (71) Google Scholar,4Gujar SA Pan D Marcato P Garant KA Lee PW Oncolytic virus-initiated protective immunity against prostate cancer.Mol Ther. 2011; 19: 797-804Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Additionally, a recent study described concomitant inhibition of the infiltration and protumor effects of myeloid-derived suppressor cells and regulatory T cells.5Gujar S Dielschneider R Clements D Helson E Shmulevitz M Marcato P et al.Multifaceted therapeutic targeting of ovarian peritoneal carcinomatosis through virus-induced immunomodulation.Mol Ther. 2013; 21: 338-347Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In a murine melanoma model, reovirus-mediated priming of an antitumor cytotoxic response was independent of both virus replication and oncolysis.6Prestwich RJ Ilett EJ Errington F Diaz RM Steele LP Kottke T et al.Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication.Clin Cancer Res. 2009; 15: 4374-4381Crossref PubMed Scopus (129) Google Scholar A similar observation has recently been reported for the attenuated Maraba virus MG1 in the same model. Indeed, administration of MG1 resulted in a replication-independent, rapid, and intense activation of NK cells (Jiqing Zhang, Ottawa). For at least these two RNA viruses, the adjuvant role of virus-associated molecular patterns determined therapeutic efficacy. Such properties may be of particular interest in a perioperative setting. Indeed, the immunosuppression that follows surgery is associated with high risk of metastatic cancer recurrence.7Tai LH de Souza CT Bélanger S Ly L Alkayyal AA Zhang J et al.Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells.Cancer Res. 2013; 73: 97-107Crossref PubMed Scopus (146) Google Scholar It is speculated that activation of immune cells such as NK cells by replication-incompetent viruses has the potential to prevent tumor recurrence.8Tai LH Zhang J Scott KJ Tanese de Souza C Alkayyal AA Ananth AA et al.Perioperative influenza vaccination reduces post-operative metastatic disease by reversing surgery-induced dysfunction in natural killer cells.Clin Cancer Res. 2013; (e-pub ahead of print 30 August 2013)PubMed Google Scholar The adaptive antitumor immune response is commonly generated within a few weeks after OV administration, but a clinical impact of immunotherapy may not become apparent in short-term follow-up. Intriguingly, an ongoing human clinical trial involving the engineered poliovirus PVS-RIPO for the treatment of high-grade glioma appears to fit this emerging paradigm (Matthias Gromeier, Duke University)—tumor shrinkage was delayed to several months after local infusion of PVS-RIPO. Biopsy samples illustrated massive cancer cell necrosis and infiltration of macrophages and lymphocytes. Involvement of OV oncolysis at that time point was excluded, as viral clearance was achieved within 2 weeks postinjection because of a strong humoral response. Mechanisms in understanding these results will probably require better characterization of the interactions among poliovirus, infected brain tumor cells, and the immune system. OVs have been armed over the years with immunomodulatory factors to enhance their immunotherapeutic ability. Regardless of the protein expressed from the virus, such strategies allow for tumor-localized delivery at high local concentrations while avoiding toxicity that potentially arises from systemic administration. Transgenes encoding cytokines such as GM-CSF or interleukin-12 (IL-12) have been inserted into various OV backbones. One research group recently found that expressing IL-12 from an oncolytic HSV increased interferon-γ (IFN-γ) release, inhibited angiogenesis, and reduced the number of immunosuppressive regulatory T cells within the tumor.9Zhang W Fulci G Wakimoto H Cheema TA Buhrman JS Jeyaretna DS et al.Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models.Neoplasia. 2013; 15: 591-599Abstract Full Text PDF PubMed Scopus (58) Google Scholar Expression of trastuzumab, a monoclonal antibody targeting HER2, from an oncolytic Ad resulted in improved efficacy in HER2-positive cancers (Paula Savola, Helsinki). New studies are investigating the ability of measles virus (MV) armed with CTLA4 or PD-L1 antibodies to prolong survival (Guy Ungerechts, Heidelberg). Other research groups have armed VACV with TRAIL (Rinat Maksyutov, Koltsovo) or CD40L (Karolina Autio and Suvi Parvainen, Helsinki) to induce apoptosis and promote T-cell expansion, respectively. The presence of the VACV-soluble type I IFN-neutralizing protein B18R within the tumor environment has previously been shown to enhance HSV and vesicular stomatitis virus (VSV) antitumor activity.10Fu X Rivera A Tao L Zhang X Incorporation of the B18R gene of vaccinia virus into an oncolytic herpes simplex virus improves antitumor activity.Mol Ther. 2012; 20: 1871-1881Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar,11Paglino JC van den Pol AN Vesicular stomatitis virus has extensive oncolytic activity against human sarcomas: rare resistance is overcome by blocking interferon pathways.J Virol. 2011; 85: 9346-9358Crossref PubMed Scopus (44) Google Scholar,12Le Boeuf F Diallo JS McCart JA Thorne S Falls T Stanford M et al.Synergistic interaction between oncolytic viruses augments tumor killing.Mol Ther. 2010; 18: 888-895Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Recently, B18R has been expressed from a new immunomodulatory platform, the nonpathogenic commensal bacterium Escherichia coli. Tumor “preconditioning” with B18R expressing E. coli followed by treatment with VSV led to enhanced OV infection and greater therapeutic efficacy (Michelle Cronin, Cork). Overexpression of tumor-associated antigens (TAAs) from OV genomes has also been exploited to generate potent tumor-specific T-cell responses. To extend the strategy to different types of tumors, corresponding immunogenic TAAs will need to be identified. The TAA dopachrome tautomerase has been targeted for OV-mediated murine melanoma immunotherapy.13Bridle BW Stephenson KB Boudreau JE Koshy S Kazdhan N Pullenayegum E et al.Potentiating cancer immunotherapy using an oncolytic virus.Mol Ther. 2010; 18: 1430-1439Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar Dopachrome tautomerase is currently being investigated for the treatment of glioma in murine models together with the glioma-associated antigens EphrinRA2 and ED-B. Oncolytic VSV13Bridle BW Stephenson KB Boudreau JE Koshy S Kazdhan N Pullenayegum E et al.Potentiating cancer immunotherapy using an oncolytic virus.Mol Ther. 2010; 18: 1430-1439Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar and Maraba virus both display potent ability. In a strategy involving an oncolytic Maraba MG1 to response against the human tumor antigen generated strong responses University). will be into patients with advanced in the In to targeting one immunogenic it has been that targeting even responses are have therapeutic by a overall antitumor response. an with brain melanoma displayed survival following treatment with a from human melanoma J Kottke T J F P Diaz RM et expressed melanoma to tumor-associated antigens that Biotechnol. 2012; PubMed Scopus Google Scholar Such an prevent of and Indeed, the profile of from that of primary a only be by with from but not from in the of melanoma with from prostate cancer and A analysis led to the of TAAs to tumor in the of oncolytic virotherapy has been on the tumor barriers that the the tumor and various to delivery, and efficacy. 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