Expediting Viral Therapies For Cancers To the Clinic
Authors: Yuman Fong
Journal: Molecular Therapy (2016)

The first immuno-oncolytic virus specifically designed for cancer was an engineered herpesvirus created in 1991 by Bob Martuza and his colleagues and was directed at the uniformly fatal malignant glioma.1Martuza 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: 854-856Crossref PubMed Scopus (782) Google Scholar Since then, many viruses have been engineered and tested against this disease, with most based biologically on the great difference in cellular replication of malignant gliomas compared to nonreplicating neighboring neurons. Two and a half decades later, we have come to a very exciting period in the development of engineered viruses as treatment for cancer in general, and for gliomas in particular.2Peters C Nigim F Chiocca EA Rabkin SD Oncolytic viruses on the cusp of success?: proceedings of the 9th International Conference on Oncolytic Virus Therapeutics.Mol Ther Oncolytics. 2016; 3: 16016Abstract Full Text Full Text PDF Scopus (5) Google Scholar In October 2015, talimogene laherparepvec, an immuno-oncolytic herpesvirus, was approved for treatment of metastatic melanoma.3Fong Y Oncolytic treatment for cancer recommended for approval.Mol Ther. 2015; 23: 1131Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar For gliomas, Westphal et al. conducted a phase III randomized trial in patients with resectable glioblastoma and compared either (i) surgical resection of the tumor and perilesional injection of sitimagene ceradenovec (an adenovirus-carrying herpes simplex virus thymidine kinase) followed by intravenous ganciclovir or (ii) resection and standard care alone. Although overall survival was not altered, median time to death or re-intervention was lengthened.4Westphal M Yla-Herttuala S Martin J Warnke P Menei P Eckland D et al.Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial.Lancet Oncol. 2013; 14: 823-833Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Recently, Cloughesy et al. reported exciting results of a phase I trial using vocimagene amiretrorepvec in treatment of recurrent malignant glioma. This agent is a retroviral vector that preferentially delivers the yeast gene coding cytosine deaminase to dividing cancer cells. When used with the prodrug 5-fluorocytosine, high-grade glioma cells are killed. In this phase I trial, the median survival of the 43 evaluable patients was 13.6 months, significantly longer that the 7.1 months of the control arm of another contemporary trial of treatment for recurrent glioma.5Cloughesy TF Landolfi J Hogan DJ Bloomfield S Carter B Chen CC et al.Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma.Sci Transl Med. 2016; 8: 341ra75Crossref PubMed Scopus (127) Google Scholar Remarkable results have also been seen in the work by Matthias Gromeier et al. using a modified poliovirus (PVS-RIPO) for recurrent gliomas,6Goetz C Dobrikova E Shveygert M Dobrikov M Gromeier M Oncolytic poliovirus against malignant glioma.Future Virol. 2011; 6: 1045-1058Crossref PubMed Scopus (37) Google Scholar with reports of near-complete responses and a subject surviving 5 years.7CBS News Promising brain cancer trial given breakthrough status by FDA 12 May 2016 http://www.cbsnews.com/news/promising-duke-university-polio-brain-cancer-trial-given-breakthrough-status-60-minutesGoogle Scholar These and other engineered viruses are providing hope of effective therapy in a cancer that has proven highly resistant to conventional therapies. Despite this excitement, the 20-year interval from successful engineering of the first oncolytic virus to approval of the first clinical agent highlights the slow pace at which novel gene therapies traverse the trial and regulatory-approval process. For recurrent gliomas (as in many other deadly cancers targeted by viruses—including recurrent pancreatic cancers or refractory triple-negative breast cancer), the median survival is on the order of 4–6 months.1Martuza 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: 854-856Crossref PubMed Scopus (782) Google Scholar Years and decades in a trial and approval timeline represent failed translation of scientific discovery. A regulatory approval path established in 2012 in the United States, called “breakthrough therapy designation,” was meant to provide a fast track to advance to market agents with highly promising results in early testing.8US Food and Drug Administration Fact Sheet: Breakthrough Therapies. Food and Drug Administration Safety and Innovation Act (FDASIA) http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htmGoogle Scholar The US Food and Drug Administration (FDA) has put PVS-RIPO on this path. This and other expedited-review pathways, including “fast track,” “priority review,” and “accelerated approval,” aim to speed to clinical use the most promising agents for the most life-threatening of illnesses. However, these accelerated pathways will probably trim only months, not years, off the approval process. In addition, most new cancer therapies represent substantial forward progress, but not revolutionary breakthroughs. Thus, only 21 agents have received breakthrough therapy designation. We need additional paths to allow agents with substantial promise to move quickly to widespread trials across the entire nation. This would not only expedite collection of data for approval evaluation but also increase patient access. In the European Union, a very innovative “conditional marketing authorization” (MA) approval route has been established by the European Medicines Agency.9European Medicines Agency Conditonal marketing authorisation http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000925.jsp&mid=WC0b01ac05809f843bGoogle Scholar For agents meant to treat debilitating or life-threatening diseases—particularly if the disease is rare—conditional MA may be granted if the agent fills an unmet need and the benefit–risk balance is positive, even if data for definitive establishment of efficacy are still forthcoming. The conditional MA status can be renewed yearly for 5 years, during which time comprehensive data must be gathered and presented to justify conversion to full marketing approval. In this approval path, an agent treating a rare, fatal disease with no current treatment may be granted conditional approval after early phase I or II studies if found to be very safe and showing some signs of efficacy. This pathway allows (i) wide access to the new agent and (ii) revenue during the final trial phases. Overall it substantially encourages promising agents to move forward into postregistration data collection. This pathway to approval makes the European Union a highly desirable place for novel gene therapy development. It will also probably make the European Union a destination for “novel therapy tourism” for desperate patients stricken with rare diseases facing limited therapeutic options at home. The United States should consider a similar program for conditional approval of novel therapies. If that is to be reasonable in the United States, however, the FDA should help set reasonable charges for new agents. At present, the FDA is not allowed to know the proposed charges during a new drug approval process, because that would be considered “rationing.” Thus, many very expensive drugs have been approved despite very low efficacy. This is also one of the reasons that costs of many medicines are substantially lower in other parts of the world. If a drug is to be registered for novel therapy status after early safety trials—in part in exchange for access to the shorter, less expensive path—the FDA must be able to help set a reasonable price based on costs of development, costs of manufacturing, and potential impact. There are worries that an accelerated approval approach with nonrandomized treatments in different patient groups, at many centers, and with possible crossover designs may lead to results that are difficult to interpret and therefore not definitive. Thus, in taking such an approach, the investigators would need to work early and closely with regulatory agencies in the preapproval process to plan trials with appropriate end points to secure required data for final regulatory approval. Ideally, treatments for rare diseases and rapidly fatal diseases should optimally be tested through consortia of investigators with access to all of the most promising novel agents. This allows for the most rapid accrual to trials of promising agents, and allows early testing of combinations of multiple promising agents. Obtaining and sharing the same correlative scientific data aiming to predict response and outcome will aid in decisions on the best agents and best combinations of agents, as well as in understanding mechanisms of resistance. Having a fluid method of placing subjects on the next open cohort of rolling phase I trials, or moving subjects quickly from one trial to another when progression occurs, will give patients the best chance of benefiting from clinical trials. Having such consortia for rare cancers with open access to biological data will allow a panel of collaborating experts to peer review each other's work. It will also allow a better interface between researchers and national funding agencies, foundations, and investors. Funding many interrelated, coordinated trials allows much greater likelihood of clinical or scientific returns from research funding investment. Productive consortia, along with early conditional approval of safe promising agents, will ensure that novel therapies move quickly to the effective treatment of fatal diseases as quickly as possible. The opinions expressed in this editorial do not necessarily represent the views or official positions of the Society, its officers, the Journal, or its editorial team.