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Oncolytic viruses get a boost with first FDA-approval recommendation The future of cancer-killing viruses lies in their potential to augment cell and antibody immunotherapies.

Elie Dolgin a long-awaited era of viral therapies in milestone commitments) to for cancer and provide a powerful acquire the product’s inventor, BioVex A virus engineered to infect and tool for enhancing the efficacy of the Group. In the therapy’s Phase III destroy tumour cells stands on the latest immune-stimulating antibodies trial, 16% of the 295 participants cusp of regulatory approval by the and cell therapies. “It’s an exciting who received intralesional doses US Food and Drug Administration time for our patients,” says Howard of T-VEC experienced a durable (FDA). On 29 April, members of an Kaufman, Chief Surgical Officer at response — their tumours shrank for expanded advisory committee to the Rutgers Cancer Institute of New at least 6 months — whereas only 2% the agency voted 22 to 1 in favour Jersey, New Brunswick, New Jersey, of the 141 participants who received of allowing sales of talimogene USA, who led the T‑VEC trials. subcutaneous shots of granulocyte– laherparepvec (T‑VEC) — a version “This will open up a completely macrophage colony-stimulating factor of the herpes simplex virus that both new class of drugs.” (GM‑CSF) showed such a response. attacks cancer cells and enhances The FDA will make a full Although patients who took antitumour immune responses — licensing decision by 27 October. T‑VEC gained an average of just for the treatment of unresectable An evaluation for European 4.4 months of life over those who and recurrent melanoma. marketing authorization is expected took GM‑CSF — with median If approved, T‑VEC will become before the end of the year. survival times of 23.3 months and the first tumour-targeted viral T‑VEC is being developed by 18.9 months, respectively — 11% agent to reach pharmaceutical the biotech giant Amgen, which of T‑VEC recipients showed no shelves outside of China. Such a in 2011 promised to pay up to signs of cancer after treatment. stamp of approval could usher in US$1 billion (including $575 million This complete response rate

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surpasses even those seen in trials for all great timing that we actually have things to leads to earlier expression of the glycoprotein recently approved immunotherapy drugs take the brakes off the antitumour immune US11, which also enhances replication in approved for melanoma, although the response as well”. cancer cells.) study population included more patients Some investigators are also beginning T‑VEC, like several other products in with earlier-stage disease, clouding direct to combine oncolytic virotherapy with the oncolytic pipeline, also has an added comparisons. adoptive T‑cell therapies. Last year, for element of immune stimulation deliberately example, a research team from the Baylor built into the virus. Scientists generally Go together College of Medicine in Houston, Texas, USA, include transgenes that encode a range of Many researchers expect to see even better reported that an armed oncolytic adenovirus cytokines and chemokines in their viruses, response rates when T‑VEC is combined boosted the efficacy of a chimeric antigen to stimulate various lymphocyte populations with checkpoint-blocking antibodies — receptor (CAR) immunotherapy in mouse and drive immune responses. The most and trials are ongoing to test two-hit models of neuroblastoma (Cancer Res. 74, widely used such cytokine is GM‑CSF, which regimens. Drug developers are pairing 5195–5205; 2014). The Finnish start‑up TILT is incorporated into T‑VEC and three other T-VEC with Bristol-Myers Squibb’s Biotherapeutics plans to launch a Phase I trial mid- to late-stage clinical candidates (TABLE 1). , a cytotoxic T-lymphocyte of this combination strategy for melanoma While the majority of the oncolytic protein 4 (CTLA4)-specific antibody, in 2016. pipeline involves genetic engineering, in a Phase Ib/II study. Big pharma is taking notice, and thinking some drug developers instead rely on the The preliminary data “suggest that there beyond T‑VEC. “They’re reaching out to inherent tumour-destroying properties is in fact a significant added benefit of the virus companies now to say, ‘we’d like to work of some viruses. Viralytics’ CVA21, for combination,” says Kaufman, one of the trial with you to do combination therapies’,” says example, uses a proprietary formulation of investigators who reported early findings Frank Tufaro, Chief Executive of DNAtrix, a common-cold coxsackievirus to infect and from this study at this year’s meeting of the which is developing the oncolytic adenovirus enter cells through the intercellular adhesion American Society for Clinical Oncology. DNX-2401 for glioblastoma. molecule 1 (ICAM1) surface protein, which Plus, “almost all of the side effects we see are In January 2015, the AstraZeneca is overexpressed on many cancer cells. related to the ipilimumab,” notes surgical subsidiary MedImmune also announced a Oncolytics Biotech similarly makes use oncologist Robert Andtbacka, another deal to test its portfolio of immunotherapeutic of the natural properties of its RNA virus. investigator from the University of Utah’s agents together with an engineered strain The respiratory enteric orphan virus Huntsman Cancer Institute, in Salt Lake of vesicular stomatitis virus from Omnis preferentially replicates in Ras-activated City, Utah, USA. “We don’t seem to have Pharmaceuticals. cells, which cannot mount a proper antiviral a substantial increase in toxicity, which response, making cancer cells its preferred is reassuring.” Late last year, Kaufman, An infectious approach breeding ground. The company’s unmodified Andtbacka and their colleagues also began Oncolytic viruses are built to replicate in proprietary formulation of the oncolytic enrolling melanoma patients to receive Merck and rupture cancer cells — inducing the virus, called pelareorep, is in mid-stage trials & Co.’s programmed cell death protein 1 release of tumour antigens and generating for lung, breast, colon, pancreas and other (PD1)-specific antibody pembrolizumab anticancer immunity, while leaving normal cancers, after having suffered a set‑back in with or without T‑VEC. cells alone. As such, they often need careful a Phase III trial in head and neck cancer. Based on the preliminary combination genetic engineering. In the case of T‑VEC, “The differences between the viruses are data, “I think clinicians are going to make that this meant boosting the herpesvirus’ ability bigger than people realize, and that just means leap of faith” — and prescribe both therapies to hone in on cancer cells, by deleting the we have more shots on net” to find something together — “if the insurance companies let us,” viral gene encoding infected cell protein 34.5 that works for each kind of cancer, says says Sanjiv Agarwala, Chief of Medical (ICP34.5). By deleting ICP47, which blocks Bradley Thompson, Oncology and Hematology at St. Luke’s antigen presentation on infected cells, viral of Oncolytics. “We’re all different, and I think Cancer Center in Bethlehem, Pennsylvania, engineers aimed to induce a more potent we’re all getting a sense now of where our USA, who is involved in the pembrolizumab immune response (the deletion of ICP47 also agents work, where they don’t work and why.” trial. “It’s a matter of what’s going to be reimbursed.” John Bell, a senior scientist at the Ottawa Table 1 | Selected oncolytic viruses in development Hospital Research Institute in Ontario, Drug Sponsor Indication Phase Canada, who directs the Canadian Oncolytic Talimogene laherparepvec* Amgen Melanoma BLA Virus Consortium, describes the coupling of cancer-attacking viruses with checkpoint CG0070* Cold Genesys Bladder cancer II/III blockade as “a match made in heaven”. Pexastimogene SillaJen Biotherapeutics II Although researchers originally thought of devacirepvec* these viruses as killing machines that would CVA21 Viralytics Melanoma II replicate inside cancer cells and induce Pelareorep ‡ Oncolytics Biotech Various solid tumours II cell lysis — hence the name ‘oncolytic’ Enadenotucirev PsiOxus Therapeutics Various solid tumours I/II virotherapy — many viral products act more like cancer vaccines. DNX-401 DNAtrix Glioblastoma Ib “It’s incredibly exciting that we now ONCOS-102* Oncos Therapeutics Various tumours I recognize that [oncolytic viruses] stimulate *Granulocyte–macrophage colony-stimulating-factor-producing oncolytic virus. ‡RNA virus. antitumour immunity,” Bell says, “and what BLA, biologics license application.

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Viral marketing and his colleagues at Harvard Medical These first-generation viruses were Although sales of oncolytic virotherapies School in Boston, Massachusetts, USA, “so attenuated that they’d be safe but, at the will probably be modest compared with described the first laboratory-modified same time, they were not effective,” says Bell. those of other emerging oncology drug virus for combatting brain tumours in “We had to re‑invent ourselves by getting classes, these viruses could still be important mice (Science 252, 854–856; 1991). new virus platforms out there that had a money-makers. In a report released last year, In the early days of engineered little more ‘oomph’ to them and that would Valerie Kellogg, a pharmaceutical analyst virotherapy, however, many researchers be therapeutically useful as well as safe.” with BCC Research, estimated that the global and companies took a cautious approach, Bell is watching the early-stage pipeline market for oncolytic virotherapies will reach which led to products such as ONYX‑015 — for better things to come. “There’s still a bit $6.4 billion by 2023. “the original flagship of the whole field,” of a hangover from the early days,” he says, Douglas Loe, a biotech analyst with Euro as Bell describes it. Onyx Pharmaceuticals’ “but the ones that are coming up behind are Pacific Canada, agrees that the “relatively ONYX‑015 was a modified adenovirus that the ones that are more potent”. minor side-effect profiles” of these products contained gene deletions that were designed Researchers will convene this month could make for a strong market potential. to facilitate its replication in cells that were in Boston for the 9th International The field’s projected pay day has been defective for the p53 pathway, but it also Conference on Oncolytic Virus Therapeutics. a long time in the making. The idea of had weak proliferative ability. (Controversy In previous years, after the high-profile treating cancer with viruses dates back over ONYX‑015’s mechanism of action and disappointments of ONYX‑015 and other over a century to a 1912 report that a rabies Pfizer’s acquisition of Onyx’s development products, “people were fairly sombre” at this vaccine that was administered to a woman partner, Warner–Lambert, led to the annual conference, says meeting organizer after a dog bit her led to remission of a product’s abandonment in 2003 ahead of Antonio Chiocca, Neurosurgeon-in-Chief large cervical tumour. Physicians dabbled a planned Phase III trial. However, Chinese at the Brigham and Women’s Hospital in with viral therapy throughout the twentieth regulators approved an almost identical Boston, Massachusetts, USA. With T‑VEC century, but it wasn’t until the emergence of product, H101, for the treatment of head on the verge of regulatory approval, Chiocca modern genetic engineering that the field and neck cancer in 2005; it sells barely above expects this year’s gathering to have “a much really took off. In 1991, Robert Martuza $3 million per year.) more positive outlook.”

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