Immunotherapy is being hailed as a game-changer in cancer therapy – and for the patients whose lives have been significantly extended as a result of cutting-edge therapy this is definitely the case.
But there are many patients who do not respond to therapies such as Merck & Co’s Keytruda (pembrolizumab) – for instance in melanoma, where the response rate to the PD-1 drug is about a third, depending on the indication.
As a result, pharma companies looking for ways to increase the chances of patients responding to the therapy are turning to oncolytic viruses.
Oncolytic viruses are genetically modified so that they can be injected into tumour sites and induce an immune attack from the body.
The thinking is that they could augment the attack from T-cells called in when patients are treated with checkpoint inhibitor drugs.
These drugs are designed to overcome a common defence surrounding cancer cells – the PD-L1 protein secreted on their cell membranes that allows them to dodge detection from the immune system.
Igor Puzanov, professor of medicine and director of early phase clinical trials at New York’s Roswell Park Cancer Institute, has been interested in oncolytic viruses for more than a decade and is part of a group of scientists who think that they could offer a solution to the problem of non-responders.
There is evidence that these oncolytic viruses can provoke a reaction in tumour cells that causes them to become ‘hot’ to the immune system.
At the ASCO conference Puzanov referred to early-stage trials showing that combining the oncolytic virus used in Amgen’s Imlygic (talimogene laherparepvec) with Keytruda can produce a stronger response than either of the two components taken on their own.
Data from a phase Ib study published last year that Puzanov co-authored showed a response rate of 62% in advanced melanoma patients. Those treated with the combination had an increased expression of PD-L1 and elevated levels of the CD8+ T cells. There were also higher levels of interferon gamma, a protein associated with an elevated immune response to certain infections.
Puzanov and other authors suggested that the combination therapy changes the area around the tumour that makes it more vulnerable to immunotherapy.
While Imlygic has been on the market for several years, Puzanov told pharmaphorum that there is much more to come from oncolytic viruses. Imlygic not only causes tumour cells to self-destruct – it also codes for the protein known as granulocyte-macrophage colony-stimulating factor (GM-CSF) that gives the immune system a boost. In the future oncolytic viruses that code for other cancer killing agents to boost their performance. “Some of the new viruses in development are really interesting. Some of them have a [CTLA-4 inhibitor] included – they will have everything together,” he said.
Another property of oncolytic viruses is that even though they are often injected directly into tumours, the immune system will also begin to attack any other tumours that are present after the injection. The immune system can also be stimulated by the range of cancer antigens emitted by the tumour cells as they are broken up by the virus. According to Puzanov, this turns the existing immunotherapy paradigm on its head – rather than targeting a single antigen on a cancer cell’s surface, it creates the possibility of a broader attack from the immune system.
Merck gave oncolytic viruses a multi-million dollar endorsement earlier this year with its $394 million acquisition of the Australian biotech Viralytics. Roy Baynes, chief medical officer at Merck Research Laboratories, described the company’s technology based around the coxsackie virus as “intriguing”.
Immediately before ASCO, the biotech raised a further $8.9 million in a public offering to give it the capital it needs for further development of the oncolytic virus it has developed.
The team came armed with data showing their oncolytic virus, pelareorep, caused cells from a range of cancers, including HR+ breast cancer, triple negative breast cancer, to express biomarkers that would make them respond to Merck’s commonly used checkpoint inhibitor Keytruda.
The data showed that pelareorep, an unmodified immune-oncolytic virus that stimulates an innate response from natural killer and dendritic cells, also causes cancer cells to express biomarkers that would generally work well with immunotherapy.
Unlike many other oncolytic viruses such as Imlygic, pelareorep only affects tumour cells and does not need to be injected directly into the cells and can administered using an intravenous drip. This means that the virus can be used to target tumours that are difficult to reach using an injection.
Grey Wilkinson, translational scientist at Oncolytics, said:
The next step is to develop the virus in combination with chemotherapy in metastatic breast cancer.
Oncolytics is also developing the virus as a combination with Celgene’s Imnovid (pomalidomide) and Revlimid (lenalidomide) in myeloma, and is looking to combine it with Keytruda and other immunotherapy combinations.
Oncolytics CEO Matt Coffey said: “Multiple myeloma does not lend itself to checkpoint inhibitor treatment. But eight days after treatment with pelareorep we have 98% of cells showing as PD-L1 positive.
Standard therapy for glioblastoma is surgery followed by chemoradiation and then adjuvant chemotherapy, which produces a median overall survival of 15 months, with only 3–5% of patients living five years or more.
With SurVaxM, MimiVax is taking a completely different approach – delivered through a subcutaneous injection, it is a peptide-mimic immunotherapeutic vaccine that targets survivin, a cell-survival protein present in 95% of glioblastomas and many other cancers.
Early results from the phase II study suggest that SurVaxM could improve upon this – of the 63 patients treated so far, the team at MimiVax found 91% of patients were still alive 12 months after beginning treatment. This compared with 61% in an historical analysis of patients treated with standard therapy alone. After six months 96% of patients achieved progression-free survival, compared with 54% among the historical control group.
A further 13 of the 63 patients continue to be without progression after more than a year on the study, according to the results announced at ASCO. There are also still a couple of patients still alive after four or five years, who were treated in a phase I study.
CEO Michael Ciesielski said in an interview with pharmaphorum: “There is something phenomenal here.”
There’s a long way before the drug makes it to market, but MimiVax’s work demonstrates the potential of alternative immunotherapies in forms of cancer that have until now proven difficult to treat.
The message from ASCO was that there are a wide range of immunotherapies that could enhance the performance of already marketed drugs, or work on their own. It’s a hugely exciting field that could create new options for patients with some of the most difficult-to-treat cancers.
Richard Staines is Senior Reporter at pharmaphorum. He has been a journalist since the 1990s and has written for websites, newspapers and magazines. He has always had an interest in health, and has been focusing on the pharma industry since 2010, interviewing industry leaders and covering stories on topics including regulation, mergers and acquisitions, and the latest clinical developments.