Ontario researchers prepare to test Maraba-based oncolytic vaccine therapy in clinical trial
Around the world researchers are developing drugs and vaccines to protect us from dangerous viruses. A research group in Ontario however is using viruses for good by developing virus-based immunotherapies for cancer. Now they are getting ready to test one of their most promising therapies in patients for the first time.
Dr. John Bell and his collaborators are developing an innovative oncolytic vaccine strategy using an oncolytic virus derived from the Maraba virus. Dr. Bell is director of the Immuno- and Bio-therapies Program (ORBiT) at the Ontario Institute for Cancer Research and is also senior scientist, Cancer Therapeutics at the Ottawa Hospital Research Institute and a professor in the Departments of Medicine and Biochemistry, Microbiology and Immunology at the University of Ottawa.
The Maraba virus and other oncolytic viruses work by selectively replicating in and destroying cancerous cells. They are able to do this because mutations within cancerous cells cause them to lose the natural protection against viruses that normal cells have, making them more susceptible to infection. This means that few normal cells will be harmed and patients should experience far fewer side effects.
Bell is a world leader in the field of oncolytic viruses and has recently enjoyed success with a therapy called JX-594, which is currently being tested in clinical trials. His group is now building on that success and believes it made a significant leap forward with the development of their Maraba-based oncolytic vaccine therapy.
The process of creating the new therapy began with one of Bell’s collaborators looking for an RNA virus that could be used as a starting point. Dr. David Stojdl of the Children’s Hospital of Eastern Ontario led the search and tested a library of viruses against 60 different cancer cell lines. The Maraba virus, which was first isolated in Brazilian sandflies in 1984, showed the most promise.
Although Maraba is already a potent oncolytic virus the researchers saw room for improvement. “Through genetic engineering Dave created a new version called MG1, which has increased anti-cancer properties and a better safety profile,” explains Bell.
Once the right virus was found and modified, Bell’s colleagues at McMaster University, Drs. Brian Lichty, Byram Bridle, Jonathon Bramson and Yonghong Wan began working to pair it with an anti-cancer vaccine against a commonly expressed tumour antigen Mage A3 to increase its effectiveness. Oncolytic viruses destroy cancer cells through the traditional method of infection and replication, but they also work by generating an immune response from the body against cancer. The adenovirus vaccine that the McMaster team paired with Maraba virus gives it a unique advantage over other immunotherapies.
The vaccine serves to prime the immune system meaning that the patient will generate a stronger anti-cancer response than if they were treated with the single virus alone. In animal models this combination showed promising results so Bell and his team began to prepare for testing in humans.
To be tested in a clinical trial the oncolytic vaccine comprising the Maraba virus and the Mage A3 adenovirus vaccine have to be prepared in pharmaceutical-grade GMP manufacturing facilities. Bell and his collaborators have established a GMP facility for the Maraba virus at the Ottawa Hospital Research Institute and a facility for the adenovirus vaccine at McMaster University in Hamilton, ON. “Getting these facilities up and running was a major challenge for our group. I am happy to say now that both the virus and vaccine have passed toxicology testing and have been deemed safe to test in humans,” explains Bell.
In anticipation of conducting a clinical trial Bell has already been in contact with regulators at Health Canada. So far the response has been positive. “Given that this is an emerging field we wanted to be as proactive as possible,” says Bell. He plans on submitting a formal Clinical Trial Application with Health Canada in the first quarter of 2014.
Bell expects that the trial will begin in the second quarter of 2014 and run for 18 to 24 months. Participation in the trial will be limited to those with solid tumours that express the Mage A3 antigen. Seventy patients are expected to enroll during the course of the trial.
“When this trial opens we will have hit our biggest milestone to date in the development of the Maraba-based therapy. We will finally be able to assess the safety of the therapy and get some preliminary information on the clinical benefit,” says Bell. One of the main advantages of the Maraba-based therapy is that so far in animal models it has shown only a few minor side effects. “Given our initial testing we are expecting side effects such as nausea and fever in patients, but luckily these can be easily treated with over the counter medications,” says Bell.
Although Bell is happy to see his research into the Maraba virus progressing to a clinical trial, he remains focused on the big picture and knows this is only a first step. “If things go well in this initial clinical trial we could then test the therapy in a larger trial, start others to test different versions of the Maraba virus we have developed and to test the virus in combination with other therapies.”
Dr. Neil Berinstein, director of Translational Research for ORBiT Program, sees this and other clinical trials as being key to the advancement of the field and the widespread use of immunotherapies in the clinic. Berinstein has spent his career working in the field in both academic and industry settings and believes that they are ready for primetime.
“Over the last 20 years there has been a steady increase in the understanding of how the immune system functions in cancer and now we have tools which have been proven to be clinically valuable. I think we are going to see an explosion of interest in the field because there is more confidence now that the immune system can be a potent form of cancer therapy,” says Berinstein. “We have this great understanding of cancer at a molecular and cellular level and now it is possible to turn this understanding into useful clinical agents and strategies.”
Berinstein believes that multiple cancer immunotherapies will be in widespread use in the next five to 10 years. He points to checkpoint inhibitors, a type of immunotherapy that is being used in the treatment of melanoma, as an example of increasing interest in the field.
“Once these inhibitors were shown to be useful in the treatment of melanoma clinicians started thinking about using these types of therapy in other cancers,” he says. “Several major pharmaceutical companies are working to develop these right now and there are also several large and important cancer vaccine trials underway. Immunotherapies are beginning to gain traction on a wide scale.”
While Berinstein sees immunotherapies as becoming a more effective and common form of treatment for cancer he believes that they will be best used in combination with other forms of therapy such as chemotherapy, radiation and newer targeted therapies. Dr. Bell agrees, “While the Maraba-based therapy could be used as a frontline therapy it will probably be best used when it is in combination with some other form of treatment. I think that this is necessary given the complexity of cancer and to provide the maximum benefit for patients.”
Bell and Berinstein are both excited about the increased interest in immunotherapies from the pharmaceutical industry and clinicians, but believe that a concerted effort needs to be made to educate people about the field.
“I’ve had both patients and clinicians raise an eyebrow when you suggest treatment with a virus,” Bell says. “But once they learn more about it they are onboard and really want to understand what’s behind it.” Berinstein thinks that we may see a similar trend amongst regulators, “Once this first generation of immunotherapies gain the approval of regulators and prove to be effective and important therapeutic tools in cancer, it should become easier for future therapies of this kind to reach the clinic more quickly. Further evidence that these drugs are safe and effective in clinical use will be a big step forward for the field.”
As research in immunotherapies grows Berinstein believes that it is important for Canada and Ontario to leverage their existing strengths and establish themselves as world leaders.
“In a field as diverse as immunotherapies you cannot be a leader in all areas. However in Ontario we have a foothold in cancer virology because of Dr. Bell, who is internationally recognized as a leader, and his network of collaborators. Through ORBiT at OICR we are attempting to bring all these pieces together and accelerate the science. The recent support and optimism for the field present us with a great opportunity that we must seize.”
About the author:
Hal Costie is a senior communications officer at OICR