First the Mice, then the Women....

"It was absolutely amazing to see that we could cure cancer in most of our mice -- even in models that are normally resistant to immunotherapy."
Dr. Marie-Claude Bourgeois-Daigneault, post-doctoral fellow. research lab. Dr.John Bell, The Ottawa Hospital

"They both bring something to the table. The viruses, they initiate the immune response, and then the immune checkpoint licenses the immune system, engages it, and allows it to be active. We doubled down on immune stimulation, and when we did that, we found it was very effective in preventing [cancer] relapses."
"The real problem is that everyone [researchers in the field] is just throwing stuff against the wall to see what sticks. What we're saying is, 'Let's stop doing that'. Why not, instead, have a rational approach and say, 'This actually makes biological sense so let's combine these things this way."
"That's part of what this study was designed to do: to try to find an indication that makes sense and has potential clinical applicability."
Dr. John Bell, immunotherapy researcher, senior research scientist, The Ottawa Hospital

The Ottawa Hospital

Viruses, highly evolved agents for infection, are capable of doing more than simply infect; they colonize and destroy human cells. That's the negative; the positive is that scientists have discovered that viruses appear suited to manipulation, to attack malignant tumours with genetic mutations making them susceptible to viral attack. And oncolytic viruses also have the advantage of triggering a wider immune response against tumours, in the process 'training' the system to identify and attack tumorous cells if they return.

Post-doctoral fellow Dr. Bourgeois-Daigneault, working under University of Ottawa Professor Dr. Bell, engaged in a mouse study specifically designed to follow a typical course of a woman's breast cancer treatment for "triple negative" breast cancer, an especially aggressive form of the disease. The study discovered the most effective treatment course took advantage of three stages of the administrative of an oncolytic virus, followed by surgery, the process completed by administering an immune checkpoint inhibitor.

The results of the study, successfully treated in mice through a combination of immonutherapies specifically meant to 'weaponize' the immune system in different ways, was published in Science Translational Medicine, a medical journal specializing in the publication of research advancing the prevention, diagnosis and treatment of disease. This was a validation that immunotherapies are simply more powerful when used in a combination protocol rather than alone.

Image: Shutterstock

Staged immunotherapies (an oncolytic virus before surgery followed by a checkpoint inhibitor) cured 60 to 90 percent of mice with triple negative breast cancer which has conventionally been treated using surgery, radiation and chemotherapy, with limited success to show for the endeavour. When used in isolation, neither the checkpoint inhibitor nor the virus showed a significant impact on overall survival rates with surgery. The results of the study, however, was to offer more supportive evidence of the full benefit of immunotherapy resulting when cancer treatments are linked in combination therapy.

Oncolytic viruses are capable of invading a tumour to attack it, while at the same time triggering a broad immune response against certain types of cancer cells. Checkpoint inhibitors are used to shut off a communication path used by tumours to 'mislead' the immune system, shutting down T-cells whose purpose is to fight cancer. One fly in this ointment is that checkpoint inhibitors operate positively only for a minority of cancer patients, leading to a scientific race in an effort to isolate an immunotherapy cocktail capable of a broader success rate.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive disease for which treatment options are limited and associated with severe toxicities. Immunotherapeutic approaches like immune checkpoint inhibitors (ICIs) are a potential strategy, but clinical trials have demonstrated limited success in this patient cohort. Clinical studies using ICIs have revealed that patients with preexisting anticancer immunity are the most responsive. Given that oncolytic viruses (OVs) induce antitumor immunity, we investigated their use as an ICI-sensitizing approach. Using a therapeutic model that mimics the course of treatment for women with newly diagnosed TNBC, we demonstrate that early OV treatment coupled with surgical resection provides long-term benefits. OV therapy sensitizes otherwise refractory TNBC to immune checkpoint blockade, preventing relapse in most of the treated animals. We suggest that OV therapy in combination with immune checkpoint blockade warrants testing as a neoadjuvant treatment option in the window of opportunity between TNBC diagnosis and surgical resection.

Science Translational Medicine Journal

Image of the Maraba virus, which was combined with an immune checkpoint inhibitor to cure aggressive breast cancer in mice.