Using Oncolytic Viruses to Boost Response to Immune Checkpoint Inhibitors

Two unrelated research papers in Science Translational Medicine report how treatment with oncolytic viruses (OVs) can switch on the body’s immune system against different forms of cancer, and render traditionally hard-to-treat tumors susceptible to checkpoint inhibitor therapy.

In one of the reported studies, scientists at the University of Leeds in the U.K. describe positive data from an early clinical trial in nine patients with either glioma or brain metastases, who were given intravenous oncolytic human Orthoreovirus (reovirus) therapy prior to surgery to remove their tumors. The findings showed that the intravenously delivered virus could cross the blood-brain barrier and infect tumors, and there was evidence that the virus also stimulated the immune system to target the tumor. The findings have led to the start of a clinical trial in which patients are receiving reovirus in combination with radiotherapy and chemotherapy following surgery.

Commenting on the published data, Adel Samson, a medical oncologist at the Leeds Institute of Cancer and Pathology, says “This is the first time it has been shown that a therapeutic virus is able to pass through the brain-blood barrier, and that opens up the possibility that this type of immunotherapy could be used to treat more people with aggressive brain cancers.” Dr. Samson is co-lead author of the team’s Science Translational Medicine Paper. “This study was about showing that a virus could be delivered to a tumour in the brain. Not only was it able to reach its target, but there were signs it stimulated the body's own immune defences to attack the cancer.” The published paper is entitled, “Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade.”

In the second set of published studies researchers in Canada, funded by the Alliance for Gene Therapy (ACGT),§ report a 60-90% cure rate in three mouse models of triple-negative breast cancer (TNBC) – which is typically the most aggressive form of breast cancer – following combined oncolytic virus and checkpoint inhibitor therapy. “It was absolutely amazing to see that we could cure cancer in most of our mice, even in models that are normally very resistant to immunotherapy,” states Marie-Claude Bourgeois-Daigneault, at the Ottawa Hospital Research Institute, for the ACGT researchers. “We believe that the same mechanisms are at work in human cancers, but further research is needed to test this kind of therapy in humans.” The team describes the mouse studies in a paper entitled, “Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy.”

Immunotherapy using checkpoint inhibitors, including programmed cell death protein 1 (PD-1) monoclonal antibodies, have produced unprecedented results in recent years in solid malignancies, Dr. Samson and colleagues write. However, only a small subset of patients respond and derive significant benefit. The concept of combining an oncolytic virus with checkpoint inhibitor therapy “deserves attention,” they suggest; “OV delivery to tumors can enhance T cell infiltration, hence priming the tumor immune microenvironment for immune-mediated therapy when combined with PD-1/PD-L1 axis blockade … We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade.”

To test whether oncolytic virus administered intravenously could reach tumors in the brain, the researchers recruited nine patients with either high-grade glioma or with brain metastases into the Phase Ib window of opportunity trial reported in Science Translational Medicine. Each patient received a single intravenous infusion of oncolytic reovirus ahead of planned surgical resection of the brain tumor 3-17 days later.

Subsequent examination of the brain tumors showed evidence that the virus had crossed the blood-brain barrier, infected each tumor, and triggered the recruitment of cytotoxic T cells to the tumor site. Compared with tumors from control patients, tumors from reovirus-treated patients also exhibited higher expression of PD-L1, induced by IFNs. “We further found evidence for both peripheral and tumor induction of IFNs, key cytokines in reovirus-mediated activation of immune cell populations,” the authors state.

Based on their clinical data, the team then tested combination therapy using oncolytic virus followed by immune checkpoint inhibitor blockade in a mouse model of glioma. The results confirmed that the combination therapy improved survival compared with either form of treatment on its own. “These results support the development of combined systemic immuno-virotherapy strategies for the treatment of both primary and secondary tumors in the brain,” the authors conclude. They also reference the ACGT-funded research published in the same issue of Science Translational Medicine. “In support of our findings, preclinical research using Maraba virus in murine models of triple-negative breast cancer has also shown OV- induced tumor inflammation, immune infiltration, and up-regulation of PD-L1, leading to enhanced survival when Maraba virus is combined with PD-1 checkpoint blockade.”

Commenting on published the window of opportunity clinical study by the Leeds researchers, co-lead author Alan Melcher, Professor of Translational Immunotherapy at The Institute of Cancer Research, London, stated, “In our study, we were able to show that reovirus could infect cancer cells in the brain. And, importantly, brain tumours infected with reovirus became much more visible to the immune system. This small-scale clinical trial allowed us to ask a crucial biological question about cancer immunotherapy and gain insights which can now be tested further, both in the laboratory and in the clinic. Now we know we can get reovirus across the blood-brain barrier, we have begun clinical studies to see just how effective this viral immunotherapy can be at extending and improving the lives of patients with brain tumours, who currently have very limited treatment options available to them.”

The ongoing trial is being led by Susan Short, Professor of Clinical Oncology at the University of Leeds. One glioblastoma patient enrolled in the study is has started receiving combination therapy, and in the months following tumor removal will receive 16 doses of virus along with chemotherapy and radiotherapy. “ “The presence of cancer in the brain dampens the body's own immune system,” professor Short comments. “The presence of the reovirus counteracts this and stimulates the defence system into action. Our hope is that the additional effect of the virus on enhancing the body's immune response to the tumour will increase the amount of tumour cells that are killed by the standard treatment, radiotherapy and chemotherapy.”

The ACGT-funded researchers reporting separately in Science Translational Medicine tested sequential therapy using the oncolytic Maraba virus, and immune checkpoint inhibition, in three different mouse models of triple negative breast cancer that were shown to be resistant to immune checkpoint inhibitor monotherapy. The tumor-bearing animals were first treated using the oncolytic virus, and then checkpoint inhibitor therapy was started after tumor resection. The combined approach was designed to mirror how women with this form of breast cancer might be treated. 

The results showed that none of the animals treated using checkpoint inhibitor therapy alone survived, and the survival rate for animals receiving oncolytic virus therapy on its own was just 20-30%, even though the Maraba virus was capable of replicating inside the tumors and triggered an immune response.

In contrast, combining oncolytic virus therapy with immune checkpoint blockade resulted 60-90% of the TNBC mice surviving. “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,” the authors conclude. “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.”

“Our immune system is constantly trying to recognize and kill cancer cells, but the cancer cells are always trying to hide from it,” comments co-responding author, ACGT grantholder Dr. John Bell, senior scientist at The Ottawa Hospital and professor at the University of Ottawa. “When you infect a cancer cell with a virus, it raises a big red flag, which helps the immune system recognize and attack the cancer. But in some kinds of cancer this still isn't enough. We found that when you add a checkpoint inhibitor after the virus, this releases all the alarms and the immune system sends in the full army against the cancer.”

The researchers also reference the studies by professor Samson’s team in Leeds. “Our findings are in line with the ones obtained by Samson et al., where they show that the intravenous infusion of oncolytic reo-virus to glioblastoma patients promotes T cell recruitment to the tumors and leads to the up-regulation of PD-L1 by tumor cells.”

Clinical trials are already ongoing to evaluate oncolytic viruses, including Maraba, in combination with checkpoint inhibitors in cancer patients. “To date, OV trials have largely been carried out in advanced cancer patients, whereas we propose that, at least for TNBC patients, the data presented here provide a rationale for treating very early in disease progression,” the Ottowa researchers state. “Given the bleak outlook for most TNBC patients, we suggest that early treatment of an otherwise apparently healthy patient with a replicating virus therapeutic is warranted. Similarly, ICIs have been largely tested in TNBC patients with advanced disease; however, we argue that there is a rationale and an urgent need to test these therapeutics in patients early in their diagnosis when they have more robust immune systems and minimal disease burden.”