While the current COVID-19 pandemic has understandably generated widespread fear of viral contagion, some scientists are looking at viruses through a different lens: as healers rather than carriers of disease. Their research concerns oncolytic viruses—naturally occurring or genetically engineered viruses that can selectively infect and kill cancer cells while having minimal impact on normal cells.
This field is far from new. The first report of oncolytic viruses dates back to 1904, when a 42-year-old woman with myelogenous leukemia went into remission after coming down with the flu. Over the years, researchers have worked on genetically engineering various types of viruses to reduce their pathogenicity and improve their ability to kill cancer cells.
But progress has lagged, in part because of incomplete understanding of how to harness these viruses. In the early decades, most researchers thought that all they needed was to develop viruses that selectively infect and kill cancer cells. Their work hinged on the idea that oncolytic viruses take advantage of the fact that many cancer cells have faulty interferon pathways, which is their major defense against viruses. Without this response, cancer cells are more vulnerable than normal cells to viral infection (Front Immunol 2018;9:866).
The problem was that these engineered viruses were not clinically useful. Even though many of them killed cancer cells very well, they could not possibly reach and infect every last cancer cell in real-world patients.
The field reached a turning point after researchers made a critical discovery: a successful oncolytic virus needs to perform not one, but two tasks. In addition to selectively infecting and killing cancer cells, oncolytic viruses need to wake up the host immune system so that it can recognize and clear cancer cells.
The key to understanding this development is knowing that viral infection induces both innate and adaptive immunity. Adaptive immunity is required for long-term antitumoral immunity, while innate immunity creates an anti-viral response. Tumors create their own “cold” immunosuppressive microenvironment in order to evade immune recognition. Oncolytic viruses designed to stimulate the immune system can convert the tumor bed into a “hot” or inflammatory environment. Doing so not only helps fight the cancer, but has the potential to create longer-term immunological memory that may protect against relapse. For these therapies to work well, they need to balance anti-tumoral against anti-viral responses to give oncolytic viruses enough time to work before being cleared by the immune system (Front Immunol 2018;9:866).
To address these issues, scientists are taking a multi-pronged approach. They are genetically modifying viruses to decrease their pathogenicity, while at the same time improving their ability to target tumors, kill cancer cells, and stimulate the immune system. Techniques include insertion of tumor-specific promoters, viral gene knockout, capsid modification, and insertion of transgenes that express antibodies, cytokines, costimulatory molecules, and other immune proteins.
To extend the therapeutic window, they have been developing ways to mask viral surface proteins, as well as carrier systems using stem and other types of cells. They are even considering a “Trojan Horse” approach that shields viruses from the immune system, then releases them once they reach the tumor bed (Mol Ther Methods Clin Dev 2020;17:349-358).
“It is mind-boggling the number of amazing ideas that are out there for delivery, for arming, and for altering oncolytic viruses. The next few years are going to generate all kinds of new ideas and discoveries,” Grant McFadden, PhD, told Oncology Times. He is a professor at Arizona State University and Director of the Biodesign Center for Immunotherapy, Vaccines, and Virotherapy in Tempe, Ariz.
Currently, about 118 clinical trials are evaluating oncolytic viral therapy using 13 different kinds of viruses and a wide range of transgenes. While most researchers have focused on oncolytic adenoviruses, herpes simplex virus (HSV), and the vaccinia virus, a range of other viruses are under investigation including polioviruses, measles virus, Newcastle disease virus, and even Zika virus. Many trials are phase I, but some are farther along (Mol Ther Oncolytics 2019;15:234-247).
“We're now at the stage where it's very exciting in the field because many of the clinical trials are now getting more advanced,” McFadden noted.
Among recent developments, the most noteworthy is T-VEC, which received FDA approval in 2015 for the treatment of metastatic melanoma, making it the first oncolytic virus therapy to gain licensure. T-VEC is a genetically modified herpes virus that has been engineered to carry the human gene for granulocyte-macrophage colony-stimulating factor (GM-CSF). Results from a phase III randomized, open-label clinical trial showed that patients with metastatic melanoma treated with T-VEC had significantly longer overall survival compared to those treated with recombinant GM-CSF (J Clin Oncol 2015;33(25):2780-2788).
Synergy of Oncolytic Viruses & ICIs
Scientists are now looking to the next levels of discovery, and the most promising line of research appears to be next-generation viruses combined with immunotherapies, particularly immune checkpoint inhibitors (ICIs).
“It's been obvious for quite a while that, if oncolytic viruses could act in synergy with ICIs, this would be a match made in heaven. And we're now all convinced that it is a match made in heaven,” McFadden said.
ICIs work by liberating the immune system, but they can only work if the immune system still has the capability of responding. If a patient has never generated an immune response to their tumor, ICIs cannot work to re-activate an immune response that never existed in the first place. Oncolytic viruses have the potential to change this situation by eliciting a new immune response to the tumor, which may improve the ability of ICIs to unleash the immune system, McFadden explained.
“Most people know that when ICIs work they can be like magic, but the majority of patients don't respond to ICIs. Many of us researchers in this field think that virotherapy will be part of the magic clue to how you can take patients who don't respond to ICIs and make them responders,” he said.
Researchers are eagerly awaiting results from a randomized clinical trial evaluating T-VEC combined with the anti-PD-1 antibody pembrolizumab compared to placebo in patients with unresectable melanoma (KEYNOTE-034, NCT02263508).
While oncolytic viruses are carefully engineered to be safe in humans, some researchers point out the continued need to consider their safety, particularly in elderly and immunocompromised patients. At least one study has found that patients with chronic inflammation may not respond as well to oncolytic viral therapy as those with low levels of chronic immune activation, suggesting a need for careful patient selection (Mol Ther 2016;24(1):175-183).
Another challenge concerns dosing strategies, and whether oncolytic viruses can be dosed high enough to be clinically useful.
“This is one of the challenges of the field. Cancers hide in different places and getting the virus to different cancers can vary from straight forward to very hard depending on the cancer,” McFadden said.
Perhaps one of the biggest challenges concerns solid tumors. So far, viral therapy has shown only limited efficacy against solid tumors. Several hurdles lie in the way, including physical barriers, tumor heterogeneity, impaired viral infiltration, and poor tumor vasculature (Mol Ther Oncolytics 2019;15:234-247). Route of administration is also an issue—about 80 percent of solid tumors cannot be reached by direct intertumoral injection. IV administration has the potential to reach primary as well as metastatic cancers, but the host immune response may pose a major obstacle to systemic administration (Front Immunol 2018;9:866).
“One of the biggest challenges of the next several years is whether any of the viruses that are being developed can be used for systemic administration. That's the million dollar question that can only be answered with clinical trials,” McFadden concluded.
Veronica Hackethal is a contributing writer.