Despite decades of research, and significant medical breakthroughs, cancer mortality rates remain high, while efficacious therapeutic options vary greatly across cancer types. This heterogeneity in effective treatment options is due in part to cancer’s ability to elude recognition by the immune system. As such, additional, novel approaches for harnessing the immune system are needed to safely and effectively inhibit tumor growth and progression.
While the connection between viruses and cancer has been studied for decades, progress in developing efficacious, safe and practical viral-based oncology therapies has been slow. Research and findings over the last decade, however, are finally yielding the insights needed to develop and commercialize treatments able to capitalize on such therapies’ longstanding promise. Could recent breakthroughs, therefore, signal the turning point from which the potential of viral-based cancer treatments will finally materialize?
Throughout history, it has been demonstrated that human viruses cause disease and some cancers, and have been regarded as harmful. It wasn’t until the 1950’s that the concept of using a virus to kill cancer cells was initially explored. It was at that time that the first oncolytic virus (OV), a vaccine strain of rabies, was evaluated in clinical studies. By the 1970’s, however, research into the role of oncolytic viruses stalled due to both manufacturing challenges, as well as chemotherapeutic approaches’ emergence as the preferred approach to treating cancer. Research into oncolytic viruses regained momentum in the 1980’s, however, after many of the challenges with manufacturing viruses were addressed, while awareness of chemotherapy’s limitations began to be understood. A tragic setback with recombinant viruses in 1999, when Jesse Gelsinger became the first person to be publicly identified as having died in a clinical study using a viral vector, led many to question the safety and viability of oncology viral therapies once again. Despite many challenges and setbacks, the first oncolytic viral therapy in decades – a genetically modified herpes simplex type-1 virus for intra-tumoral injection– was finally approved by the FDA in 2015. Today, there are approximately 15 viral oncology therapies in mid- to late-stage of development across upwards of 50 clinical trials.
While there are a growing number of oncolytic viruses under development, they all fundamentally share the same goal of destroying cancer cells and stopping tumor progression without damaging healthy tissue. Oncolytic viruses exploit the aberrant cellular signaling pathway in tumors, thereby creating a favorable environment for viral infection and amplification in tumor cells. Breast cancer, the most common cancer affecting women, is but one of the tumor types which contain those aberrant cellular signaling pathways. Of note, OVs’ replication rates and cytolytic effect will differ across tumor types. Therefore, the response to each OV may differ between tumor type.
However, research in the last decade suggests that the most important aspect of the mechanism of action for some oncolytic viruses may be the launch of a virally-induced immune response against the tumor. The current hypothesis is that the viral infection will induce cancer cells into cell death pathways that will incite a local inflammatory response and further elicit innate and adaptive immune responses that could potentially control the tumor growth. Thus, the cytolytic effect of some OV’s may not be of the magnitude of that of systemic cytotoxic agents. In most cases, the induction of innate and adaptive immune responses may be ultimately responsible for controlling the cancer progression. The selectivity and the magnitude of the elicited immune response by each type of virus will vary across patients with different tumor types.
Despite such rapid advancements in the development of intratumorally-administered oncolytic viruses, technical and logistical challenges unique to that route of administration remain. Specialized training, for instance, may be required to ensure consistent administration of the required therapeutic dose. Additionally, because dosing tends to be dependent on the number of tumors injected, doses can vary greatly among patients with the same malignancy, making it difficult for providers, patients, and payers to accurately predict each patient’s cost of therapy. Systemic, intravenous administration of OV’s has the potential to address these intra-tumoral administration challenges via its systemic effect and ease of administration. More evidence, however, is needed to determine if intravenous administration will live up to its promise of a more convenient, safe and easy approach to the administration of OV’s.
Many oncolytic viruses are also increasingly under evaluation in combination with other cancer modalities, as oncologists attempt to optimize cancer treatment approaches. Because neither chemotherapy nor radiation typically discriminate between cancerous and healthy tissue, careful titration and monitoring is often required to address potential toxicity issues with these commonly used treatment modalities. By entering and replicating in cancerous cells, while sparing healthy tissue, OV’s may be able to address some of the inherent safety considerations common to treatment with chemotherapy and/or radiation. OV’s selectivity, along with their synergistic effect when combined with chemotherapy and/or radiation, may result in improved efficacy when compared to treatment with chemotherapy and/or radiation alone. Recent evidence also suggests that oncolytic viruses may synergize with immune checkpoint inhibitors by creating a highly immunogenic “hot tumor” phenotype, making them potentially more responsive to therapy than less immunogenic “cold tumors”, which are not as easily recognized by the immune system. OV’s may make “cold” tumors “hot” by inducing a local inflammatory reaction in the tumor microenvironment, thereby allowing the tumor to become more fully recognizable by the immune system which has been further activated by the co-administration of the checkpoint inhibitor. In this manner, the immune system remains engaged even after the tumor is removed – a potential breakthrough in cancer treatment. Ongoing clinical research will help determine the potential efficacy, safety, and viability of combining OV’s with existing therapies.
The mechanism of action of the systemically-administered, oncolytic viral immunotherapy, Reolysin, has allowed Oncolytics Biotech to shape the therapy’s clinical development path to now potentially treat patients with metastatic breast cancer (mBC). In combination with the current standard-of-care for mBC (paclitaxel), Reolysin demonstrated a statistically significant increase in overall survival and a clinically meaningful increase of seven months, compared to the patients treated via paclitaxel alone. The combination therapy was also safe and well tolerated which supports a positive benefit/risk ratio for further development.
Ongoing advancements are bringing us closer than ever to making cancer into a manageable condition in much the same way that HIV or diabetes are now treated. There is high potential for many cancers to be amenable to treatment with oncolytic viruses, and studying these viruses will remain at the forefront of cancer research for years to come.
Dr. Gutierrez is board certified in internal medicine and completed a fellowship in medical oncology. Most recently he has held progressively senior clinical development positions designing and implementing both early and later-stage oncology clinical studies at a range of U.S. and European companies including Sellas Life Sciences Group, Bristol-Myers Squibb, Sunesis Pharmaceuticals Inc., Biomarin Pharmaceutical Inc., Proteolix, and Oculus Innovative Sciences. Prior to that, he held a series of academic and consulting positions. Over his 32 year career, he has authored and co-authored more than 90 peer-reviewed publications and abstracts and presented at numerous conferences. He received his MD and a PhD in Biomedical Sciences from the National Autonomous University of Mexico.
Oncolytics is a biotechnology company developing Reolysin, an immuno-oncology viral-agent, as a potential treatment for a variety of tumor types. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers. Oncolytics’ clinical development program emphasizes three pillars: chemotherapy combinations to trigger selective tumor lysis; immuno-therapy combinations to produce adaptive immune responses; and immune modulator (IMiD) combinations to facilitate innate immune responses. Oncolytics is currently planning its first registration study in breast cancer, as well as studies in combination with checkpoint inhibitors and IMID/targeted therapies in solid and hematological malignancies.