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4:52 PM
 | 
Aug 08, 2019
 |  BC Innovations  |  Tools & Techniques

Checkpoint inhibitors are bringing oncolytic viruses back into the spotlight

Pharmas are getting back into oncolytic viruses, thanks to checkpoint inhibitors

Early clinical readouts for next-generation oncolytic viruses are hinting at high efficacy when combined with checkpoint inhibitors, and pharmas are off to the races to find the best pairings.

After more than two decades of development, oncolytic viruses have yielded little clinical efficacy, partly because companies haven’t fully understood or exploited modality, and partly because safety concerns led them to start cautiously with attenuated viruses.

However, a newly uncovered immune-stimulating mechanism for oncolytic viruses and growing demand for agents that synergize with checkpoint inhibitors have triggered a resurgence of interest.

“No pharmas want to miss out on the next complementary checkpoint inhibitor partner,” said Arthur Kuan, CEO of Cold Genesys Inc.

Pharma and VC investment in oncolytic viruses has trended up over the last ten years from less than $2 million in 2010 to over $100 million in 2015 and $50-$100 million each year since.

Over the past three years, at least nine pharmas have acquired or partnered with oncolytic virus companies (see Table: “Pharma’s Oncolytic Virus Deals”).

“Checkpoint inhibitors saved oncolytic viruses.”

Matt Coffey, Oncolytics

Oncolytic viruses were initially thought to work by preferentially targeting and replicating in cancer cells, then killing them through lysis. The field has since learned that a second mechanism may be equally if not more relevant -- when an oncolytic virus infects a tumor cell, it marks it for immune destruction.

After the cell dies, its tumor antigens are released and detected by T cells, leading to a powerful innate and adaptive immune response (see “Infectious Enthusiasm”).

“In the last 24-36 months, we realized that the viruses weren’t really causing a lot of lysis. They were causing a lot of immunological activity. We don’t think of it as a virus, but as a delivery system of double-stranded RNA that will then engage the immune system,” Matt Coffey, CEO and co-founder of Oncolytics Biotech Inc., told BioCentury.

He said that oncolytic viruses “address all the limitations of checkpoint inhibitors” by remodeling tumors to encourage immune cell infiltration, and by increasing expression of checkpoint proteins that are downregulated in many cancers but are required for the inhibitors to work.

Kuan noted that oncolytic viruses may be better than other immune stimulators, such as toll-like receptor or STING agonists, because those lack their own cancer killing capabilities. “All they’re doing is stimulating the immune system, without providing any direction.”

And with more funding and pharma interest, oncolytic virus technologies have evolved to include a wide variety of viruses, genetic modifications to improve efficacy, different payloads to further stimulate immune activity and new delivery mechanisms.

The jury is still out on which viral properties will fare best in checkpoint combinations, but a spate of trial readouts over the next couple years should start to answer that question.

Checkpoint potential

All eyes are on Amgen Inc.’s Phase III melanoma trial which couples its oncolytic virus Imlygic talimogene laherparepvec (T-Vec) with PD-1 inhibitor Keytruda pembrolizumab from Merck Inc.

Amgen hasn’t provided a timeline for the data; according to ClinicalTrials.gov, the primary completion date is July 29, 2022.

“That piece of data will be a milestone for the whole field. We have reasons to believe based on earlier stage trials that the combination does increase the overall response rate, but a lot is hinging on whether viruses improve checkpoint responses,” said Kuan.

A Phase II trial tested Imlygic with CTLA-4 inhibitor Yervoy ipilimumab from Bristol-Myers Squibb Co.

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