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Feb 29, 2016
 |  BioCentury  |  Product Development

Infectious enthusiasm

How oncolytic viruses are coming of age in cancer immunotherapy combinations

After over two decades of scant effectiveness against cancer, oncolytic viruses could be close to finding their place in immuno-oncology combination regimens, where they could both be potentiated by and improve response rates to checkpoint agents. Meanwhile, the next generation of viruses may become more potent on their own by doubling as gene therapy vectors to enable tissue-specific delivery of therapeutic proteins and nucleic acids.

Companies have been studying oncolytic viruses since the 1990s, but only one has been approved in the U.S.

In the first decade of the 2000s, investment was steady but modest. But financings dramatically increased following the 2011 acquisition of BioVex Inc. by Amgen Inc. for $425 million up front and up to $575 in milestones.

The deal gave Amgen Imlygic talimogene laherparepvec (T-Vec), then in Phase III testing (see "The BioVex Effect").

BioVex learned from earlier attempts that may have blunted products' efficacy in an attempt to mitigate safety concerns related to administering a replicating virus. The company deliberately engineered Imlygic for improved potency on multiple fronts. Last year the modified herpes simplex virus type 1 (HSV-1) carrying the gene for GM-CSF became the first oncolytic virus therapy approved in the U.S.

Though a game changer for the field of oncolytic viruses, Imlygic also illustrated how far the therapies still have to go to reach full potential, when patients with more advanced disease fared poorer than expected in its Phase III program.

Adding checkpoint agents to oncolytic viruses could be one way to improve responses in more patients, as it is now understood these agents may synergistically improve each other's efficacy in ways that could better address larger or more distant lesions. Most if not all oncolytic virus players plan to combine their therapies with checkpoint agents, and already a few pharmas have started to test combinations.

Atlas Venture's Jason Rhodes said the VC chose to invest in oncolytic platform play Replimune Ltd. last year in part because of the expectation that the viruses will become hot commodities for combination regimens.

"Our view is anyone in the immuno-oncology space should have an oncolytic virus, and people may in fact want different ones, depending on what specific products they have in their portfolio," he said.

Oncolytic virus companies are also building on the idea that the viruses themselves can express proteins that complement their activity. In addition to delivering immunomodulatory proteins like GM-CSF, several companies are using viruses to deliver their own checkpoint agents, modify protein expression in tumorsin vivo, or track viral spread and activity.

One major unresolved question is whether it is better to give the viruses locally or systemically. While systemic administration may be easier and doesn't require an accessible tumor, the virus must find its way to tumors and reach therapeutic concentrations before the immune system learns to recognize and disarm the invader.

Preceded by caution

An oncolytic virus preferentially infects cancerous cells over normal cells and kills the infected cancer cells by replicating within them, leading to lysis.

In the 1990s, Onyx Pharmaceuticals Inc. became the first company to engineer a virus meant to fight cancer. But Onyx's program showed little cell-killing activity, and the program was scuttled in 2003.

In 2005, China approved the first oncolytic virus, Oncorine (H101) from Shanghai Sunway Biotech Co. Ltd., to treat head and neck cancer. Oncorine is a modified adenovirus with deletion of an E1B-55kd segment.

It would be another decade before Imlygic's approval in the U.S. One of the main challenges was an overabundance of caution about the safety of administering replicating viruses, according to Oncolytics Biotech Inc. Chairman, President and CEO Brad Thompson.

"People in the initial trials were quite cautious with the viruses, and may have overattenuated them because it wasn't known how safe it would be," said Robert Coffin, CEO of Replimune and founder and CTO of BioVex.

In fact the viruses have...

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