For decades, scientists have known that viruses can kill cancer cells. The challenge has been harnessing that power safely and effectively.

Buoyed by advances in immunotherapy and drug discovery, a new wave of researchers and companies is poised to make a run at that challenge over the next few years with a class of therapies known as oncolytic viruses.

“We’re just on the brink of some really exciting developments in our field,” said Charlotte Casebourne, CEO of Theolytics. Based in Oxford, England, the company hopes to move its lead oncolytic virus candidate into clinical trials over the next two to three years.

The field is based on a relatively simple premise. A virus is injected into tumor cells; the virus replicates and blows up – or lyses – the tumor cells; the immune system recognizes the remaining tumor cells and clears them out.

The premise was discovered decades ago in patients who came down with viruses alongside cancer. The viruses attacked the cancer but they also could harm patients.

Early research focused on attenuated viruses, which generally proved too weak to do much. Recent advances are solving that challenge while addressing new ones, such as preventing the immune system from turning on the virus.

“Right now, it’s about finding that Goldilocks, that perfect happy medium,” said Greg Delgoffe, a cancer immunologist and associate professor at the University of Pittsburgh.

The field got a shot in the arm in 2015 when Amgen won approval from the U.S. Food and Drug Administration for an oncolytic virus therapy called T-VEC. Based on a genetically modified herpes simplex virus and marketed as Imlygic, it is used to treat melanomas that cannot be surgically removed.

“We have this example which provides us with really nice clinical proof of concept that efficacy is possible with oncolytic viruses as a technical approach,” Casebourne said in a Zoom interview.

T-VEC, however, is injected directly into a tumor. Some of the newer therapies are designed to be injected intravenously, allowing them to move through the body to clear cancer.

Theolytics’ lead candidate is TheoAd281, an adenovirus-based therapy that targets ovarian cancer. Clinical trials will focus on its safety and efficacy as a monotherapy, delivered intravenously, before delving into its potential in combination with other therapies, Casebourne said.

The company was founded in 2017 by Casebourne and researchers Margaret Duffy, Kerry Fisher and Len Seymour. It raised $6.8 million in a Series A round in early 2021 led by Epidarex Capital and Taiho Ventures, with participation from existing investor Oxford Sciences Innovation.

In addition to Amgen’s approved therapy, the field has benefited from advances in drug discovery and gene sequencing, Casebourne noted. Theolytics uses a proprietary phenotypic platform to figure out which virus variants might be effective against particular tumors, Casebourne said. The platform speeds up the discovery process to between 12 and 18 months, she added.

Valo Therapeutics also is banking on a platform approach. The company attaches peptides to oncolytic viruses as a means of directing the immune system against tumor cells.  Its lead candidate, PeptiCRAd 1, is expected to enter phase 1 trials this year, most likely for treating melanoma and non-small cell lung cancer, according to Paul Higham, CEO of Valo, which is based in Oxford, England.

The use of peptides is based on research by Vincenzo Cerullo, a professor and head of the drug research program at Helsinki University in Finland.

“Because it’s actually a simple process to attach peptides on the surface of the oncolytic virus, we can be extremely flexible in terms of what we attach to the viruses,” Higham said. “We can select all different kinds of peptides to stimulate all different kinds of immune responses.”

Different tumors may require different peptides, he said. “The most effective therapies in the future are going to be those that are most specific to the patient being treated, and our platform really allows to do that.”

Another contender in the space is CG Oncology, based in Irvine, California. In December, the company raised $47 million in a Series D round led by Kissei Pharmaceutical Co. Ltd. CG’s main oncolytic virus candidate, CG0070, is being examined in several clinical trials.

A phase 3 trial is testing the candidate as monotherapy for a form of bladder cancer. A phase 2 trial is studying CG0070 for the same indication but in combination with Merck’s Keytruda, a checkpoint inhibitor. The candidate is injected directly into the tumor.

Checkpoint inhibitors release the brakes on the immune system while the oncolytic virus strengthens the immune response, said Arthur Kuan, CG’s CEO. “I think oncolytic viruses will continue to emerge as one of the best combination partners with checkpoint inhibitors.”

The company is planning to move into other cancers this year, Kuan said in a phone interview. He and others expect that future oncologists will have a range of viruses to choose from based on a range of factors, including the type and location of the cancer.

It may be years before therapies win approval, Kuan said. But he believes the oncolytic virus field is coming into its own.

“We’re definitely in a rising-tide environment with many catalysts coming up in the next 12 to 18 months,” he said.

The field’s challenges over the years have made investors somewhat leery, said Dr. Mark McCamish, CEO of San Diego-based IconOVir Bio.

For its part, IconOVir was able to overcome investor skepticism by explaining how the field has overcome some of its earlier challenges, McCamish said. Those challenges have included creating an oncolytic virus that could escape detection by the immune system and confer lasting immunity against a tumor. IconOVir Bio raised $77 million earlier this year in Series A funding to advance its platform for creating oncolytic virus therapies. The platform is based on more than a decade of research by company co-founder Clodagh O’Shea of the Salk Institute for Biological Sciences.

“It’s data-driven. It’s not just a story,” said McCamish, who previously led immune-oncology company Forty Seven before it was bought last year by Gilead Sciences.

IconOVir is hoping to start clinical trials of its lead candidate, IOV-1042, in the first half of 2022. Derived from the common cold virus, IOV-1042 has been shown in preclinical research to infect and kill a range of tumor cells, including head and neck, bladder, lung and breast.

“I think it’s an exciting field and an exciting time,” said McCamish. “And if the science comes to fruition, it’s a great opportunity.”

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