Since the debut of Imlygic in 2015, no other oncolytic virus cancer therapies have been approved by the FDA and EMA. However, we’re seeing the first signs that the Covid-19 pandemic may help the field get out of the rut.
Earlier this month, the Oxford-based firm Theolytics raised €5.6M in a Series A round. This is the first round in several months for a European startup focusing on oncolytic viruses — viruses modified to kill tumor cells and spare healthy cells. The company was spun out of the University of Oxford in 2019 with the aim of engineering adenoviruses to fight cancer.
Adenoviruses are commonly used as vectors for a wide range of therapies. One of the most famous examples is the Oxford vaccine for Covid-19, which was approved by the UK earlier this month and could get the EMA’s OK by the end of January. The approval has blazed a trail to the market that companies working on other applications of adenoviruses can follow.
“I think the recent approval [of the Oxford Covid-19 vaccine] is a really nice boost for adenovirus-based products in terms of validation, of clinical potential, and also large-scale manufacturing and cold chain distribution,” said Theolytics’ CEO, Charlotte Casebourne.
Oncolytic viruses have been in development for decades. They are designed to infect cancer cells and rip them apart, releasing cancer antigens. These antigens are picked up by the immune system, which mounts a defense against the tumor. One big advantage of this approach is that the genetic material of different types of viruses can be built up and tweaked like lego to tailor their efficacy, safety, and compatibility with combination therapies.
Despite the promises of oncolytic viruses, there are just two approved therapies: Amgen’s Imlygic, which was greenlit for treating melanoma by the FDA and EMA in 2015, and Oncorine, which Shanghai Sunway Biotech took to the Chinese market in 2005. Another oncolytic virus called Rigvir was approved in Latvia in 2004 but withdrawn in 2019. Although Imlygic’s approval was a major milestone for the biotech industry in the last decade, strong competition from the immunotherapy drugs Yervoy, Opdivo, and Keytruda has made it struggle commercially.
There are lots of oncolytic viral immunotherapies under development, but the only one in sight of approval is Daiichi Sankyo’s teserpaturev, which is awaiting a regulatory decision in Japan. Another advanced candidate — a liver cancer treatment developed by the French biotech Transgene — was abandoned in phase III in 2019.
Why have new oncolytic viruses been slow to reach the market? One reason is that it takes between five and seven years to discover new candidates. The process involves tedious iterations of viral modification and screening. To speed this up, Theolytics screens millions of viral candidates in parallel — a more Darwinian approach that, according to Casebourne, can take just 18 months.
However, there are other speedbumps that need to be overcome. One is that viruses targeted at human cells are naturally hard to test in animals.
“It is difficult to demonstrate the full range of the expected human immune response to our therapy in animal models,” said Paul Higham, CEO of the Finnish company Valo Therapeutics, which also develops adenoviral oncolytic viruses. “We have to use different models to highlight particular aspects of the response and thereby build an overall picture.”
Another obstacle is that the immune system tries to destroy viruses before they can establish themselves, and many people already have immunity to some of the viruses used to develop treatments based on oncolytic viruses. This means that oncolytic viruses often need to be injected right into tumors to avoid contact with the immune system, which is technically harder than going through an intravenous route.
These problems can only be overcome gradually. Testing on human tumor samples in place of animals as much as possible can improve the clinical relevance of preclinical work. Additionally, careful screening can reveal which strains can be delivered intravenously. According to Casebourne, the worldwide distribution of the Oxford Covid-19 vaccine is unlikely to prime the immune system against Theolytics’ oncolytic virus because it’s a different type of adenovirus.
The next generation of oncolytic viruses could pack a punch. One of Transgene’s oncolytic virus candidates, currently in phase I trials, is engineered to act simultaneously as a checkpoint inhibitor — a drug that prevents cancer cells from hiding from the immune system — and a pro-inflammatory drug, as well as to block immune-suppressing cells.
“These types of multi-armed viruses are really promising and can directly deliver in the tumor multiple payloads such as immune modulators and boosters,” said Transgene’s CSO, Eric Quéméneur.
Other companies working on next-generation oncolytic viruses include TILT Biotherapeutics and Valo Therapeutics in Finland. Valo’s candidate, for instance, equips the virus with the genetic tools to kickstart cancer-busting T cells and is due to begin a phase I study early this year. The German company Oryx is ready to start phase III trials of an oncolytic virus derived from a rat virus that can cross into the brain to treat brain cancers.
European deals centered on oncolytic viruses underwent a dry spell in late 2020, but Theolytics’ Series A round is a sign that investor interest is increasing. Another is that Transgene’s stock price has recently recovered to the levels that it was at before the stunning phase III failure of its lead candidate in 2019.
“Our portfolio has significantly evolved in the last two years as we have been able to apply our knowledge and experience in developing new, more powerful oncolytic viruses,” said Quéméneur. “Oncolytic virotherapy is clearly making significant progress and generating a much higher level of industry interest reflecting the promise of this approach.”
Compared to Europe, deals centered on oncolytic viruses have been bustling in the rest of the world. Earlier this month, the US company IconOVir bagged €63M in a Series A round to push ahead a pipeline of cancer-killing viruses. December also saw an impressive €300M deal struck between the Japanese Astellas and the US company KaliVir to develop an oncolytic virus based on a type of viral vector called vaccinia, the same as that used in Transgene’s candidates.
“We have indeed seen more investment in startups developing oncolytic viruses,” Quéméneur said. “This is encouraging for Transgene … and we are very pleased to see the growing interest in oncolytic viruses.”
Many European oncolytic virus companies also switched their efforts to fighting the Covid-19 pandemic last year — a trend also seen across immuno-oncology as a whole. Valo joined a partnership to co-develop a Covid-19 vaccine in April. Themis Bioscience, an Austrian company acquired by MSD last year for its Covid-19 vaccine program, had oncolytic viruses in development. Even the German messenger RNA specialist and Covid-19 vaccine extraordinaire BioNTech has a foot in the oncolytic virus space.
The University of Oxford’s adenovirus legacy, cemented by the approval of its Covid-19 vaccine, could draw ever more investors and companies to oncolytic viruses. Sophisticated bioinformatics and gene editing tools like CRISPR/Cas9 could also speed up the progress over the next decade.
“The oncolytic virus space has just scratched on the surface of what is possible for this technological approach,” said Casebourne. “The field is really on the brink of a very exciting phase where I hope we will really start to see some positive results.”
Cover image from Elena Resko