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Valo Therapeutics Advancing Plans for Oncolytic Virus Treatments With Tailored Immunogenic Peptides


NEW YORK – Valo Therapeutics has reimagined oncolytic virus treatments by adding an exterior coating of tumor-specific peptides designed to stimulate an immune response against the tumor.

This enhancement, according the company, has opened development pathways for personalized therapy based on its PeptiCRAd technology.

PeptiCRAd uses electrostatic interactions to attach immunogenic peptides with a positively charged lysine tail to the negatively charged outside surface of a virus or bacteria. It was developed at the University of Helsinki, which spun out Valo in 2016.

The Finnish firm's lead product, PeptiCRAd-1, is an engineered adenovirus coated with NY-ESO-1 and MAGE-A3 tumor antigens genetically modified for increased tumor cell infection, high viral replication within the tumor, and increased immunogenicity. It also carries two co-stimulatory molecules as transgenes. One encodes a CD40 ligand to drive CD8+ T-cell responses. Another encodes an OX40 ligand for increased clonal expansion and survival of CD8+ T cells, and formation of a larger pool of memory T cells.

In nature, oncolytic viruses infect and kill cancer cells. Their potential as therapeutics has been harnessed through engineering of oncolytic viruses to have specific cancer-fighting properties. The US Food and Drug Administration approved Amgen's Imlygic (talimogene laherparepvec) for melanoma as the first oncolytic viral immunotherapy in 2015, and a number of others are in clinical trials, including some that use biomarker strategies and others in which oncolytic viruses are being combined with autologous CAR T-cell treatments.

Examples include a Phase I trial of the oncolytic virus Vaxinia (CF33-hNIS) and Merck's Keytruda (pembrolizumab) in metastatic solid tumors started by Imugene and City of Hope in May; and Phase I and Phase II trials by Vyriad of an attenuated measles virus and vesicular stomatitis virus alone and in combination with checkpoint inhibitors. The biomarker of interest in the City of Hope/Imugene and Vyriad trials is PD-L1 expression. Meanwhile, Mustang Bio is testing out an oncolytic virus with an autologous CAR T-cell therapy in brain cancer patients.

According to Valo CEO Paul Higham, what differentiates Valo's approach from others is the peptide coating, which gives the virus additional vaccine-like properties on top of the oncolytic effect of the virus. Because the peptides are attached weakly to the virus exterior by electrostatic charge rather than chemical bonds, they are released in the tumor environment, stimulating an immune response.

"Oncolytic viruses in the past stimulated a strong immune response. But most of that has been directed against the virus itself, not against the tumor," said Higham. "We're really shifting the focus of the immune system away from the virus and onto the tumor."

In preclinical research, the Helsinki-based company has shown that a PeptiCRAd virus targeting MAGE-A1 eradicated tumors in humanized mice with melanomas and increased the population of MAGE-A1-specific CD8+ T cells. "We've seen in our preclinical work, we have something close to a 90 percent response rate in the mice that we've treated," said Higham, adding that the effect is increased when a PeptiCRAd therapy is combined with checkpoint inhibitors.

Higham said Valo has also conducted experiments in which two identical tumors are grafted onto a mouse, one on the right side and one on the left, and PeptiCRAd therapy is injected into one of the tumors. Researchers observed an expected effect in the PeptiCRAd-injected tumor, but they also saw a "really strong effect" on the untreated tumor on the other side of the body.

"The only way you can really explain that is that we've stimulated the immune system in the right way and the relevant immune cells – mainly T cells – have gone throughout the mouse's body, identified that there's a tumor on the other side, and attacked that tumor," Higham said. Those results from mouse studies suggest that in humans this therapy could be active against metastases via a systemic immune reaction, even when only the primary tumor is treated.

Valo is hoping to see this effect in an upcoming Phase I clinical trial, in which it is combining PeptiCRAd-1 with Keytruda in 15 patients with melanoma, triple-negative breast cancer, and non-small cell lung cancer. Higham said patients in the study will receive four injections of PeptiCRAD-1 into their tumors followed by checkpoint inhibitor therapy "to take down any barrier there may be to T cells getting in and killing tumor cells." Researchers will measure changes in immune cells throughout the body indicating they are recognizing tumor antigens as well as patients' responses to therapy.

Valo, which is currently raising money for the study, has started recruiting patients at sites in Germany and expects to begin dosing patients before year end. The trial will report data before the end of 2023. "Within less than 18 months from now, we hope to have the full results of the study available," Higham said.

The company's acquisition of the PeptiCHIP platform from the University of Helsinki last month adds personalization capability to its development plans for its pipeline of PeptiCRAd therapies. PeptiCHIP combines microfluidic chip technology with a software algorithm to identify antigens from a tumor. Valo plans to develop individualized, n-of-1 therapies by using PeptiCHIP to test a patient's tumor for antigens and treating the patient with a PeptiCRAd therapy targeted to those antigens specifically.

That could happen in one of two ways. First, the company could create a bespoke therapy based on the patient's tumor antigen profile. A second option, Higham said, might be to create a library of the most common peptide antigens patients with a specific tumor type tend to have and cross-match an individual's PeptiCHIP analysis with that library to find an off-the-shelf PeptiCRAd therapy.

While a similar analysis using conventional methods might take two or three days, Higham said that Valo hopes to develop a method that will complete the tumor antigen analysis in two to three hours.

Toward that end, Higham said Valo's Phase I study would serve as proof of concept to show that the PeptiCRAd platform works. Once that's established, the company will expand into personalization strategies. That would put the start of clinical trials at least two years out, Highman estimated.

Another possibility being explored by Valo is repeating the antigen screening periodically during treatment and in follow-up in order to adapt the therapy to changes in the tumor, which often leads to loss of effectiveness of immunotherapies over time. "The targets we initially choose may not, six months or a year down the line, be the most relevant targets," said Higham. "We may have the adaptability to flex with the tumor as it changes."

While Valo is able to go after a variety of cancers with PeptiCRAd therapies, one limitation is that the tumor must be accessible to inject with a needle. Higham said that liver cancer and bladder cancer could be future areas of study for the company, but that with personalized therapy, the type of cancer "becomes a little bit irrelevant because we're treating individual tumors in a particular patient. If we can get biopsy sample from them, we can create a therapy."

Comparing a personalized PeptiCRAd therapy to autologous CAR T cell-therapy, which is also an n-of-1 treatment, Higham noted that adapting the therapy to changes in the tumor would require starting over, which would be expensive and time-consuming. "CAR T therapies can cost up to $400,000," Higham said. "Our therapy would be well below $100,000 because we're using a simpler, off-the-shelf oncolytic virus. That doesn't change. We just change the antigens."

In terms of regulation, Higham said the pathway for its Phase I PeptiCRAd product is "fairly straightforward." The company has permission from the German Regulatory Agency to proceed with its Phase I trial, and oncolytic viruses are an established mode of therapy. "The trickier thing is the adaptability we want to build in regarding the personalized therapy, and there may be a number of ways of doing that," Higham said.

That's where the use of a library may be helpful. "What we'd aim to do is have the peptides in the library approved by the regulatory authority so we're then free to select down from that library at any time and not have to seek individual regulatory approval for each patient or each therapy."

Because the peptide-coating technology is applicable to any oncolytic virus, Higham said that Valo is talking with other oncolytic virus companies about potential partnerships to apply the PeptiCRAd technology to their viruses. "It's a way our technology platform can [move] forward into Phase II and III studies very quickly, because we'd simply be enhancing what's already there," Higham said.

The firm is eyeing opportunities to work with companies developing checkpoint inhibitors or cell-based therapies, as PeptiCRAd therapies can potentially be combined with those, as well as with companies in need of a platform for validating neoantigens.