Contagious Enthusiasm

An individual with cancer faces plenty of challenges, so when a viral infection sets up camp in the body, it’s never welcome news — that is, unless the virus has been modified and introduced intentionally to kill cancer.

That’s the concept behind oncolytic virus therapies, which are generating attention from researchers and pharmaceutical developers for their potential to create a new class of immuneenhancing drugs.

U.S. clinical trials are exploring more than 16 genetically modified virus therapies, used either alone or in combination with other treatments, according to an industry report and a search of the ClinicalTrials.gov database. The therapies rely on delivery systems including the coxsackievirus, herpes simplex type 1 (HSV-1), the poliovirus and the human rhinovirus — also known as the common cold.

The only oncolytic virus approved by the Food and Drug Administration is Imlygic (T-VEC; talimogene laherparepvec), a form of HSV-1 that has been genetically modified to express granulocyte-macrophage colony-stimulating factor — a substance produced by the body that contributes to the immune system’s effectiveness. Approved in 2015 for the treatment of melanoma that has recurred in its original location and is inoperable, Imlygic is injected into cancers on or below the skin or in lymph nodes.

According to Robert H.I. Andtbacka, M.D., a leading investigator of the drug, Imlygic has proved to be a durable, well-tolerated therapy that is effective alone in patients with minimal or no visceral disease, meaning that cancer has not spread much to internal organs. For patients with visceral disease, Imlygic combination therapies would be more effective than Imlygic alone, he said during a presentation at the 14th Annual International Symposium on Melanoma and Other Cutaneous Malignancies® in New York City in February; it was hosted by Physicians’ Education Resource®, a sister business of CURE®.

Although Imlygic is the only oncolytic virus approved by the FDA and its indication is to treat melanoma, multiple clinical trials of these therapies are assessing efficacy against numerous cancer types.

The rare and aggressive brain cancer glioblastoma has been a primary target for oncolytic viruses, such as the engineered poliovirus PVS-RIPO, due to an urgent need for durable therapies, said Samuel D. Rabkin, Ph.D., an associate professor of surgery at Harvard Medical School and an associate virologist at Massachusetts General Hospital, both in Boston.

“You have a disease for which the life span is rather limited, and that provides opportunities and dire needs for new strategies to treat it,” he said. Oncolytic viruses in development include Cavatak (CVA21), a formulation of coxsackievirus type A21.

It is being studied in combination with the PD-1 proteininhibiting immunotherapy Keytruda (pembrolizumab) in melanoma, prostate, lung and bladder cancers. In the United Kingdom, oncolytic virus candidate NC-348 has been approved for use in human trials. Its developer describes the drug as a genetically modified adenovirus armed with two proteins that activate T cells, which form the body’s army against dangerous invaders. This type of therapy exerts a direct toxic effect on the tumor, spreads to fight tumors further away and appears to enhance the efficacy of other immunotherapies, said Andtbacka, a surgeon and investigator at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, where he also is an associate professor in the division of surgical oncology.

“We know that with these therapies we can also change the tumor microenvironment,” he said in an interview with OncologyLive®, a sister publication of CURE®. “In patients who don’t respond to PD-1 inhibition, we can use these intralesional therapies to … make some of these nonresponders into responders.” For example, stimulating tumors to express a wider array of mutations would render them more susceptible to treatment with PD-1 inhibitors.

Andtbacka pointed out two trials that could lead to an expanded role for Imlygic in melanoma: a phase 2 study of surgery with or without Imlygic pretreatment in patients who have surgically resectable stage 3b/c melanoma (NCT02211131), and the phase 3 MASTERKEY-265/ KEYNOTE-034 study of Keytruda with or without Imlygic in those with previously untreated, unresectable stage 3 or 4 melanoma (NCT02263508). Imlygic and other oncolytic virus therapies could be effective in other tumor types, as well, including liver metastases, he added: “We really are expanding this into other cancers.”

MECHANISMS OF ACTION

The approval of Imlygic has served as a proof of concept for the modality. “It’s an exciting time for oncolytic viruses, and now that there’s been a virus approved by the FDA, there’s more interest in the field,” Rabkin said.

The concept of using viruses as anticancer agents dates back more than 100 years, to when doctors first observed temporary clinical remission of cancer after naturally acquired systemic infections. These observations led to multiple clinical trials that treated patients who had cancer with nonengineered viruses. Natural virulence could not be controlled, however, and the viral therapy fell out of favor with researchers and clinicians. Throughout the 1950s and 1960s, numerous attempts involved new animal models and methods of virus propagation, but these efforts were abandoned following limited success.

Over the past two decades, however, the advent of genetic engineering and better knowledge of molecular and cancer biology have refined oncolytic virus therapy design, and the strategy has re-emerged as a potentially powerful therapeutic option for advanced cancers. Although success has been observed in clinical trials assessing oncolytic virus single drugs, preliminary results from early-stage clinical trials suggest that combinations with other forms of therapy may further enhance the clinical efficacy of oncolytic viruses.

Cancer cells in general serve as excellent hosts for oncolytic virus replication; often, impairments in their protection mechanisms against viral infections allow for increased viral replication. In addition, other hallmarks of cancer — including resistance to cell death, evasion of growth suppressors, genome instability, stress from DNA damage and avoidance of immune destruction — provide advantages for increased oncolytic virus efficacy.

Capitalizing on all this, oncolytic virus therapies are designed to keep viral replication in cancer cells from damaging normal cells. Scientists accomplish this by choosing nonpathogenic viruses that attach themselves only to surface proteins on cancer cells and not to healthy cells (for example, Reolysin [pelareorep]) or by directly engineering the genome of the virus to prefer cancer cells (for example, Imlygic and G47 delta, both derived from herpes simplex virus-1 [HSV-1]).

The latter strategy — genetic engineering of virus particles — has become the standard for therapeutic development because it gives scientists good control over the viral replication process. For instance, viruses with deletion of the HSV-1 gamma(1)34.5 gene, such as Imlygic and G47 delta, are unable to replicate in normal cells, which block them by shutting off protein synthesis. These viruses can, however, replicate in cancer cells. Deletion of the alpha 47 gene (also in Imlygic and G47 delta) is another common tactic thought to enhance the antitumor immune response.

Toca 511 (vocimagene amiretrorepvec), which is being tested in the brain cancer glioma, employs a different strategy. It is a replicating nonlytic retrovirus — it inserts its DNA into cells without destroying them. The virus provides instructions for the manufacture of the cytosine deaminase (CD) protein, which is able to turn 5-fluorocytosine, an antifungal agent, into the chemotherapy 5-fluorouracil, explained Clark C.

Chen, M.D., Ph.D., the Lyle French Chair in Neurosurgery and head of the department of neurosurgery at the University of Minnesota in Minneapolis. A surgeon injects the virus into the site of highest tumor concentration in the brain. Later, the patient is given oral, extendedrelease 5-fluorocytosine, which the CD gene converts into 5-fluorouracil, activating the immune system against cancer. Other engineered viruses work by inserting RNA rather than DNA into cancer cells.

It was initially thought that oncolytic viruses killed just the cancer cells into which they were injected, but Masahiro Toda, M.D., Ph.D., and colleagues demonstrated that the technique acts systemically, shrinking tumors that are both at and distant from the injection site. This could play a critical role in generating durable responses in patients with metastatic or aggressive disease.

CLINICAL CONSIDERATIONS

Rabkin and Howard L. Kaufman, M.D., chief medical officer of the biotechnology company Replimune, agreed that, because of new techniques in interventional radiology and minor surgery, direct injection of the virus is possible for most tumors and would be more effective than IV administration, which tends to kick off an immune response against the drug. “With modern neurosurgical techniques, almost all areas (of the brain) are accessible to biopsy,” Rabkin said. “If you can perform a biopsy, you can deliver the virus.”

Early trials have shown that oncolytic virus therapy is generally well-tolerated and does not seem to trigger many of the immune-related toxicities associated with immune checkpoint blockade drugs, such as Keytruda. Studies investigating combinations of oncolytic viruses and checkpoint inhibitors have demonstrated side effects consistent with checkpoint blockade alone.

“The effect of the virus tends to be very local. Even though it may have systemic effects, I think they’re probably less likely to lead to severe adverse events than checkpoint blockade,” Rabkin said.

He and Kaufman noted ongoing concerns about systemic spread or transmission to other household members, although neither has been reported in clinical trials. Some patients have reported mild, self-limiting symptoms consistent with the common cold, such as a runny nose, cough and fever from CVA21, but the overall safety profile is relatively good, Kaufman said.

The modified forms of HSV-1 used in oncolytic therapy are less likely to cause infection than is the unengineered form of the virus, to which most of the population has been exposed, Rabkin said. Also, infections could easily be treated with antiviral agents in the rare event of a spread.

On the other hand, an overly strong immune response to the oncolytic virus could lead the body to produce neutralizing antibodies that diminish the antitumor effect. A study of patients whose cancers did not respond to chemotherapy evaluated the effectiveness of using different oncolytic adenovirus therapies with additional immunotherapy treatments to destroy cancer cells. Researchers found that disease control (stable or better) was achieved with 67 percent of the combinations. Importantly, even though patients’ bodies produced antibodies against the adenovirus, this did not limit viral replication.

When oncolytic treatments are made from viruses against which most of the population has been vaccinated, such as measles or vaccinia, efficacy may be especially compromised by antiviral immunity. Strategies under investigation aim to minimize the development of antiviral antibodies and improve delivery of the oncolytic virus to the tumor.

Luckily, the diversity of viruses available for use in oncolytic therapy is a strength of the platform, said Kaufman, who called for further research into the strategy for various types of cancer.

Additional trials should be conducted to identify the optimal setting and dosing of these treatments — it may turn out that patients can achieve long-term results with just a few doses, Kaufman said. “We may not need to give it as frequently as we have been,” he said. “We need to do more work to understand whether we’re overtreating some patients.” Using these drugs in the frontline setting would be most desirable, because it could result in the use of fewer toxic agents later on, he and Rabkin said.

Although clinical trials are in their early stages, the two doctors are optimistic about the possibilities of oncolytic virus therapy. “I think it’s a strategy that has a lot of potential and opportunity,” Rabkin said. “There’s a lot of diversity in the agents being looked at.”