GINA BATTAGLIA, PH.D.

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 

®. “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.”

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 &mdash; 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 &mdash; 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.

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.”

Articles

Oncolytic, or engineered, viruses that infect and kill cancer cells are showing promise.

Contagious Enthusiasm

THE FIRST TARGETED TREATMENT for breast cancer that overexpresses the protein HER2 was approved in 1998, vastly changing the therapeutic landscape for women with this disease subtype.

That drug, Herceptin (trastuzumab), no longer stands alone. Since then, the FDA has approved four additional targeted therapies that can help improve outcomes for women with HER2 (human epidermal growth factor receptor 2)-positive breast cancer, which is aggressive and associated with lower overall survival. The most recent, Nerlynx (neratinib), was approved recently.

With several options available, efforts now focus around refining, combining and sequencing these treatments. Doctors and scientists are working to figure out how to predict which patients will benefit from presurgical or extended treatment with HER2- targeted therapies, and how to treat patients with triple-positive breast cancer, which is driven not only by HER2, but also by hormones.

Experts discussed those issues during a recent

® panel moderated by Adam M. Brufsky, M.D., Ph.D. OncLive® is part of the family of publications that includes

Due to a broadening of the pathologic criteria that define the subtype, more patients than ever are being diagnosed with HER2-positive disease.

Unfortunately, this can lead to some patients being put into that category even though targeted therapies for the subtype won’t help them.

The panelists indicated that this variability among patients classified as having HER2-positive disease highlights the need for ways to improve patient categorization, making it more possible to predict response to anti- HER2-targeted therapies.

In the meantime, Herceptin should be considered for all patients classified as having early-stage HER2-positive disease in the presurgical setting, even if the PAM50 or 70-gene assays predict low therapeutic response or low genomic risk, some of the panelists agreed. One exception might be smaller tumors that have not spread to any lymph nodes — in those cases, surgery might come first.

Considering the low toxicity of Herceptin, “you need to have a very strong reason not to give it,” said Aditya Bardia, M.B.B.S., M.P.H, a medical oncologist at Massachusetts General Hospital. Kimberly Blackwell, M.D., professor of medicine at the Duke Cancer Institute, added that the importance of preventing recurrence is worth the risk of using Herceptin to treat an early-stage, low-risk tumor, even if it’s not entirely clear that the tumor will respond.

Triple-positive breast cancer is not only HER2-positive, but is also driven by the hormones estrogen and progesterone. This can complicate treatment, because the hormonal activity interferes with the effectiveness of Herceptin and chemotherapy drugs, the experts pointed out.

For instance, in patients with metastatic, HER2-positive disease, estrogen receptor (ER) expression in more than 30 percent of cancer cells significantly predicted a lower probability of response to chemotherapy plus Herceptin, an analysis showed.

As a result, panelists said, treatment for these patients should involve combinations and sequences not only of chemotherapy and HER2-targeted drugs, but also of therapies that block the body’s production of cancer-fueling hormones. Known as endocrine therapies, these help to prevent the treatment resistance that can occur from targeting a single pathway.

The same principle is proving true, the panelists said, when two anti- HER2 therapies are used together, after chemotherapy has been completed, to maintain the benefit of previous treatments.

While these pairings tend to improve outcomes in patients with HER2-positive disease, those with locally advanced or metastatic triple- positive breast cancer may not benefit as much if inhibition of the HER2 pathway enhances ER signaling, Blackwell said. That’s why the PERTAIN study aimed to investigate whether adding endocrine therapy would improve response to dual HER2 blockade in postmenopausal patients with hormone receptor-positive and HER2-positive locally advanced metastatic breast cancer.

This open-label, phase 2 trial randomized participants one-to-one to receive Perjeta (pertuzumab), Herceptin and an aromatase inhibitor (AI), which stops the body from producing estrogen, versus only Herceptin and an AI. Some patients also received chemotherapy with docetaxel or paclitaxel 18 to 24 weeks before starting the AI/anti-HER2 therapy. A primary analysis showed that median progression-free survival was longer with the three-drug regimen than with the two-drug therapy (18.9 versus 15.8 months) and was generally well-tolerated.

According to Blackwell, these results support her practice of adding the AI therapy after chemotherapy in patients with triple-positive disease. Combining an AI with anti-HER2 agents after chemotherapy may be more effective than combining hormonal therapy with chemotherapy, as was done in a study known as B-52, Bardia said, and suggested the need for additional research on treatment sequences.

The panelists cautioned against directly comparing the B-52 and PERTAIN results, because the studies involved different patient populations (non-metastatic versus metastatic disease) and used different primary outcome measures (pathological complete response versus progression-free survival).

They agreed that optimizing the sequence of chemotherapy, endocrine treatment and HER2-targeted drugs for patients with triple-positive breast cancer will require further research to clarify the interactions between the ER and HER2 signaling pathways.

In some later-stage disease, it can be beneficial to follow standard anti- HER2 treatment with another HER2 blocker, the panelists said. That drug, Nerlynx, is a tyrosine kinase inhibitor of HER1, HER2 and HER4, and also inhibits a different protein involved in some breast cancers, the epidermal growth factor receptor (EGFR). The drug’s most common side effect is diarrhea.

In the ExteNET trial, extended postsurgical therapy with Nerlynx demonstrated clinical activity in patients with HER2-positive metastatic breast cancer, even in those with prior exposure to other anti-HER2 agents and taxane-based chemotherapy. Findings showed that 12 months of Nerlynx significantly improved two-year disease-free survival (93.9 percent versus 91.6 percent with placebo) in patients with early-stage HER2- positive breast cancer who had completed Herceptin-based therapy before and after surgery less than two years prior to trial enrollment.

Extended therapy with Nerlynx was especially helpful in those with ER-positive disease. On this basis, the FDA approved Nerlynx on July 17, 2017. If additional studies support this use, it should be discussed with all patients who have triple-negative disease, even if they’ve been through standard treatment and are reluctant to take another drug, Blackwell said.

“Our job is to help (patients) participate in these decisions,” she said. “I’m going to have plenty of patients who say, ‘You’ve got to be crazy,’ but I will feel obliged to at least discuss it and document it in my notes.”

Extended therapy with Nerlynx is most appropriate for patients with large “HER2- addicted” tumors, metastasis to lymph nodes and disease that responds well to the initial regimen of HER2-targeted therapy, the panelists agreed.

Despite uncertainty about the clinical benefits, Blackwell said she tends to err on the side of overtreatment, provided that the patient can physically and financially tolerate the medication and the therapy does not definitively reduce duration of survival.

“For that individual patient sitting in front of me, I want to be able to say, ‘We’ve done everything within reason to prevent your breast cancer from coming back,’” she said.

More and more, treating HER2-positive breast cancers involves combining an array of drugs.

Piling on Drugs to Treat HER2-Positive Breast Cancer

According to a recent retrospective cohort analysis of a large national database, patients with a history of breast cancer have a higher risk of developing thyroid cancer than do the general population, particularly if they receive adjuvant radiation therapy.

Lead investigator Jennifer H. Kuo, assistant professor of surgery at Columbia University, New York City, presented these findings on March 5, 2015, at The Endocrine Society’s 97th Annual Meeting in San Diego, Calif.

“There should be a greater awareness [of the link between the cancers] so patients can be treated appropriately in a timely manner,” says Kuo.

Although several single-institution studies have proposed an increased risk of thyroid cancer in patients with a history of breast cancer, analysis of a population-based sample across multiple institutions had not been performed previously. The retrospective analysis by Kuo and colleagues at the National Cancer Institute’s Surveillance, Epidemiology, and End Results 9 (SEER 9) investigated data in patients diagnosed with breast and/or thyroid cancer from 1973 to 2011.

This study included data on 707,678 patients with breast cancer and 49,663 patients with thyroid cancer. Of these, 1526 patients had developed thyroid cancer after a diagnosis of breast cancer. These patients were compared with patients who developed only breast or only thyroid cancer, respectively.

Although Kuo indicated that multiple factors likely play a role for the association between the two cancers, she stated that adjuvant radiation therapy for breast cancer probably contributes to future development of thyroid cancer. A greater proportion of patients who developed thyroid cancer after breast cancer received adjuvant radiation therapy compared with those with breast cancer only (47.9 percent versus 44 percent).

Patients who subsequently developed thyroid cancer also had smaller breast cancer tumors and a greater percentage had invasive ductal carcinoma than did patients with breast cancer only. According to Kuo, patients with smaller tumors generally tend to receive lumpectomy followed by adjuvant radiation therapy, while patients who have larger tumors often have a mastectomy (which does not require adjuvant radiation therapy).

“The pendulum has definitely swung toward breast conservation therapy [for treatment of breast cancer], and that has only been made possible with radiation therapy,” says Kuo.

The researchers also found that patients with thyroid cancer and a history of breast cancer had a greater incidence of tall-cell variant papillary, oxyphilic variant follicular or anaplastic thyroid cancers. Kuo stated that these more aggressive forms of thyroid cancer are often associated with previous radiation exposure.

According to Kuo, the median interval between the diagnosis of breast and thyroid cancers is consistent with general findings on radiation-induced cancers, which further supports a potential link between radiation therapy for breast cancer and subsequent development of thyroid cancer. However, according to Kuo, this link does not suggest a need for alternatives to current indications for radiation therapy in breast cancer.

“I don’t think it’s a big enough argument to make against adjuvant radiation therapy [for treatment of breast cancer],” says Kuo.

Although the study did not investigate the contribution of systemic factors, Kuo pointed to the possible influence of estrogen in both cancers. She indicated that hormones, particularly estrogen, are likely involved in development of breast cancer and that some literature supports a link between estrogen and incidence of thyroid cancer.

Kuo plans to investigate whether tamoxifen, a common therapeutic agent used for five years after breast cancer diagnosis, is associated with an increased risk of thyroid cancer. Although Kuo indicated the mechanism responsible for a potential link is unclear, she suggested it may be related to estrogen.

“We do know tamoxifen is estrogen related, and there is evidence to suggest that estrogen increases the incidence of thyroid cancer,” says Kuo.

According to Kuo, the study results indicate that patients with a history of breast cancer should receive a dedicated thyroid examination every year for the first five years after breast cancer diagnosis, particularly if they had received radiation therapy for breast cancer.

Furthermore, Kuo indicated that researchers must have an improved understanding of the etiology behind the rising incidence of thyroid cancer following breast cancer to improve diagnosis and treatment.

According to a recent analysis of a large national database, patients with a history of breast cancer have a higher risk of developing thyroid cancer than the general population, particularly if they receive adjuvant radiation therapy.

GINA BATTAGLIA, PH.D.

Contagious Enthusiasm

Piling on Drugs to Treat HER2-Positive Breast Cancer

Higher Risk of Thyroid Cancer Among Those With Breast Cancer History

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