Rochester, Minnesota - Rene Maleski knew it was bad news when the young ultrasound tech who was scanning her abdomen suddenly stopped and left the room, crying. The technician returned a few minutes later to tell Maleski she would need to see the radiologist that day, and she should probably bring her husband with her. That afternoon, Maleski came face to face with her new reality: the pelvic scan showed tumors covering her ovaries, climbing up her aorta, and invading her lymph nodes. She had stage-three ovarian cancer.
Within days, the mother of five was on the operating table, as doctors laboriously removed every tumor. She endured 18 rounds of chemotherapy, and for a time that was enough. But within two years, the cancer was back. “It was very disappointing,” said Maleski. “I realized that I was probably going to die from cancer.”
Then her doctor suggested they try something outlandish – an injection of the measles. Maleski didn’t hesitate. A healthy eater, she had struggled mentally with chemotherapy and the thought of purposely “dumping major toxins into your body.” She was willing to try anything to avoid more chemo.
Maleski is one of hundreds of patients who have received cancer-killing viruses in over 25 different clinical trials at the Mayo Clinic. When she was first diagnosed, her CA125 levels — a standard biomarker of ovarian cancer – were 1600. While she was on the measles trial, those levels dropped to 4 (anything below 35 is considered normal). The dramatic results stem from almost a quarter of century of studies at Mayo, one of the oldest virotherapy programs in the world.
Reloading the virus
Scientists first suspected a connection between cancer remission and viruses in the early 1900’s, when they noticed that some cancer patients unexpectedly went into remission after a bout of the flu or chicken pox. But taking a potentially deadly virus — which clinicians have made every effort to eradicate — and turning it into a therapy has not been easy. In the 1950’s and 60’s, researchers made several attempts, injecting patients with a wide variety of wild type viruses, occasionally with promising results. By the 1970’s and 80’s, however, advances in radiation and chemotherapy made the search for such alternative cancer treatments seem unnecessary.
Decades later, scientists now realize that while there are some cancers that can be cured by conventional methods, there are many others that cannot. This year more than 600,000 Americans are expected to die of cancer – more than 1,600 people a day.
“We know that in order to do better we need to think outside the box, and one way to accomplish that is by revisiting the old concept of viruses as cancer killers,” said Eva Galanis, M.D., who heads Mayo’s molecular medicine department. “Viruses have been around for millennia. They have survived evolution by mastering the ability to kill human cells very effectively. The principle behind virotherapy is to take this destructive power and harness it to specifically attack cancer cells while sparing normal cells.”
Viruses are deceptively simple – just a tangle of genetic material encased in a protein shell. To survive, they must latch onto the surface of living cells, push their way in, and hijack the cell’s machinery to replicate themselves, before bursting out of that cell to infect others. As a result, many viruses are naturally drawn to cancer cells, which grow and replicate more quickly than normal cells. Cancer cells also frequently overexpress receptors that viruses use to hack into cells, making them an even more attractive host.
Nevertheless, the Mayo Clinic’s molecular medicine team didn’t want to infect cancer patients with potentially dangerous, wild type versions of virus. Thankfully, years of research have greatly increased the understanding of viral biology, and advances in various laboratory techniques have made it possible to engineer kinder, safer, but also more effective viruses.
The measles virus was selected, along with ovarian cancer as a target over a decade ago by Stephen Russell, M.D., Ph.D., who came to Mayo from Cambridge University to establish the Molecular Medicine Program, which later became a department. Preclinical findings were published by Kah Whye Peng, Ph.D., of Mayo, and Dr. Galanis was in charge of the subsequent clinical trials. In its natural form, the measles virus can cause serious damage – high fever, hacking cough, full-body rash, and in rare cases, death. But the longer it is grown in the laboratory, the less adept the virus becomes at causing disease. One domesticated form of the virus, the Edmonston B strain, has been used to safely vaccinate millions of children against the measles.
Dr. Russell designed the next generation measles virus (with the help of then Ph.D. student David Dingli). To see if the engineered versions of this weakened strain was still strong enough to target and destroy cancer cells, it was injected it into cancer avatars – mice with patient’s ovarian tumors growing inside them. The tumors shrank by 80%.
But to move this approach to the clinic in order to benefit patients, they would need vats of virus, far more than the researchers could routinely generate in the laboratory. Dr. Russell designed Mayo’s own vector production facility, and recruited Mark Federspiel, Ph.D., to run the established facility. To this day it remains one of the only academic sites in the world capable of manufacturing clinical-grade engineered viruses for patient use. Dr. Russell also created a toxicology and biodistribution laboratory, led by Kah Whye Peng, Ph.D., to convincingly demonstrate safety in relevant animal models prior to human testing.
“It was a huge, expensive, and tedious team effort, but it demonstrated that this approach had promise,” said Dr. Galanis. “Because we had established a vector production facility as well as a viral toxicology laboratory in house, we were able to move from the clinical discovery to a first-in-human clinical trial in a fraction of the time that it would take even industry to do. For our first study, it was just three years from proof of principle to the first patient being treated.”
In that first ovarian clinical study, 21 patients with heavily pretreated recurrent cancer were given varying doses of the Edmonston strain of the measles virus. Patients in the study achieved a median overall survival of 12 months, which is twice longer than the expected median survival of 6 months. What’s more, among 37 patients with resistant ovarian cancer treated with the virus, the median overall survival in patients who received the highest doses was an extraordinary 26 to 38 months. The researchers tested the measles virus on other cancers in the lab, again with remarkable results.
“Ovarian cancer, glioma, multiple myeloma, hepatocellular cancer, breast cancer, mesothelioma, head and neck cancer, sarcoma –- the virus eliminated tumors in pretty much every model the molecular medicine teams have tested,” says Dr. Galanis.
Recently Dr. Galanis’ group hit another important milestone by activating the very first human trial of stem-cell delivery of a cancer-killing virus. In this study, the researchers in collaboration with the Mayo Clinic’s Cell Therapy laboratory, led by Allan Dietz, Ph.D., use a tiny amount of the patient’s own fat tissue to generate stem cells that they then infect with measles virus before administering to ovarian cancer patients. “This represents an important breakthrough,” says Dr. Galanis. “Infected stem cells help the virus to “hitchhike” to tumor sites, improving delivery and protecting them from the immune system. If successful, it could drastically change the way we deliver viruses to cancer patients”.
Many researchers believe that cancer-killing viruses – formally known as oncolytic viruses –could represent one of the most important advances in cancer treatment. When these viruses destroy cancer cells, they release hundreds of new infectious virus particles to annihilate the remaining tumor. At the same time, the infected cells secrete chemicals called danger-associated molecular pattern molecules that trigger the antitumor immune response. The ability to both directly kill cancer cells and recruit immune cells to join the fight means that viruses have the potential to successfully treat advanced cancers that have failed other therapies.
Recently, Dr. Galanis and her colleagues began to explore ways to strengthen this immune response to cancer. They combined the measles virus with anti-PD-1, an antibody that unleashes the immune system and is the key ingredient of drugs such as pembrolizumab or nivolumab. The researchers showed that this combination of virotherapy and immunotherapy significantly increased the survival of mice with malignant brain tumors. They went on to test a variety of different immune-boosting genes in a variety of different cancers. This fall, the group will launch the first phase I clinical trial testing one of these designer measles viruses (in this case, carrying the gene for NAP, a protein that activates white blood cells) in patients with metastatic breast cancer.
One question future trials will address is whether the immune response awakened by the virus can in turn make conventional methods more effective. “There have been case reports where patients didn’t experience much success with chemotherapy or radiation, but after they received virotherapy, those same treatments suddenly became effective,” said Dr. Galanis. “Plus, similarly to other immunotherapy strategies, we have found that even if patients progress, they can live much longer than we otherwise would have expected.”
For her part, Rene Maleski responded remarkably well to the measles virus. However, a few months after she finished the trial, her CA125 values crept back into the danger zone. “It was extremely frustrating,” she said. “I would have kept taking the virus if I could, but the FDA limited study treatment to six months in this trial.” Instead, Maleski is undergoing more rounds of chemotherapy, which are working better than ever before. At last count, her CA125 was 11.
Though it is too early to tell, virotherapy may one day serve not only as an adjunct but also as an alternative to current treatments. Compared to the ravages of chemotherapy and radiation, Maleski said the side effects of virotherapy were “nothing.” The only complaint she had was a day or two of bloating; other patients have experienced cold-like symptoms, such as a low-grade fever or headache. Thus far, most participants of virotherapy trials have had more advanced disease, but Dr. Galanis would to like test the approach in people earlier in their treatment course to determine if it could also improve their quality of life as compared to chemotherapy. The program is currently running a randomized phase II trial in recurrent ovarian cancer patients that compares the measles virus side by side with chemotherapy.
Dr. Galanis believes that ongoing virotherapy trials could result in a number of different viral therapy products being approved for cancer treatment over the next three to five years. “Our goal is, of course, to eventually increase the likelihood of cure for patients with cancer,” she said. “So, it’s a long road ahead of us, but I feel we have come a long way also, and so in this context I am quite optimistic.”
The FDA has already approved the first virotherapy, the drug Imlygic, to treat late-stage melanoma on the skin and lymph nodes. The NIH’s database ClinicalTrials.gov currently lists more than 75 clinical trials, testing a menagerie of engineered oncolytic viruses including measles, herpes, vesicular stomatitis virus, adenovirus, HIV, and smallpox. Given the chance, Maleski said that she would wholeheartedly sign up for another infusion of virus.
“These trials, they offer options. They offer hope.”