This article appeared in the July/August 2021 issue of Discover magazine as "When Viruses Heal." Subscribe for more stories like these.
Sitting in an isolated room at Beth Israel Deaconess Medical Center in Boston, Frank Nielsen steeled himself for the first injection. Doctors were about to take a needle filled with herpes simplex virus, the strain responsible for cold sores, and plunge it directly into his scalp. If all went well, it would likely save his life.
Nielsen was a cancer survivor and, once again, a cancer patient. His melanoma, which had responded to conventional treatments the first time around, had returned with a frightening aggressiveness. Within weeks, a lump on his scalp had swelled into an ugly mass. Unlike the first time, options like surgery weren’t viable — it was growing too quickly.
As a last resort, his doctors turned to a cutting-edge drug known as T-VEC, approved in 2015 in the U.S. But the treatment, part of a promising field of cancer care known as immunotherapy, doesn’t sound much like a drug at all. T-VEC consists of a genetically modified virus that acts as both soldier and scout within the body, attacking tumor cells directly and calling in reinforcements from the immune system. Nielsen’s doctors hoped it would team up with the immunotherapy drug Keytruda, which enables the immune system to recognize and destroy tumor cells, to bring his cancer under control.
For nearly a year, Nielsen, a mechanical engineer in central Massachusetts, traveled to Boston every three weeks to have the drug injected into the tumors on his scalp. He would come home with his head swaddled in bloody bandages, aching after as many as 70 separate injections in a single session. There, he would prepare himself for the inevitable fever, nausea and vomiting, as his body reacted to the sudden presence of a live virus.
But the grueling regimen paid off. After the fifth round of treatment, Nielsen says, he began to see a visible change in the lumps on his scalp. It was a moment of relief for the 61-year-old. “I yelled to my wife and ran to the bedroom and was showing her,” he says. The T-VEC treatments eventually dissolved Nielsen’s tumors to the point where Keytruda alone could work. Roughly two years later, he remains free of cancer.
Someday in the near future, dozens of cancer patients could be in remission with similar stories to tell.
Infecting a cancer patient with a virus — a procedure that once would have raised eyebrows, if not malpractice lawsuits — might soon be routine. It’s taken more than a century of work, and a few hairraising experimental trials along the way, but a viral cure for cancer could be emerging.
In the mid-1800s, doctors treating cancer patients started to notice something odd: People with infectious diseases sometimes saw their tumors shrink. Case reports of the phenomenon date back to before scientists even understood what viruses were. For example, a leukemia patient in 1896 saw her cancer briefly dissipate, a seeming miracle, after contracting what was likely influenza.
Researchers began an audacious, often risky search for a cancer cure based on pathogens a few decades later, purposefully infecting cancer patients with a variety of viruses to see if they would prove curative. One 1949 trial gave the hepatitis virus to patients with Hodgkin’s lymphoma. The results were mixed: Seven patients experienced a temporary improvement in their cancer, but at least one died from hepatitis.
Potentially deadly side effects notwithstanding, researchers pressed on. Trials of what we now call oncolytic viruses — pathogens that infect and kill tumor cells — continued through the 1960s. They included experiments with the viruses that cause West Nile, mononucleosis and a form of encephalitis, among others.
The idea was that a virus would penetrate a tumor cell, replicate, and eventually kill it, then invade other cancer cells throughout the tumor and repeat the process, says Samuel Rabkin, a neuroscientist at Harvard Medical School and Massachusetts General Hospital who works with oncolytic viruses. He says that, hypothetically, “the process would basically go round and round until there were no cancer cells left.”
Many early oncolytic virus trials would never fly today. In some experiments, scientists injected infectious fluids or body tissue directly into cancer patients. One 1974 study in Japan fed patients pieces of bread soaked with infectious liquid. Participants in these trials often got sick, sometimes severely — with fevers, bleeding and brain inflammation as side effects. Though many trials reported promising reductions in tumors treated with viruses, the success was always temporary.
“I don’t think it cured anyone,” says Stephen Russell, a hematologist at the Mayo Clinic and oncolytic virus researcher, of the early experiments. Viruses offered only temporary reprieve from the inevitable.
For most patients in those antiquated trials, their immune systems likely cleared the viruses from their bodies before the cancer could be eliminated — if the virus didn’t kill them first. Their stories point to the obvious drawback of oncolytic viruses: The curative agent is a longtime archnemesis of the human race.
We now know that some viruses do indeed go after cancerous cells in the body, with occasionally surprising effectiveness. Cancer cells possess a few traits that viruses tend to like, including rapid reproduction and a high level of metabolic activity, Rabkin says. This can make a tumor cell an ideal home for a virus, until the virus destroys it and moves on to another cell.
For decades, experts’ knowledge of that biological relationship failed to translate into an effective cancer treatment. Following numerous trials with steep mortality rates and little real success, research on using viruses as a cancer treatment dropped. In the 1970s, new cancer therapies like radiation treatment and chemotherapy began to mature, giving patients other options. It would take years of significant scientific advances until viruses returned to the forefront of cancer care.
Friend and Foe
In 2013, a Minnesota woman named Stacy Erholtz received an experimental treatment for her multiple myeloma, a cancer of the blood plasma cells. Doctors injected a massive dose of an attenuated measles virus into her body. The genetically modified pathogen homed in on tumors, killing cancer cells and kickstarting a process that recruited her immune system to finish the job. Her cancer eventually went into complete remission, a startling success for an oncolytic virus, says Russell, who helped develop her treatment.
It’s likely that cases like Erholtz’s, in which the patient is successfully treated with just an oncolytic virus and nothing else, are outliers. But in the last decade, researchers have begun using viruses in combination with other drugs to effectively treat cancer in a wider range of patients. The combination that saved Nielsen’s life — an oncolytic virus and an immunotherapy drug — may soon be a viable treatment for multiple forms of cancer. Dozens of clinical trials are currently testing oncolytic therapies for cancer; recent years have seen a wave of interest in the field, with big pharmaceutical companies investing in or acquiring biotech start-ups. While T-VEC is the only oncolytic cancer drug in the U.S. so far, more will likely follow.
The days of feeding people virus-soaked bread are long gone. Scientists today have the ability to precisely manipulate viruses, as well as a more nuanced understanding of how oncolytics work. But perhaps most important of all has been the advent of a groundbreaking class of cancer drugs known as checkpoint inhibitors, which enable the immune system to take on cancer. The first drug of this kind, ipilimumab, was approved by the FDA in 2011. The key breakthrough came when researchers discovered that cancer cells depend on a unique cloaking mechanism to survive. The body’s immune cells display on their surfaces proteins called checkpoints, which normally modulate the immune system so that it doesn’t destroy healthy cells. When an immune cell recognizes a checkpoint, it’s like an automatic off-switch: The cells stop dividing. Tumor cells co-opt this mechanism by displaying matching checkpoints, causing any curious immune cells to stand down.
Checkpoint inhibitor drugs, the backbone of modern immunotherapy, block those checkpoints on immune cells, effectively removing the ability for cancer cells to bind with them. The discovery has led to treatments for advanced cancers, like metastatic melanoma, that were once seen as a death sentence.
When it comes to fighting invaders, the immune system relies on specialized members of its fleet: T cells, which learn to recognize and kill interlopers. But there aren’t always enough T cells nearby to do the job effectively, something that’s hampered the success of immunotherapy drugs. That’s where the viruses come in — they call more T cells to the site of the tumor.
“When a virus is given to a tumor, the tumor becomes infected tissue,” says Vincenzo Cerullo, an oncolytic cancer vaccine immunologist at the University of Helsinki. That catalyzes swarms of T cells to rush to a tumor, ready to defend the body. Today, checkpoint inhibitor drugs are effective in only a small percentage of patients. Add in a virus, however, and that percentage can double or triple.
This combination of treatments is marking a turning point for cancer research, says James Allison, an immunologist at the University of Texas MD Anderson Cancer Center. In 2018, Allison was a co-recipient of the Nobel Prize in Physiology or Medicine for his work on checkpoint inhibitors.
For cancer treatments before the advent of immunotherapy, “you had to kill every last tumor cell if you’re going to cure somebody,” he says. Now all doctors need to do is get the immune system involved and give it the tools to take over.
And, as Allison and others have shown, the beneficial effects of a viral infection extend beyond the site of a single tumor. Allison found in experiments that injecting mice with a virus slowed the growth of not only the tumor the researchers targeted, but tumors elsewhere in the body as well. T cells, once marshalled, are primed to move throughout the body, attacking cancer cells wherever they find them. Allison calls this a systemic immunity to cancer, and it’s become a goal for oncolytic virus researchers all over the world.
Giving the body the means to fight off tumors itself could offer a cure for even hard-to treat metastatic cancers that spread quickly and lethally.
A Body in Battle
Nielsen was lucky in one sense — the tumors that colonized his scalp were all close together and raised above the surface of his skin. That made it easy for doctors to inject a virus directly into them. But some tumors can be hard to access, and others spread throughout the body as they metastasize, making them more difficult to target with treatments.
Researchers are currently working to better adapt oncolytic treatments to be delivered through an IV. Theoretically, when a virus can move freely throughout the body and spread its immunogenic clarion call, even the most hard-to-access tumors could be targeted and wiped out. Though some trials of oncolytic viruses have used intravenous administration, scientists say more work is needed to make them fully effective.
The promise of more flexible treatment methods would help boost another goal in the field: developing so-called vaccines for cancer. The drugs promise to not only fight off tumors, but to turn the body itself into a cancer-killing machine. It’s a tall order, but cancer experts have reason to be hopeful, in part because the tools they’re using to build treatments have proven extraordinarily adaptable.
Russell calls viruses the world’s best Lego set. “You can take any virus and add new genes, engineer the existing genes, dismantle and rebuild,” he says.
Today, oncolytic viruses already make use of a small genetic mutation that helps them avoid infecting normal cells. But there’s potential to make more sweeping modifications to viruses, in turn creating more precise and effective treatments.
Russell, with a biotech company he helped found called Vyriad, is experimenting with adding a gene to a virus that enhances the immune system’s response. Like the chemicals that stimulate immune cells and attract them to a pathogen, Vyriad’s engineered virus has a similar effect. Here, viruses are being led to human cells that have gone rogue. Russell says the process should help doctors give higher doses of an oncolytic virus without endangering the patient.
A different approach might be to focus on simply making viruses more provocative to the immune system. Cerullo refers to it as arming the virus. T-VEC, for example, has a genetic modification that allows it to express a compound that the body uses to stimulate the immune system. Like sharks to blood, immune cells mobilize at a whiff of these molecules. Engineering an oncolytic virus might guarantee it gets noticed, ensuring a strong immune response against the tumor.
Ultimately, the goal is to make it so that a patient’s body is capable of recognizing and fighting cancers it has seen before, resulting in a kind of immunity to cancer. It would remove one of the final legacies of cancer for patients like Nielsen, who must live every day with the unsettling risk of recurrence lurking over them. Oncolytic viruses might turn a cancer diagnosis into something much like a viral infection — frightening and uncomfortable, but treatable.
Frank Nielsen’s name is a pseudonym, to protect his privacy.
Nathaniel Scharping is a freelance writer and editor based in Milwaukee.