The measles virus is being tested as part of a possible treatment for multiple myeloma. Credit: EYE OF SCIENCE/SPL

Eric Bartee, a specialist in molecular medicine at the University of New Mexico in Albuquerque, describes using viruses to treat cancer as “the oldest survivable cancer therapy”.

The first documented case of what is now called oncolytic virotherapy dates from 1897, when George Dock, a physician in Michigan, noticed a significant remission of leukaemia in a women after she had flu. A more recent, but equally serendipitous, discovery involves a child in Uganda with Burkitt’s lymphoma who, in 1971, went into remission after he contracted measles. In the 1990s, researchers in Canada found that a common virus called reovirus destroyed infected cancer cells. And in 2005, Grant McFadden, a virologist at Arizona State University in Tempe, was studying a rabbit virus that, he thought, had no implications for human health, when he discovered that it attacked human cancer cells.

Since anti-cancer effects were first observed, physicians have tried to harness viruses to treat cancer. In the 1800s, doctors “didn’t even know what a virus was, but they were using them as cancer treatments”, says Bartee. A person with leukaemia was paired with someone with flu, who coughed on a rag that they gave to the person with leukaemia.

In the last century, virotherapy went through cycles of renewed interest and disappointment. The use of tissue cultures reignited the field in the 1950s, with experiments on naturally occurring, or wild-type, viruses in people with terminal cancer. But wild-type viruses proved to be dangerous, and interest “stalled out for a few years”, says Bartee. The advent of the polymerase chain reaction and genetic recombination in the 1980s made it possible to modify viruses to make them safer for use in people. These developments led researchers to revisit virotherapy, but interest waned when the engineered viruses did not produce the results that researchers had hoped for.

Now virotherapy has returned to the cancer therapeutic arena once again. “It’s come back with a vengeance in the last 15 years with the development of immunotherapy,” says Bartee. Therapies that boost the body’s own immune response to cancer are a promising approach to treatment that avoids the immune compromise caused by chemotherapy, and viruses seem to generate such a response.

Oncolytic virotherapy is particularly promising for multiple myeloma, which has a poor prognosis and limited treatment options. The viruses that are used target cancer cells, but do not damage healthy cells — an advantage in therapy for any type of cancer. And many of the viruses naturally disseminate throughout the body, hunting down cancer cells. This is particularly useful in multiple myeloma because, McFadden says, it “loves to hide” in the bone marrow, bloodstream and spleen. Unlike therapies that target types of cancer involving a single genetic mutation, virotherapy is effective against cancer cells with a wide variety of genetic mutations — and one person’s multiple myeloma often involves numerous mutations. Some viruses are proving to be a particularly good fit for multiple myeloma because they target the receptors found on myeloma cells and, in some cases, lead to a remission in days.

After the cycles of hype followed by dashed hopes, oncolytic virotherapy is entering a more realistic phase. Experiments in cells and animals, as well as nine trials in people with multiple myeloma, have had mixed results — even from one person to another. But there have been a few high-profile successes. As McFadden puts it, “We haven’t yet accomplished it, but we can see victory out there in the distance.”

Calling the immune system

The viruses that researchers use are called oncolytic because they destroy, or lyse, the tumour cells that they infect. The viruses also use the tumour cells as factories to produce even more virus particles that spreads to neighbouring cells, killing large areas of the tumour in a few days. Bartee says the virus works from the middle outward: “You make these tumours implode on themselves.” But the effect is only temporary. “The cells you never infected come right back, almost immediately,” Bartee says.

Virotherapy has a second effect, however, that has surprised researchers. The immune system ‘sees’ the infection and activates immune cells such as T cells, which attack not only the infected cells but also any abnormal cells — including uninfected tumour cells. After the virus makes the tumour implode, T cells can penetrate it more easily, finding and cleaning up remaining tumour cells.

When researchers realized that the immune system was helping to attack the tumour, Bartee says the field completely reversed its perspective on this approach to therapy. “They were looking for ways to kill the immune system off because the immune system stopped the replication of virus,” he says. “Now, they are looking at using virus in combination with things that drive the immune system even more.”

Researchers will have to prove that the viruses that are candidates for multiple-myeloma therapy have these two effects: tumour lysis and immune response. The viruses also have to work specifically for multiple myeloma. Flavia Pichiorri, a researcher at City of Hope’s Hematologic Malignancies Research Institute in Duarte, California, says a virus’s suitability for this type of cancer depends on several factors: whether receptors on the surface of the myeloma cells are targeted by the virus, whether the virus can enter myeloma cells and whether the immune cells will respond to the infection. Most importantly, the viruses must also be safe to give to people with cancer.

What’s special about Stacy

One virus that fits the bill is the measles virus, which is the subject of a long-term multiple-myeloma trial at the Mayo Clinic in Rochester, Minnesota. Researchers are using the Edmonston strain of the virus, which is used in vaccines and causes few or no symptoms. Stephen Russell, a haematologist at the Mayo Clinic, explains that the virus has changed since the 1950s, when it was first grown experimentally. Growing the virus for vaccine development in cancer-cell lines resulted in changes that allowed it to bind to human cells using the CD46 protein, which is expressed at high levels in all human cancers, and particularly in multiple myeloma. “It is intrinsically happier in cancer cells than in normal cells,” says Russell.

Researchers injected several people with myeloma with a single high dose of the virus. One of the participants, Stacy Erholtz, in whom other therapies had failed, went into complete remission very quickly. At the age of 56, “Stacy is now beyond seven years, and she’s still doing great,” says Russell. Two of her tumours did reoccur — one nine months after the virotherapy and the other after two and a half years — but both regressed completely after radiotherapy. Since then, her bone marrow has remained cancer-free.

Stacy Erholtz was treated with a high dose of the measles virus.Credit: Mayo Clinic

But other participants did not have such positive outcomes. “We did see tumour regressions in other patients, but never complete and never durable,” says Russell. “It’s been very difficult to reproduce, and obviously it’s been frustrating to us. We puzzled over what was special about Stacy.”

Erholtz had been vaccinated as a child and had a robust T-cell response against the measles virus. This helped the virus to activate her immune response against the tumour. But, because of two stem-cell transplants to treat multiple myeloma, she did not have any of the antibodies against measles that would normally be found in a person with previous infection or vaccination and that might keep the virus at bay. She also had a very high number of genetic mutations in the myeloma cells — indeed, the fifth-highest level in a large multiple-myeloma database. Russell says these three factors might work together to provide an optimal environment for virotherapy.

Other viruses are also being tested. The Mayo Clinic is conducting human trials with vesicular stomatitis virus (VSV) to treat not only multiple myeloma but also two other blood cancers: acute myeloid leukaemia and T-cell lymphoma. VSV naturally infects cattle, mainly in Central America and the southern United States and can cause a flu-like illness in humans. VSV has shown powerful anti-tumour activity in mouse models1 and is particularly active against multiple myeloma. Russell and his colleagues are also experimenting with coxsackievirus A21, which causes a mild upper-respiratory illness in humans, and mengo virus, which causes myocarditis and encephalitis in many mammals, although only mild illness in humans.

Another contender is reovirus, which has been studied as a possible myeloma therapy in six human trials. This common human virus normally causes only minor symptoms in the lungs or gut, says Don Morris, an oncologist at the University of Calgary in Alberta, Canada. In fact, Morris’s team tested people in the lab and found that most had been exposed to the virus. Morris says the virus is also a strong oncolytic — many different types of cancer are sensitive to it in cell and animal experiments.

Pichiorri was involved in the first human trial of reovirus for multiple myeloma to establish the virus’s safety as a therapy, and is now working on two other phase I trials. At her centre, researchers are also studying the potential of herpes simplex virus 1, which causes cold sores, to treat multiple myeloma.

Morris says this research is generating excitement and optimism in the field, but Pichiorri cautions that there have been setbacks in reaching the twin goals of safety and effectiveness. “It’s a learning process. It’s something that needs to be explored, but we also need to be careful. It’s teaching us.”

Jumping the hurdles

Barriers to virotherapy’s effectiveness keep popping up. As a result, researchers say successfully deploying this technique to treat multiple myeloma will require viruses to be engineered or combined with other therapies.

McFadden studies the myxoma virus, a poxvirus that infects certain rabbit species. So far, it has been tested in mouse models and in tumour samples from people with cancer, including those with multiple myeloma. But it needs a boost to be more effective. This is particularly important in multiple myeloma, which, McFadden says, can come roaring back if any cells evade therapy. “For multiple myeloma,” he says, “the real clinical unmet need is killing those final cells.”

To make the myxoma virus a better killer, McFadden “arms” it with a “secret sauce recipe” of genes from other organisms (he declined to provide any details of the formulation while the research is pending publication). These transgenes help the virus to destroy cancer cells and ‘wake up’ the immune system so that it recognized these cells. The transgenes can improve the presentation of antigens that recruit immune cells, prevent the tumour from growing its own blood supply, or lead to programmed death of tumour cells for clean-up by the immune system.

Another way to boost virotherapy involves immune checkpoints. These are proteins that normally put a brake on the immune system to stop it attacking healthy tissue. They are overexpressed on tumour cells, allowing cancer to evade detection by the immune system.

Checkpoint proteins can be blocked using a class of drugs called immune checkpoint inhibitors, which allow the virus to attract immune cells to the tumour. Researchers have tested reovirus in combination with immune checkpoint inhibitors in multiple myeloma, but although the approach was successful in mouse models, it proved toxic in people2. Human trials were put on hold about three years ago, and researchers including Morris are still working on a solution.

Reovirus is also being paired with the multiple-myeloma drug bortezomib. Using cell lines and mouse models, Morris’s team has shown that reovirus and bortezomib work synergistically3. Bortezomib belongs to a class of drugs that inhibit proteasomes, cellular complexes that break down proteins. Morris found that the drug not only helps the virus to kill more tumour cells, but also allows the virus to infect more neighbouring cells and to continue to call on the immune system. “It’s the drug that keeps on giving,” says Morris.

But Pichiorri, who is treating people with reovirus and proteasome inhibitors, says the combination is not working in people the way animal models have suggested it would. “The drug is doing something different in the presence of the virus,” she says.

One of the barriers to effectiveness that researchers have encountered is the powerful effects of virotherapy. “When we treat with viruses, it wakes up a dormant immune system,” explains Pichiorri. “But this can also be dangerous because it can cause a cytokine storm.” A cytokine storm is an overwhelming response of the immune system that can be fatal, as has occurred in many cases of COVID-19. “Viruses have to be used carefully,” she says, “because there is a weak line between doing good and doing bad.”

Researchers are also puzzling over how to ensure the virus reaches multiple myeloma in the bone marrow. “You can’t just give a systemic injection and hope it’s going to go where you need it to,” says Pichiorri. She, McFadden and Russell talk about using carrier cells that can deliver a virus to the bone marrow. Pichiorri favours using antibodies or a type of immunotherapy called CAR T-cell therapy; McFadden recommends adding the virus to transplant cells during bone-marrow transplants. Russell says his team is looking at cells that can evade the antibody response that most people will have to the measles virus. Such cells could include mesenchymal stem cells, tumour cells, or immune cells such as natural killer cells or T cells.

If these barriers can be overcome, viruses could someday become a mainstay of multiple-myeloma therapy. But their precise role is still to be determined. Bartee says the outcome of current trials of drug therapies and immunotherapies, including virotherapy, will set future directions. “It’s going to be a race — whether immunotherapy will outrace drug therapy.”

Russell, however, is fully behind virotherapy. “It will change multiple myeloma treatment in ten years,” he predicts. “The race is on.”