Follicular lymphoma, a cancer of the white blood cells, is usually incurable. Patients cycle through periods of therapy that partially shrink their cancers, before the disease progresses again. That’s what appeared to be happening with a 61-year-old man in Italy: Diagnosed with cancer in August of 2019, he promptly began a course of chemotherapy, completing it in February 2020. All that was left to do was monitor the tumor’s growth.
So when a June scan revealed that the patient’s tumor appeared to be growing, Martina Sollini, a professor of nuclear medicine at Humanitas University in Italy, and her colleagues weren’t surprised. Until the biopsy came back negative. Another biopsy and a follow-up scan in September confirmed the original findings: The cancer had gone into complete remission. His medical team was left to figure out how. They turned to a curious explanation: Perhaps the cancer’s sudden remission had something to do with the fact that the patient had, that spring, been infected with SARS-CoV-2. After ruling out other possibilities, they published a case study in February, documenting one of a few instances over the course of the pandemic in which researchers suspect that a case of COVID-19 might have caused a tumor to shrink. And while the phenomenon is rare, it shows the potential of carefully administered viral therapies to treat cancer in the future.
It’s well-known that some viruses, like the human papillomavirus and hepatitis B, can cause cancer. But what’s far less understood is the flip side of infections: their potential to cure rather than cause diseases. Cases of infections linked to cancer remission—including blood, kidney, lung, and skin cancers, and even cancers that have spread to other organs—have been documented for thousands of years. The earliest mention dates back to 1550 B.C. and the words of the Egyptian polymath Imhotep, whose recommended cancer treatment involved purposefully infecting tumors and then cutting into them. And then there’s the 13th-century story of Peregrine, an Italian priest who later became canonized as the patron saint of cancer patients. Afflicted with a tumor of the leg that eventually burst through his skin and caused a massive infection, his physician was stunned to find that the cancer had disappeared shortly before Peregrine was due for an amputation. He lived until the age of 85. The cancer never returned.
“Viruses are friends and foes.” — Mitesh Borad, medical oncologist, the Mayo Clinic
Centuries later, in 1891, a New York bone surgeon named William Coley began his decadeslong attempt to cobble together sporadic case reports into a system of cancer treatment. Mixing together several strains of heat-killed bacteria into a “vaccine”—a formulation he’d change well over a dozen times over his career—he injected cancer patients with the hope of the infection burning the disease out of them. And, in a startling number of cases, it worked. In the 1990s, pharmacologists at the biotechnology company Amgen analyzed 170 patient records of advanced cancer patients treated only with Coley’s toxins—about one-third by Coley himself— and found that 64 percent went into remission. But Coley struggled to explain why his method worked, and his successes proved difficult for others to replicate. In 1894, the Journal of the American Medical Association issued a scathing critique of Coley’s toxins: “During the last six months, the alleged remedy has been faithfully tried by many surgeons, but so far not a single well-authenticated case of recovery has been reported.” Coley’s boss at Memorial Hospital in New York—world-renowned cancer pathologist James Ewing—banned the use of the toxins in the hospital, though for a while, they were still used elsewhere.
Coley’s toxins gradually faded out of the limelight, supplanted by advances in radiation therapy and chemotherapy and their more reliable results in treating cancer. In 1962, the U.S. Food and Drug Administration classified Coley’s toxins as having “new drug” status, meaning that they could not be prescribed outside of clinical trials. The American Cancer Society placed Coley’s toxins on its list of “unproven methods of cancer treatment” in 1965. But that wasn’t the end of the story for the peculiar treatment. A resurgence of interest in Coley’s work came on the back of the efforts of his daughter, Helen Coley Nauts, who spent much of her life championing his cause after his death in 1936. In studying and compiling more than 1,000 meticulous records of the patients that he treated, she found that one of the key problems in replicating his work was that others were using different formulations of Coley’s toxins. Her comprehensive analysis of Coley’s nascent immunotherapy and her relentless advocacy eventually earned her the allyship of several eminent researchers, including cancer specialist Lloyd J. Old. Together, they managed to have Coley’s toxins removed from the blacklist by the late 1970s and inspired a wave of researchers who went on to make groundbreaking advances in immunotherapy. Today, oncolytic virotherapy—using genetically engineered viruses to attack and destroy tumors—is a burgeoning area of research with new therapies being tested in clinical trials for cancers ranging from rare, deadly brain tumors to skin cancer. “Viruses are friends and foes,” says Mitesh Borad, a medical oncologist at the Mayo Clinic in Arizona who is studying the use of viruses to treat liver cancer.
There are two major mechanisms by which viruses can combat tumors, says Howard Kaufman, a medical oncologist at Massachusetts General Hospital in Boston who researches oncolytic virotherapy for the treatment of melanoma and other skin cancers. The first is through directly infecting and killing tumor cells. Generally, this is easier than attacking normal cells because the warning system that alerts the immune system about infections is often defective in tumor cells. The second involves recruiting many parts of the innate immune system, including T-cells—depending on the type of T-cell, they either search out and destroy specific pathogens or help produce antibodies—and cytokines, which are proteins that help different parts of the immune system communicate. Cytokines are capable of amplifying an immune response so that it doesn’t only attack a specific target—the virus—but causes more widespread damage, including to tumors. COVID-19 in particular triggers a massive inflammatory response, which some researchers describe as a “cytokine hurricane.” While SARS-CoV-2 is an extreme example, it’s likely that viruses in general cause inflammation that is “kickstarting the immune system to not only recognize the pathogens, but also the cancer at the same time,” says Grant McFadden, the director of the Biodesign Center for Immunotherapy, Vaccines, and Virotherapy at Arizona State University.
There are, of course, reasons other than a viral infection that a tumor could shrink. After Sollini’s patient came back with a negative biopsy, she and her team considered reasons other than the SARS-CoV-2 infection. Perhaps it was an enduring effect of his chemotherapy. It’s also possible that his cancer went into spontaneous remission, which, by one estimate, may happen in 1 in 80,000 cases. But neither of these explanations proved convincing. In either of them, “we would have expected to see a progressive reduction in the size of the tumor,” says Sollini. Instead, the tumor appeared to enlarge before it went into remission—an effect suspiciously similar to the “flare phenomenon” sometimes seen in cancer patients treated with immunotherapy. This happens because T-cells are infiltrating the tumor to mount an immune response, Sollini says. But the man wasn’t on immunotherapy. It was likely that the virus helped the man’s body rally against the tumor, they concluded.
In another instance, the connection between COVID-19 and remission seems even more clear-cut: A case study published in the British Journal of Haematology in January described the strange recovery of a 61-year-old man diagnosed with stage 3 Hodgkin lymphoma and, soon afterward, COVID-19. Despite receiving no treatment for the cancer itself, his condition gradually improved over the course of his 11-day hospital stay. Four months later, scans revealed that his tumors had shrunk.
To be clear, COVID-19 is unquestionably a foe—not a cancer cure. Nor is any other infection. The phenomenon is both unpredictable and very uncommon. Another case of remission in a treatment-resistant blood cancer was reported in August. Hospitalized with COVID-19, the patient’s cancer symptoms and blood test results suddenly began to improve during the second week of his hospital stay. But the improvement in that case was temporary—shortly after the patient’s recovery from COVID-19, signs and symptoms of the cancer recurred. And many, many more cancer patients are at risk of suffering serious complications from COVID-19 rather than experiencing any sort of benefit.
What all these cases highlight is that infections activate the immune system in ways that are not yet fully understood. One day, it could be harnessed to our benefit. So far, the only oncolytic virus approved by the FDA is Amgen’s Imlygic, a modified version of type 1 herpes simplex virus—best known for causing cold sores—given the green light in 2015 for the treatment of advanced melanoma. Its effectiveness, and side effects, is comparable to cancer therapies known as immune checkpoint inhibitors like Opdivo and Keytruda, but it’s not nearly as widely used. (Cold sores have been reported in some cases of patients receiving the drug). Some of the barriers to widespread use have to do with logistics, says Kaufman. Imlygic needs to be stored in a freezer that maintains a temperature range of -70 to -90 degrees Celsius, for example, and carefully disposed of to prevent viral contamination.
Beyond that, questions remain about how best to use viruses to go after tumors. Researchers are working on figuring out if there are ways to predict which patients and cancers may be most receptive to virotherapy, and if preexisting immunity to a virus may interfere with treatment. And, of course, there’s a lot left to learn about how exactly viruses may cause tumors to shrink. “Anything we can learn about how to induce cancers to regress is positive information,” says McFadden. Ultimately, understanding how infections like COVID-19 attack tumors may bring us a step closer toward a future in which viruses are recruited as reluctant allies in treating cancer.