PHOENIX – Just as he was going to sleep one night in 2012, Robert Mock noticed a strange lump at the back of his throat.
After decades of experience in medical sales, he was concerned by the nodule, so he went to an ear, nose and throat specialist to have it examined. The doctor told him it was a cyst and put him on an antibiotic.
Three weeks later, the nodule had gotten bigger. Mock decided he needed a second opinion.
After ordering a series of CT scans, Mock’s next doctor gave him a sobering diagnosis: late-stage oropharyngeal cancer, better known as throat cancer.
• Some latent viruses like HPV are well understood to cause certain types of cancers. That’s why immunizing against those viruses is so important.
• Yet the reality remains that not everybody who gets HPV gets HPV-related cancer. The reason why may be found not in the virus itself, but in a far more complicated set of factors, the way the virus interacts with our own cells as well as with the countless other microorganisms that live inside of us.
• These many “biomarkers” may eventually allow scientists to take a more customized snapshot of a person’s health – their own genetic makeup combined with those many other microorganisms. That combination can then personalize the medical treatment they receive.
• Until that day, using vaccines to stop HPV is one of the most effective solutions we have available – but barriers remain to widespread use.
“I didn’t understand how this was possible,” Mock said, adding that he’s never smoked or chewed tobacco. But after taking a tissue sample from his throat, the lab revealed the cause of his cancer was something entirely different: a latent HPV infection.
The human papillomavirus is known for causing almost all cervical cancers, and a vaccine for HPV is often touted as a way to prevent those cancers. But HPV also causes about 70% of throat cancers. And Mock, who was in his 50s when he was diagnosed, had grown up before there was an HPV vaccine.
After Mock’s diagnosis, he faced a two-year battle with the carcinomas that had taken over his mouth, tonsils and throat. Over the course of 40 radiation and chemotherapy treatments, he lost much of the skin on his neck, the hearing in his left ear, and his salivary glands.
Almost 10 years later, Mock can only taste about a quarter of the things he used to eat. He loves the flavors he can perceive in Italian food, but says that he still struggles with a loss of appetite and a chronically dry throat.
Now, Mock says he routinely speaks to dental students around the Phoenix area to help them learn the signs of throat cancer. He also says his experience changed his understanding of latent viruses – the ones that stick around after they infect us, lurking in our cells and held in check by the immune system.
“It just made me want to do a lot more homework, after the fact,” Mock said. “I didn’t really know … how long this virus can lay dormant.”
That dormancy, which seems to have no effect for so many people but can be life-changing for a few, is a hallmark of so-called latent viruses. These infect huge swaths of the population, often starting in childhood.
Not all viruses are latent: Coronaviruses, including the one that causes COVID-19, cause infections and then leave. But other viruses like HPV lurk inside the immune system for decades, often undetected. Still, the pandemic-era focus on the potential impact of viruses has added new interest and urgency in the study of long-term viral infections of all types.
Understanding why some of those latent infections recur and cause cancer may become the key to understanding cancer immunity, too, explained Karen Anderson, a professor and medical oncologist at the Biodesign Institute at Arizona State University. She is interested in better understanding the transition from an acute HPV infection, in which the virus is actively replicating and spreading, to an infection in which the virus persists and ultimately has the potential to cause cancer.
“(HPV) persistence can be for decades, and the cancer may end up developing many decades later,” Anderson said. “If we’re going to figure out how to make cancer immunotherapy work well … I think we learn a lot by figuring this out with some of these chronic viruses like HPV.”
The surface of your skin, your nose, mouth, lungs, stomach and intestines are teeming with a rainforest of bacteria, viruses, fungi and other tiny organisms that help keep you alive: the microbiome. That means “figuring out” chronic viruses also means figuring out how they interact with the other tiny species that colonize our bodies.
“Nothing – not cancer, not viruses, nothing – grows up on its own. It doesn’t happen on its own. It happens in an ecosystem and that ecosystem is your microbiome,” Anderson said.
As researchers like Anderson try to fully understand how viruses like HPV work, as well as the cancers they cause, the answers they find have implications for new technologies that may one day target each person’s unique response to infection.
In the meantime, though, we already have effective vaccines for some infections like HPV and hepatitis B, which cause liver cancer. Since at least 15% of all cancers worldwide are caused by viral infections, stopping those infections before they ever arrive could dramatically reduce cancer rates.
But getting those vaccines out to the public has its own set of challenges.
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Synthesizing the microbiome, the immune system and long-term conditions
To what extent do genetics decide what our microbiome looks like? And how do our immune cells’ interactions with the different species that populate the microbiome affect our ability to tackle other viral infections from the outside world?
Scientists are still working on answering those questions, but Anderson thinks the long-term impacts could unlock new ways of treating cancer, a problem she’s been working on for decades.
“Your immune system is trained on things from 30 years ago, (or for) some of us much longer,” she said. “So how do we understand the footprints of that over a long period of time? What was the impact of your current microbiome, your prior microbiome, your inflammation over decades?”
Much like outer space or the bottom of the ocean, though, the microbiome contains a lot of uncharted territory. Last February, a team of scientists from the U.K. found over 140,000 types of bacteria-infecting viruses, known as bacteriophages, many of which had never been observed before.
Rosa Krajmalnik-Brown, another ASU professor and the director of the Biodesign Center for Health Through Microbiomes, said that developing a clearer picture of the ecosystems within our bodies is intimately tied to our own health.
“There’s cooperation and there’s competition, and understanding what leads to cooperation and what leads to competition are the key factors to be able to get to a healthy microbiota (the organisms that constitute the microbiome),” she said.
While Krajmalnik-Brown does not specifically study viruses in the microbiota, she said others in her field have hypothesized that viruses may be the driving force between which bacteria survive, thrive and die off.
And she knows from her own work that the makeup of that gut bacteria has very real consequences for human health. In a recent pilot study, Krajmalnik-Brown and her team found that children with autism who receive a transplant of gut bacteria from the microbiota of healthy donors show significant improvement in some of their symptoms, including gastrointestinal distress and even social interaction and behavior. Moreover, most of those improvements persist at least two years after the transplant.
It’s just one example of how advances in microbiome research are connected to other health conditions. Felicia Goodrum, a professor of immunobiology at the University of Arizona, also noted that a complex combination of genetics, environment and virus-host dynamics could play a role in the development of long-term diseases. “The hard part is in really getting to understand that these viruses may not be the only thing driving these diseases (like cancers),” she said.
Goodrum thinks the field may be headed toward more personalized medicine. Synthesizing research on the microbiome and the immune system, researchers like Goodrum also hope new analyses may one day help scientists and physicians figure out what makes two people respond differently to the same virus.
“Understanding that person-to-person variability is a place that I think medicine is really trying to go toward,” Goodrum said.
Biomarkers, immunity profiles and personalized vaccines
Joshua LaBaer is already working on that. LaBaer, the executive director of the Biodesign Institute at Arizona State University, wants to develop improved personalized diagnostics by better understanding biomarkers, the unique “fingerprints” of disease on the body.
“Ninety-plus percent of all people in our culture are infected with EBV (Epstein-Barr virus) … And yet some small fraction of those people go on to get cancers related to EBV, and we don’t really know why,” LaBaer said.
He hopes that if researchers can find a way to understand who’s at risk, they can tailor preventative measures to their specific biology. “Maybe those people, we need to give an additional vaccine to block the ability of the virus, to infect a certain cell type or to behave in a certain way,” he said.
Anderson envisions a future where doctors may order a unique immunological profile for their patients, just like they can already measure individuals’ cholesterol or monitor for hypertension. As she explained it, particular molecules or biological signals might tell doctors “‘Is this person circulating markers that might identify one type of cancer versus another? Have they cleared that cancer or not?’”
While new vaccines and diagnostic capabilities are still being developed, Anderson said the coronavirus pandemic has begun to open new doors for bringing novel ideas to the mainstream.
“I think what has really pushed the field forward a lot in the last two years has been our experience with coronaviral vaccines,” said Anderson, who described how the mass production of mRNA immunizations proved that the technology could be produced quickly and cost-effectively.
Now, she says, the test will be to see whether the same successes in developing vaccines against the coronavirus can be found for individualized cancer therapies. Beyond vaccines that prevent infections in the first place, she said, other types of vaccines may one day leverage a person’s unique immune cells against their unique cancer mutations. Some of those therapies are already in clinical trials, and she is watching to see whether they begin to take off on a broader scale.
“I am optimistic, certainly, about the feasibility of it,” Anderson said.
Even as those advanced technologies inch closer to reality, though, there are barriers to implementing some of the technologies that already exist.
Where we are now: HPV vaccines
Robert Mock still got his HPV vaccine after his fight with cancer, because there are multiple cancer-causing strains of HPV and he didn’t want to run the risk of getting cancer again from another strain. He wished he’d had an HPV vaccine when he was a kid, but he knows from firsthand experience as an educator that there is still resistance to the highly effective immunizations.
“The vaccine rates for HPV are horrible,” Mock said. In 2020, about 58% of adolescents had received their full course of vaccine.
Koenraad Van Doorslaer, an assistant professor at the University of Arizona who also studies HPV, said he is concerned that the arrival of SARS-CoV-2 has stunted efforts to minimize the effects of HPV. That’s partly on the research side: he says he worries that because HPV already has a vaccine, unlike other latent viruses like CMV and EBV, funding for research may be funneled away from HPV. That’s on top of COVID-19, which is now a core focus for research funding around the world.
But Van Doorslaer says that if HPV research receives less funding, that isn’t necessarily because the job is done. He explained that vaccination rates lag globally and nationally, and that COVID-19 may have also limited vaccination efforts even further. That’s both because the pandemic delayed many routine doctor visits and because the anti-vaccine movement became so much more widespread.
“We have a chance to eradicate HPV,” Van Doorslaer said, but “as long as our country doesn’t get better at vaccinating, we’re nowhere near actually getting rid of it.”
Mock said the stigma around HPV may be contributing to parents’ hesitation around the vaccine. Since the vaccine, called Gardasil, is most effective if delivered before someone becomes sexually active, most doctors recommend the vaccine for kids around ages 9-14. But Mock said that many parents worry that the vaccine will encourage their kids to engage in sexual activity at a younger age or that the vaccination may bring up uncomfortable conversations too early.
“When I do (get pushback) the common theme is, ‘My child will not have sex at 11,’” he said.
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Lisa MacKenzie agrees that the stigma around HPV and cervical cancer has been a barrier to effective education. That stigma makes it harder for patients to receive a correct diagnosis and makes it harder to promote prevention efforts, said MacKenzie, a nurse executive and cervical cancer survivor and awareness advocate who has been based in several locations around the country.
She added that it can create additional challenges for young or working women who must juggle a career, family planning and their own health.
“It’s very taboo to talk about this, because it could signify that a woman was promiscuous or (it has) such a bad stigma attached to it,” despite the virus’ overwhelming prevalence, she said.
For that reason, MacKenzie emphasized the importance of Pap tests as a diagnostic tool, as well as the need for patients to advocate for themselves if they are experiencing unusual menstrual symptoms. In addition, many vaccination campaigns aim to desexualize the HPV vaccine, instead of focusing on its effectiveness in preventing cancers later in life.
Mock said it’s not too late for older adults to get the vaccine, especially if testing indicates that they do not have HPV. A yearly Pap test can screen the cervix for HPV-associated cancer or cell changes that may lead to cancer, but there are no such routine tests for the throat.
That’s why Mock described the importance of increasing awareness of the symptoms of throat cancer, which can include a nodule like the one he had, a sharp pain in the ear or a persistent cough or sore throat.
“I speak to the (dental) students because I want them to know that when they look inside that throat when they’re cleaning the teeth, and you see (something like what I had) …that person better get that thing checked immediately,” he said.
Despite efforts such as his, HPV rates are still much higher in men than women. Mock said that means men are often unaware they have the virus and may be at higher risk of throat and penile cancers.
“Unfortunately, if a man has HPV, you’re kind of a walking time bomb,” he said.
Follow reporter Melina Walling on Twitter @MelinaWalling.
Independent coverage of bioscience in Arizona is supported by a grant from the Flinn Foundation.
This article originally appeared on Arizona Republic: HPV research may help lead to an understanding of cancer immunity
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