The mRNA-based Covid vaccines used by hundreds of millions of people may provide an unexpected benefit to some cancer patients, significantly improving survival when given within a few months of immunotherapy, according to a new study.
In a retrospective analysis of patients with advanced lung cancer, 57.2% of people who happened to get Moderna or Pfizer-BioNTech’s shot within 100 days of starting treatment with a checkpoint inhibitor were still alive three years later, compared with 30.7% of patients who hadn’t recently gotten the Covid shot.
The findings, presented at the European Society for Medical Oncology meeting on Monday, were based on data from 2,400 patients with stage 3 or 4 non-small cell lung cancer treated at the University of Texas MD Anderson Cancer Center.
Elias SayourThe researchers said they found similarly encouraging results for 750 patients with metastatic melanoma treated with checkpoint inhibitors. After 3 years, 68.4% of patients who recently got the Covid shot were still alive, compared to 45.6% of patients who didn’t, the researchers told Endpoints News.
“I honestly didn’t expect it to be that effective. It worked so well that it actually scared me,” Elias Sayour, an oncologist and pediatrician at the University of Florida College of Medicine and a co-author of the abstract, told Endpoints in an interview. “I mean, you’re talking about potentially having a universal cancer vaccine.”
The surprise results come with significant caveats. The analysis was backward-looking, which has limitations and can sometimes surface shocking findings that later, under the stricter setting of a clinical trial, turn out not to be true. But other research and some preclinical work suggest a logic behind the results. And MD Anderson researchers are planning a controlled trial that will hopefully answer whether the Covid-19 vaccines can provide a cheap, easy and immediate way to improve treatment for many cancer patients.
Inge Marie Svane“This is indeed intriguing data,” Inge Marie Svane, a cancer immunotherapy researcher at the University of Copenhagen who wasn’t involved in the study, said in an email. “It definitely needs to be confirmed in a prospective study, as associations are generally not the same as causality. There might be unidentified confounders.”
Until then, the data are sure to draw scrutiny for its dramatic results — as well as its implications for BioNTech and Moderna.
The two companies are currently developing highly customized cancer vaccines, using mRNA technology, that trains the immune system to seek and destroy cancer cells bearing mutations unique to a patient’s disease. When paired with checkpoint inhibitors like Merck’s Keytruda, the bespoke approach has yielded promising results in advanced melanoma and pancreatic cancer.
Yet the new study raises questions about how important the personalization of those vaccines really is, or if there is some other effect.
“A lot of the response to these vaccines is actually not due to us predicting which antigens are going to work. It’s actually due to the dramatic immune response that you get from mRNA vaccine, regardless of what the mRNA codes for,” Adam Grippin, the physician who led the retrospective study at MD Anderson, told Endpoints.
“mRNA vaccines, even when not targeted against tumors, still have anti-tumor effects,” Grippin said the research showed.
When asked about the results, a spokesperson for Moderna said the company does not comment on externally-run studies. BioNTech didn’t respond to request for comment.
Not expecting ‘any effect at all’
For decades, scientists have tried making vaccines that turn the immune system on cancer. But until the recent, albeit preliminary, successes of mRNA vaccine developers, the efforts have largely failed.
Why these new customized vaccines seem to be working isn’t entirely clear. But Moderna and BioNTech largely point to their individualized approach. Smaller biotechs have argued that customization is key too, but the verdict is far from final. At another cancer conference in April, some off-the-shelf vaccines targeting common genetic mutations also showed promise in early trials.
Adam GrippinThe MD Anderson study will further fuel the debate, suggesting that mRNA encoding might not be as important as the immunogenic properties of the messenger molecule and the lipid nanoparticle it’s packaged in.
A direct comparison to the personalized cancer vaccines is tricky. Moderna and its partner Merck have only recently begun testing their cancer vaccine for lung cancer. In June, the companies reported a three-year update from their Phase 2b study in advanced melanoma. When given together, the vaccine and Keytruda reduced the risk of recurrence or death by 49% compared with Keytruda alone.
But that study measured recurrence-free survival, rather than the overall survival that Grippin’s team focused on, and he cautioned against attempting comparisons at this stage.
Siow Ming Lee, a lung cancer doctor at University College London who wasn’t involved in the new study, said it might be good to include the mRNA Covid vaccine as an additional control group in clinical trials of personalized mRNA vaccines.
“This would help distinguish whether the observed efficacy is driven by the broader immune-stimulating properties of the mRNA platform or the specific immune-targeting properties of the encoded neoantigens,” Lee said in an email.
Research in mice suggests that the mRNA technology itself plays a big role, according to Grippin and Sayour. The scientists told Endpoints that mRNA vaccines with nonspecific payloads can still trigger about half or more of the effect that a tumor-targeted vaccine spurred in mice. Data in a Cell paper published in May hinted at the idea, but the scientists said they hope to publish a detailed study soon.
“It was remarkable to us. This was supposed to be a control where we showed we’re so smart, we know which antigens are important,” Grippin said. “We were not expecting it to have any effect at all.”
‘Lighting the flame’ of immune response
Drugmakers have spent billions of dollars over the past decade looking for immune-stimulating drugs that could improve patients’ responses to checkpoint inhibitors like Keytruda, Opdivo and Yervoy, which have become a backbone of cancer treatment. Yet nearly all those efforts have ended in failure.
Why something as simple as a Covid vaccine should work — if it really does — is a mystery.
Lee said that there’s “a high possibility of selection bias,” and that people more likely to get Covid vaccines may be healthier to begin with. It’s also possible that some of the benefits simply come from preventing severe and fatal cases of Covid. Grippin said he didn’t have enough cause-of-death data to determine this, but that the effect is bigger than what he’d expect from Covid protection alone.
Grippin said that his team looked at dozens of potentially confounding variables, including the age of patients, comorbidities like diabetes and heart disease, if their tumors had metastasized and to where, and whether they had also received chemotherapy, radiation, surgery or immune-suppressing steroids. But the effect of the Covid vaccines stood strong.
Svane said the finding builds on an Italian study published last summer, which suggested that cancer patients receiving checkpoint inhibitors who were also vaccinated for flu lived longer than unvaccinated patients — a median survival of 27 months versus 20.9 months.
With the Covid vaccines, the researchers found a partial explanation for why the shots seem to help — they appeared to bump up the expression of PD-L1, the protein that many checkpoint inhibitors target, making the tumors more vulnerable to the drugs.
In a larger analysis of 5,500 patients of several cancer types, people who recently got Covid shots had an average 55% increase in the proportion of tumor cells bearing the PD-L1 protein. The Covid vaccines made no difference in survival in patients who weren’t treated with checkpoint inhibitors. And influenza and pneumonia vaccines, which are not made with mRNA technology, didn’t increase PD-L1 levels.
“We think the mRNA vaccines are really lighting the flame to start an immune response, and the checkpoint blockade fans the flame and allows this anti-tumor response to take off,” Grippin said.
By reminding the body of a viral infection, Grippin said the Covid vaccines trigger the release of potent proteins called interferons, which activate immune cells throughout the body, potentially alerting the immune system to the presence of a previously stealthy tumor.
“mRNA lipid nanoparticles just look so much to the body like a virus that this may be a different animal than many of the other therapies that we’ve tested,” Grippin said. “They are much more potent activators of the innate immune response.”
Grippin said he’s still studying exactly how this works and hopes to share more details at a scientific conference or in a scientific publication later this year. And he is also still excited about personalized vaccines and sees room for both customized and off-the-shelf approaches.
“I think that personalized vaccines are always going to be superior to non-personalized vaccines, but they are not going to be widely available in the short term,” Grippin said. “If we can achieve even a portion of the benefit with a therapy that is available off-the-shelf in pharmacies across the country and around the world, that would substantially expand access to this potential immune-boosting therapy.”