A small study shows promise in deploying mRNA technology against melanoma, but fighting tumors is vastly more complex than tackling Covid.
The long-awaited cancer vaccine revolution is getting a little closer to reality. New data from Moderna Inc. and Merck & Co. suggest that after decades of failures, researchers are finally figuring out the right way to design a vaccine that can teach immune cells how to recognize and combat tumors.
Earlier this month, the companies said that when used in concert with Merck’s cancer immunotherapy Keytruda, Moderna’s mRNA cancer vaccine reduced the risk of certain skin cancers from returning or patient deaths by 44% compared with Keytruda alone.
That number justly generated a lot of excitement. It’s the first time an mRNA-based cancer vaccine has proven itself in a randomized study, and with an unambiguously positive outcome. If that result holds up in larger trials, it would be a huge advance both for the mRNA technology behind Covid vaccines and for the field of cancer vaccines in general.
But there are a lot of steps between achieving early, positive data for a subset of melanoma patients and developing a widely accessible, cost-effective treatment. Among the more daunting challenges: The vaccine needs to be tailored to the genetic makeup of an individual patient’s tumors.
The study was small, enrolling just 157 people at high risk of their late-stage skin cancer returning. (Moderna and Merck have yet to make available the full dataset, though they plan to do so at an upcoming conference.) Still, even if the results are slightly less dramatic in a bigger study, the vaccine could make a difference for patients. “That would be a substantial change,” translating into long-term remissions, says Julie Bauman, director of the George Washington University Cancer Center. Bauman led an earlier study of Moderna’s cancer vaccine.
The study enrolled melanoma patients who had undergone surgery to remove any signs of their cancer. Unlike vaccines the public is used to taking — mass-produced shots that aim to prevent people from catching a contagious disease like the flu or polio, Moderna’s cancer vaccine instead is intended to keep the disease from returning. It does that by training immune cells to recognize as dangerous proteins found on a patient’s own tumor cells.
The hope was that the vaccine would amplify the already substantial benefit of Keytruda, which blocks a method that cancer cells use to hide from the immune system. Amazingly, the combination worked.
Moderna already demonstrated its capacity for developing and manufacturing mRNA vaccines. It had been working on vaccines for cancer and infectious diseases for more than a decade when the coronavirus pandemic hit, prompting the company to pivot to developing a Covid shot that, along with a similar one developed by Pfizer Inc. and BioNTech, became the first widespread commercial application of mRNA technology.
Building a successful cancer vaccine will be much more difficult. Moderna starts with a biopsy of a patient’s tumor, which it then sequences and uses artificial intelligence to pick out the mutations likely allowing the cancer to thrive. Then, mRNAs encoded for the most relevant cancer-driving proteins are packed inside a delivery system called a lipid nanoparticle, the same kind of delivery method used in Covid vaccines.
From tumor biopsy to first vaccine dose, the process can take between eight and 10 weeks, says Moderna Chief Medical Officer Paul Burton. Repeating this over and over for each patient enrolled in the clinical trial was a major undertaking, he adds.
Now imagine doing that for a commercial drug earmarked for thousands rather than for a few hundred people in a controlled study. There are nearly 100,000 cases of melanoma annually in the US, according to the American Cancer Society. While most cases are curable when detected early, more than 7,500 people die every year of the disease.
Bringing down the “needle-to-needle” time between biopsy and immunization will be critical to ensuring the treatment isn’t just promising, but practical and accessible to anyone who might benefit from it. One way to speed things up would be to establish regional hubs to quickly process biopsies.
Another measure that eventually could accelerate the development of the melanoma vaccine would be to simplify the vaccine’s components. Currently, the vaccine targets a laundry list of 34 mutated proteins to garner the full effect. It would be worth figuring out whether returns start to diminish after, say, 15 or 20 proteins.
Researchers also would like to understand whether certain types of tumors rely on common drivers that, if discovered, could be the foundation for a more broadly designed vaccine that could have some tailor-made components sprinkled in.
Burton says that Moderna so far hasn’t seen any common drivers that could help generalize components of the vaccine, but that data are limited — and the hope is that some clues might emerge as the vaccine is used over the long term and many more people are treated.
Scientists also still need to study the best way to use this vaccine for long-term suppression of cancer, considering, for example, whether people need to continue taking it every three weeks for life, or if they can get by with a periodic boost. And if someone’s disease progresses, does the vaccine itself need to be retooled to match new mutations that might have cropped up?
Perhaps the biggest question right now is whether the effect seen in melanoma can be extended to other types of cancer. Moderna Chief Executive Officer Stephane Bancel told CNBC recently that the company is moving aggressively into Phase 3 studies with the belief that “anywhere Keytruda works, this should work.”
Keytruda, meanwhile, is approved to treat a long list of cancers beyond melanoma—so many, in fact, that it’s expected to bring in more than $24 billion in sales in 2023. Bancel suggested that the vaccine might even make possible responses in tumors where Keytruda has failed, either on its own or by acting synergistically with Merck’s drug.
That’s an optimistic claim—worth studying, but a feat that has eluded other cancer immunotherapies. Melanoma is what’s known as a “hot” tumor, or one that features many mutations and has plenty of immune cells milling about, ready to be pushed into doing their cancer-killing job. It’s reasonable to be hopeful that Moderna’s vaccine could extend Keytruda’s benefits in other hot tumors, such as those found in lung cancer.
But “cold” tumors, or ones without that crowd of immune cells ready to be activated, are a much tougher proposition. In an earlier small study of the Moderna vaccine in solid tumors, for example, none of the patients with colon cancer — a notoriously “cold” tumor — responded, Bauman says.
Another immense challenge is the very high likely cost of a personalized therapy on top of Keytruda, which on its own carries a list price of around $185,000 per year. The only upside to that hefty price tag is that the companies will be motivated to answer these questions as quickly as possible. Indeed, Bancel has said that Moderna plans to aggressively invest in cancer.
All that money flowing into Moderna’s cancer vaccine will teach the field not just about that one product, but how to design, test and use other ones. Let’s hope that’s the catalyst for the true cancer vaccine revolution, one that could convert cancer from a potentially lethal illness into a chronic, stable disease.
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