A new personalized mRNA melanoma vaccine is being hailed by some oncologists as a major breakthrough after reducing the risk of cancer recurrence and death by 42% compared to standard treatment in a late-stage clinical trial.
Dr. Robert Vonderheide, director of Penn Medicine’s Abramson Cancer Center and president-elect of the American Association for Cancer Research, said the findings are “game-changing.”
“This will be considered the first step toward the optimal use of cancer vaccines,” said Vonderheide, who was not involved in the trial.
The experimental vaccine, called intismeran, was developed by drugmakers Moderna and Merck. Intismeran is personalized for each patient, using genomic data from the patient’s tumor. The new results will be presented on Saturday at the annual meeting of the European Society of Medical Oncology in Madrid.
The trial included 1,137 patients with stage 3 melanoma. All participants had undergone surgery to remove their tumors and were being treated with Merck’s immunotherapy drug Keytruda.
In addition to Keytruda, 757 of the participants also received the personalized vaccine; the other 380 received a placebo. Two years later, 82% of patients who received both the new vaccine and immunotherapy had not had a recurrence, compared to 70% in the immunotherapy plus placebo group.
In stage 3 melanoma, the cancer has spread to nearby lymph nodes or other sites on the skin, but it has not spread to distant organs. Cancer recurrence is “the dreaded event” for these patients, Vonderheide said. If it returns, spread to distant organs is more likely.
Dr Georgina Long, co-medical director of the Melanoma Institute Australia who led the clinical trial, said while scans might suggest the melanoma had been completely removed by surgery, invisible cancer cells could still be lurking.
“This treatment involves eliminating cancer cells that we can’t see,” Long said. “We know that with (Keytruda) alone it works very well, but not in everyone.”
Keytruda works by mobilizing immune cells called T cells to detect and destroy cancer. The vaccine also helps the immune system fight cancer. Each vaccine is created by taking the excised tumor, sequencing its genome and identifying a telltale fingerprint of abnormal proteins called neoantigens, Long said. The vaccine trains the immune system to recognize and target these neoantigens, in the same way that a standard vaccine is trained to recognize and target a virus or bacteria.
Intismeran uses messenger RNA technology, the same platform pioneered in Covid vaccine development, praised for the speed with which it can be deployed. Each patient received their personalized vaccine in just over nine weeks on average.
“They’re not on the shelves,” Vonderheide said. “They need to be made for this patient. Can this be done in a matter of weeks in order to have timely treatment? It turns out the answer to that question is yes.”
Dr. Shirin Bajaj, the new director of hHead and nNeck mMelanoma at Mount Sinai in New York, said that although Keytruda works by shutting down the immune system and allowing it to recognize cancer cells, the new vaccine likely enhances its capabilities by mobilizing additional immune cells called killer T cells.
“It basically creates an army of killer T cells that are supposed to recognize the tumor,” said Bajaj, who was not involved in the trial.
Side effects of the vaccine included pain around the injection site and a mild fever – similar to those seen with Covid vaccines.
For Dr. Gino In, an associate professor at the USC Keck School of Medicine Norris Comprehensive Cancer Center in Los Angeles, this is a major selling point. In some cases, Keytruda can cause serious organ inflammation, and previous attempts to combine immunotherapies with other drugs have not only failed to improve cancer recurrence outcomes but also resulted in more serious side effects.
“In previous trials, other drugs studied in combination with (this class of immunotherapies) caused significant, and possibly potentially permanent, side effects, particularly side effects that triggered the immune system to attack our own bodies,” In, who was not involved in the trial, wrote in an email.
Despite the positive results, investors reacted poorly when the results were disclosed on Thursday, causing Moderna’s stock price to plummet. Bajaj said this could be because while the trial results are a significant advance in the field of cancer vaccines, the difference between taking Keytruda and the vaccine compared to Keytruda alone is still relatively modest.
“The reality is, on the one hand, any difference you see is astonishing, because it’s one more option for a patient,” she said. “Is it probably useful for a handful of patients? I would say yes, but it’s hard to say whether at this point we have data to suggest that this really is the next blockbuster.”
The full data has not yet been published in a peer-reviewed journal, and Bajaj said patients in the trial still need to be followed for several years to see if the vaccine continues to offer additional benefits in terms of preventing the return and spread of melanoma as well as its effects on survival.
Additionally, Bajaj said she had questions about the scalability of the treatment. She noted that of the 1,749 melanoma patients initially selected to participate in the trial, 17% did not have tumor samples large enough for a vaccine to be created.
“It’s amazing, but I think some of the logistics are going to have to be worked out,” she said. “But nothing I saw in this study made me think the logistics were infeasible. It’s just that it will be an obstacle to achieving this at scale.”
However, Vonderheide described these results as a very welcome boost for the cancer vaccine field. In recent months, the German company BioNTech announced the failure of clinical trials of experimental vaccines against colorectal and head and neck cancers.
He suggested that intismeran’s success may be because the Merck and Moderna trial focused on preventing melanoma from reoccurring rather than prolonging the survival of advanced-stage patients.
“The field of cancer vaccines has been filled with disappointments in the treatment of patients with advanced disease,” Vonderheide said. “Some people look at these results and say, ‘cancer vaccines will never work.’ These results show that cancer vaccines are incredibly powerful when deployed in the right clinical setting. Vaccines have a preventive effect.
Still, intismeran is being studied in a separate clinical trial in patients with advanced melanoma that has already spread to distant organs.
“This is just a proof of concept,” Long said. “We are interested in advanced melanoma, but we also work on many other cancers – bladder cancer, kidney cancer, lung cancer, using this concept.”
She said researchers will also actively work to better understand why the vaccine worked to see if that can lead to other clues.
Vonderheide described the future possibilities for preventing cancer recurrence as countless. “One day we may be able to think about how to use a cancer vaccine to prevent cancer in the first place,” he said. “It’s a very ambitious and distant goal. But these results bring it even closer to reality than we think.”
Gn bussni
