Some oncologists are calling a new personalized mRNA vaccine against melanoma a breakthrough after it, in a late-stage clinical trial, reduced the risk of cancer recurrence and death by 42% compared with standard treatment.
Dr. Robert Vonderheide, director of Penn Medicine’s Abramson Cancer Center and president-elect of the American Association for Cancer Research, called the results a “game changer.”
“It will be considered the first step to fully exploit the potential of cancer vaccines”said Vonderheide, who was not involved in the trial.
The experimental vaccine, called intismeran, was developed by pharmaceutical companies Moderna and Merck. Intismeran is personalized for each patient, using genomic data from the affected person’s tumor. The new results were presented 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 receiving treatment with Keytruda, Merck’s immunotherapy drug.
In addition to Keytruda, 757 of the participants also received the personalized vaccine; the remaining 380 received a placebo. Two years later, 82% of those who got both the new vaccine and immunotherapy had not had a recurrence, compared with 70% of those who got immunotherapy plus placebo.
In stage 3 melanoma, the cancer has spread to nearby lymph nodes or other areas of the skin, but has not spread to distant organs. Cancer recurrence is the “feared event” for these patients, Vonderheide said. If it comes back, it is more likely to spread to distant organs.
Dr Georgina Long, co-medical director of the Melanoma Institute Australia, who led the clinical trial, said that while scans might suggest the melanoma has been completely removed by surgery, there may still be invisible cancer cells lurking.
“This treatment involves eliminating cancer cells that we cannot see,” Long explained. “We know that (Keytruda) on its own works very well, but not in all cases.”
Keytruda works by mobilizing immune cells called T cells to detect and destroy cancer. The vaccine also helps the immune system fight the disease. Each vaccine is created by taking the removed tumor, sequencing its genome and identifying a distinctive fingerprint of abnormal proteins known as neoantigens, Long explained. The vaccine trains the immune system to recognize and attack these neoantigens, similar to how a standard vaccine does to recognize and attack a virus or bacteria.
Intismeran uses messenger RNA technology, the same platform that pioneered the development of COVID-19 vaccines and is acclaimed for the speed with which it can be deployed. Each patient received their personalized vaccine in a little more than nine weeks, on average.
“They are not available on the market,” Vonderheide said. “They have to be manufactured specifically for each patient. Can that be done in a few weeks to provide timely treatment? It turns out the answer is yes.”
Dr. Shirin Bajaj, future director of the head and neck melanoma program at Mount Sinai in New York, said that while Keytruda works by turning off the brakes on the immune system and allowing it to recognize cancer cells, the new vaccine is likely to boost its capabilities by mobilizing additional immune cells called killer T cells.
“It basically creates an army of killer T cells meant 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 mild fever, similar to those seen with COVID-19 vaccines.
For Dr. Gino In, an associate professor at the Norris Comprehensive Cancer Center at the Keck School of Medicine of USC in Los Angeles, that’s a major plus. In some cases, Keytruda can cause severe inflammation of organs, and previous attempts to combine immunotherapies with other medications not only failed to improve outcomes in terms of cancer recurrence, but led to more serious side effects.
“In previous trials, other medications that were studied in combination with (this class of immunotherapies) caused significant and ultimately potentially permanent side effects, particularly side effects that caused the immune system to attack our own body,” In, who was not involved in the trial, wrote in an email.
Despite the positive results, investors reacted negatively when the findings leaked on Thursday, causing Moderna’s stock price to drop. Bajaj noted that this could be because, while the trial results represent a significant advance in the field of cancer vaccines, the difference between taking Keytruda and the vaccine, compared to Keytruda alone, remains relatively modest.
“The reality is that, on the one hand, any difference that is observed is incredible because it represents another option for the patient,” he said. “Is this likely to be 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 is really going to be the next bestseller.”
The full data have not yet been published in a peer-reviewed journal, and Bajaj noted that patients in the trial still need to be followed for several more years to see if the vaccine continues to offer additional benefits in terms of preventing the recurrence and spread of melanoma, as well as its effects on survival.
Additionally, Bajaj said he had concerns about the scalability of the treatment. He noted that of the 1,749 melanoma patients who were initially evaluated for participation in the trial, 17% did not have tumor samples large enough to create a vaccine.
“It’s incredible, but I think some logistical aspects will have to be resolved,” he added. “However, nothing I saw in this study made me think that the logistics are unfeasible. It’s just that it will be a hurdle to do it on a large scale.”
However, Vonderheide described the results as a welcome boost for the cancer vaccine field. In recent months, the German company BioNTech announced the failure of clinical trials with experimental immunizations against colorectal and head and neck cancer.
He suggested that intismeran’s success could be because the Merck and Moderna trial focused on preventing melanoma recurrence, rather than prolonging survival in patients in advanced stages.
“The field of cancer vaccines has been plagued by disappointments in the treatment of patients with advanced disease,” Vonderheide added. “Some people look at those results and say, ‘Cancer vaccines will never work.’ These results show that cancer vaccines are incredibly powerful when used in the right clinical context. Vaccines are for prevention.”
However, intismeran is being studied in a separate clinical trial in patients with advanced melanoma that has already spread to distant organs.
“This is just the proof of concept,” Long said. “We are focusing on advanced melanoma, but we are also working on many other types of cancer—bladder, kidney, lung—using this concept.”
He said researchers will also actively work to better understand why the vaccine worked, to see if that can provide more clues.
Vonderheide described the future possibilities for preventing cancer recurrence as endless. “Someday, maybe we can think about how to use a cancer vaccine to prevent cancer in the first place,” he said. “That is a very ambitious and distant goal. But these results bring that goal closer to reality than we might think.”
