The surgical procedure is straightforward to grasp. A melanoma is excised, the margins inspected, and you’re sent home cancer-free, at least theoretically. Then comes the more challenging aspect, which is the waiting period. For individuals with high-risk melanoma, the concern was never solely the tumor that surgeons excised but the wayward cells that may have already dispersed, waiting for the right moment. And five years is a long duration to remain in suspense.
Thus, a finding presented at the American Society of Clinical Oncology meeting in Chicago is quite significant. A tailored cancer vaccine, used in conjunction with a now-standard immunotherapy drug, has maintained its impact on melanoma five years post-treatment.
The vaccine is named intismeran, and it is unlike anything one would find on a pharmacy shelf, because there is no shelf. Each dose is produced for a single individual only, created from the genetic blueprint of their own excised tumor. It employs mRNA technology, the same general method that gained widespread recognition during the COVID years, except here the instructions it contains are not for a viral protein but for up to 34 mutated proteins, known as neoantigens, that identify a patient’s specific cancer. The idea is to train the immune system to recognize these markers, so its T cells will target any melanoma cell attempting to reemerge.
The trial, referred to as KEYNOTE-942, compared that vaccine plus the drug pembrolizumab against pembrolizumab alone. 157 patients, randomized in a two-to-one ratio, all with stage IIIB to IV melanoma that had already been surgically removed.
What the researchers disclosed after about five years of follow-up is the type of statistic that oncologists rarely observe in this context. Incorporating intismeran reduced the risk of cancer recurrence or death by 49 percent compared to the drug alone. The risk of cancer metastasizing to a distant organ, which makes melanoma lethal, decreased by 59 percent. Nearly 69 percent of the vaccine group remained cancer-free, in contrast to approximately 49 percent of those who received pembrolizumab alone.
“Our study provides compelling evidence to melanoma patients that intismeran vaccine therapy, when used in combination with immunotherapy, can significantly lower their risk of cancer recurrence and enhance clinical outcomes,” stated Janice Mehnert at NYU Grossman School of Medicine, the lead investigator of the study.
A Vaccine Tailored for One Individual
This is generally how the personalization operates, and it is indeed quite a comprehensive process. After surgery, a portion of the tumor is sent along with a blood sample, the blood serving as a “normal” reference so the laboratory can identify which mutations are associated with the cancer and which belong only to the patient. Next-generation sequencing analyzes everything, and a machine-learning algorithm sifts through for the neoantigens most likely to generate a response. These are encoded into mRNA, enclosed in a lipid nanoparticle, and returned as a customized vaccine. It sounds intricate, and it is, yet the trial reported that the design process was successful for about 84 percent of patients, and once a vaccine was crafted, manufacturing succeeded over 99 percent of the time. Quite impressive for something tailored from scratch for each person.
Additionally, there was an insight, hidden within the immunology, regarding why this approach might be effective. Patients receiving the combination developed more new T-cell clones than those receiving the drug alone, and notably, individuals who produced the highest number of these novel clones tended to be the ones who remained cancer-free.
Why This Approach Succeeded Where Others Did Not
None of this ensures that the results are definitive. This was a phase 2 study, the sample size is limited, and the survival data are still what researchers tactfully refer to as immature, indicating that too few patients have deceased for the differences in overall survival to be statistically confirmed (although the trend appears to favor the vaccine). The trial also excluded anyone who had previously undergone drug therapy before surgery, so its applicability to the wider population is limited.
Nonetheless, the contrast with recent history is difficult to overlook. Several previous attempts to enhance melanoma immunotherapy by combining two drugs, in trials with titles like CheckMate 915 and KEYVIBE-010, did not result in improved outcomes, and often resulted in additional side effects. The neoantigen strategy seems to be following a different route, providing more benefits without the accompanying toxicity, which suggests that directing the immune system at a tumor’s specific mutations may surpass merely amplifying the entire system. Researchers believe this principle has potential for broader application. Mehnert noted that the findings provide hope that mRNA vaccines like intismeran “could be effective.”