A new investigational cancer vaccine developed by Merck & Co. and Moderna is customized based on the genome of each patient’s tumor, designed to teach their immune system to recognize the cancer as a foreign body.
Personalized mRNA Design
The therapy, known as intismeran autogene, targets the mutations that are unique to a patient’s tumor. Merck and Moderna sequence the individual patient’s cancer and look at the mutation profile within it. They find the particular mutations that are most recognizable to the immune system, take the 34 most immunogenic of those mutations, and assemble those into an mRNA construct.
That mRNA construct is packaged in a lipid nanoparticle and sent back to the patient as an injection. It trains the immune cells to recognize their own cancer as foreign and helps the immune system better attack the cancer present in their body.
The companies are investigating the vaccine as a combination treatment with Merck’s Keytruda, a monoclonal antibody that targets the PD-1 receptor on T-cells, breaking a pathway that cancer uses to evade the immune system. The FDA granted the combination Breakthrough Therapy designation in 2023, and the companies noted that they plan to engage with regulators to pursue approval.
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Testing on Residual Disease
Merck and Moderna chose melanoma for their first trials because it has a high number of mutations and was highly responsive to Keytruda. They also focused on melanoma early in the disease course, in patients who had been treated but were at high risk of their cancer returning.
The companies began the collaboration back in 2016, approximately two years after Keytruda earned its first FDA approval. The lessons Merck learned from developing Keytruda were a key part of the design of the intismeran vaccine trials. In their experience with the Keytruda development program, they noticed that patients with certain types of mutations were more likely to respond to Keytruda. They thought it would be interesting to give Keytruda with something that activated the immune response to the particular mutations a patient has in their tumor.
One reason for this timing is the manufacturing process. It takes about six weeks for the process of sending the sample to be sequenced, the vaccine to be made and sent back to the patient, and administered as part of their therapy. The immune system has to have a chance to be trained to recognize these new antigens, work, and elicit an effect. The fact that you’re giving this therapy at the time the patient has had a tumor resection, when they’re tumor-free other than potentially any residual cells that are microscopic and not visible, gives the immune system time to work.
The Phase 2 trial, a randomized study comparing Keytruda alone to it in combination with the INT vaccine in patients with high-risk resected melanoma after surgery, showed that patients who received the combination treatment had a 44% reduction in risk of recurrence.
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Expanding to Other Cancers
While the combination therapy offers potential benefits, patients can begin with a Keytruda-only course as Moderna prepares the personalized vaccine. The Phase 3 study, which studied the same regimens in a population of about 1,100 subjects, met its primary endpoints of a clinically significant and meaningful improvement in recurrence-free survival (RFS) and a statistically significant improvement in distant metastasis-free survival.
Merck and Moderna are also investigating the combination regimen as a treatment for lung, renal cell, and bladder cancers. Some of the science that made the melanoma vaccine possible may transfer to these indications, but they are still learning just how much. Bladder cancer patients tend to be a little older, a little sicker; they’ve received more pretreatment, and so the question is whether the baseline patients enrolling in the study, who may not have as robust an immune system because of their background, will respond as well.
Understanding if there are particular mutations that can predict how a patient’s cancer will respond to the therapy could help improve the algorithm to better predict the mutations most likely to be recognized by the immune system, and help us improve the therapy.
