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.
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.
“By giving the cancer vaccine, you’re training the immune cells to respond to the mutations that are unique to a patient’s tumor,” says Jane Healy, vice president and head of Oncology Early Clinical Development at Merck & Co. “And by giving Keytruda at the same time, you are reactivating the immune system to make sure that those immune cells are recognizing the cancer, which is why we think that biologically it does make sense to give these two together.”
The positive Phase 3 results came as both Merck & Co. and Moderna were hunting for future revenue streams. Merck’s Keytruda has emerged as one of the best-selling drugs in the history of pharma, while Moderna’s SpikeVax COVID vaccine turned the R&D-focused startup into a household name within months. But Keytruda is on the cusp of losing patent protection beginning in the late 2020s, and demand for COVID vaccines has plummeted in recent years.
But while COVID vaccines were distributed en masse to patients, the potential market for intismeran autogene, as the Merck-Moderna therapy is called, will be narrower and more hands-on.
“We sequence an individual patient’s cancer, and we look at the mutation profile within their cancer,” Healy said. “We find the particular mutations that we would predict are most recognizable to the immune system, and we take the 34 most immunogenic of those mutations and we assemble those into an mRNA construct, package it in a lipid nanoparticle… and that is sent back to a patient.”
Learning from cancer genomics and Keytruda
Intismeran autogene is an individualized neoantigen therapy (INT), which is a type of personalized cancer vaccine that involves sequencing a cancer and creating an mRNA construct of the mutations that are most likely to be recognizable to the immune system.
“An important thing we’ve learned through cancer genomics is that every patient’s genetic profile of their cancer is different. Even if two patients have the same type of cancer. A patient with melanoma is different from another patient with melanoma, even though they are diagnosed with the same disease,” Healy said.
Merck and Moderna’s INT therapy is given as an injection once every three weeks for up to nine doses in combination with Keytruda.
“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,” Healy said.
Merck and Moderna 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 our experience with the Keytruda development program, we noticed that patients with certain types of mutations were more likely to respond to Keytruda,” Healy said. “We thought, wouldn’t it be interesting if we gave Keytruda with something that activated the immune response to the particular mutations a patient has in their tumor?”
The companies chose melanoma for their first trials because it has a high number of mutations and was highly responsive to Keytruda. They also chose to focus on melanoma early in the disease course, in patients who had been treated but were at high risk of their cancer returning.
“We would give this therapy and look at the rates of disease recurrence rather than trying to treat the active disease,” Healy said. ” The reason that makes more sense for this particular therapeutic is that a therapy like a vaccine takes time to be manufactured. [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, and the immune system has to have a chance to be trained to recognize these new antigens, work, and elicit an effect.”
“So, 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,” she said.
While the combination therapy offers potential benefits, patients can begin with a Keytruda-only course as Moderna prepares the personalized vaccine.
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.
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.
More than just melanoma
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, Healy said.
“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,” she said. “I think we’ll have slightly different questions for each study that we’ll learn from.”
As trials continue, one thing Healy is interested in learning is whether there are particular mutations that can predict how a patient’s cancer will respond to the therapy, she said.
Understanding if “there are particular mutations that are most predictive of response could help us improve the algorithm to better predict the mutations most likely to be recognized by the immune system, and help us improve the therapy,” she said.
Filed Under: clinical trials, Drug Discovery, Oncology
