Moderna’s mRNA Therapeutic Cancer Vaccine Shows Promise in Melanoma

Moderna is translating its success with developing mRNA-based COVID-19 vaccines into researching how the technology can be used to treat cancer. In a phase 2b trial, Moderna's mRNA cancer vaccine, in combination with Merck’s Keytruda (pembrolizumab), met its primary endpoint of recurrence-free survival compared with Keytruda alone to treat patients with stage III/IV melanoma following surgery.

Michelle Brown, M.D., Ph.D.

This is the first time an mRNA personalized cancer vaccine has demonstrated positive outcomes in randomized trials. “Other mRNA treatments have reported data in phase 1 studies but this is the first vaccine using mRNA technology that has been able to show clinical benefit in a randomized study against an active comparator,” Michelle Brown, M.D., Ph.D., program director for oncology at Moderna, said at a recent presentation for media.

In Moderna’s phase 2b trial, 150 patients with melanoma after surgery who were at high risk of recurrence were randomized to either the combination of mRNA-4157/V940 plus Keytruda or Keytruda alone. They were followed for 12 months, and the primary endpoint was recurrence-free survival. The trial showed that adjuvant treatment with the combination reduced the risk of recurrence or death by 44% compared with Keytruda alone.

Adverse events were similar to what was seen in phase 1 trials. Serious treatment-related adverse events occurred in 14.4% of patients who received the combination arm and 10% with Keytruda alone.

Melanoma is a serious form of skin cancer. The rates of melanoma have been rising over the past few decades. It is estimated there will be nearly 100,000 new cases of melanoma diagnosed and almost 8,000 deaths resulting from the disease in the United States in 2022.

Personalized cancer vaccines are individualized medicines designed to train a patient’s immune system to fight their specific cancer more effectively. Moderna’s mRNA-4157/V940 is designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patient’s tumor. Keytruda is an immunotherapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells.

“We’re advancing digital learning to use in an algorithm for sequencing but we’re also leveraging a patient’s own biology and their own immune system to actually generate a response to their personal cancer,” Brown said. “This mechanism is an advance of a biological understanding. But also it builds on the backbone of what we’ve seen with checkpoint inhibition in immune-oncology.”

Kyle Holen, M.D.

For the personalized vaccine, Moderna uses the unique characteristics of each patient’s immune system to create a specialized treatment for that patient. “We analyze patient samples from normal cells as well as tumor cells. We sequence this and we create a customized treatment that is unique to the individual,” Kyle Holen, M.D., head of development for oncology, at Moderna, said in the media roundtable.

Moderna sequences both the tumor and health cells to understand the mutations and the differences between cancer and normal cells. A patient’s RNA is then sequenced to understand how much protein is in the RNA, and HLA typing it done. All of this is fed into an algorithm to select specific neoantigens or proteins that Moderna researchers believe can create the most immunologic highest immunological response. The neoantigens are uploaded onto an mRNA strand, which is then packaged in lipid nanoparticles for delivery back to the patient through an intramuscular injection.

The entire process takes about six weeks, including sending the samples to Moderna’s manufacturing facility in Massachusetts. “The advantage of using mRNA is the speed at which we can deliver this personalized treatment,” Holen said. It can take at least two years to bring a small molecule through a process of development; it takes us two hours to develop an RNA for the same purposes.”

The companies plan to discuss the results with regulatory authorities and initiate a phase 3 study in melanoma patients in 2023. The company doesn’t yet have any details about the upcoming phase 3 study.