Moderna, Merck Chart New Course With mRNA Cancer Vaccine

Key Moments

Historic Late-Stage Success

On the night of August 13, Moderna CEO Stephane Bancel was at a Lebanese restaurant marking a friend’s birthday when he received a pivotal phone call. The message: an experimental mRNA cancer vaccine, developed jointly with Merck, had achieved its goal in a late-stage clinical trial – a milestone described as the first successful therapeutic cancer vaccine in advanced testing after more than a century of unsuccessful efforts.

Specialists in oncology have characterized the result as a potential start of an era for highly personalized vaccines designed to teach a patient’s immune system to combat their specific cancer. In a study involving more than 1,000 people with localized melanoma, the candidate vaccine prevented tumors from recurring or spreading.

Comprehensive data from the trial have yet to be disclosed, but financial markets have already begun assigning substantial commercial value to the program, with expectations running into the billions of dollars.

Bancel compared the significance of the call to the moment in late 2020 when Moderna revealed the outcome of its COVID-19 vaccine trial. “It was a moment that we’d worked really hard toward. We knew what was at stake for the planet with COVID,” he said in an interview. He drew a parallel with cancer, noting that the disease affects nearly everyone directly or indirectly. The initial wave of excitement, he added, quickly gave way to operational focus: “I went right away into, ’OK, what are all the things we have to do?’”

Merck Research Laboratories President Dean Li had a similar reaction when he heard from Eliav Barr, Merck’s head of global clinical development. Li’s immediate priorities included preparing the data for an international oncology conference, planning for U.S. Food and Drug Administration review, and applying insights from the study to other active trials. “It isn’t hallelujah,” Li recalls. “It’s boom.”

A Decade in the Making

Executives from both companies describe the achievement as the culmination of a 10-year journey. When Moderna and Merck publicly unveiled their cancer vaccine partnership in 2016, the two firms had already been collaborating for more than a year on a different vaccine initiative.

Under the cancer-focused agreement, Merck paid $200 million upfront in 2016 and an additional $250 million in 2022. The partners share development expenses and profits.

At the outset of the collaboration, Merck’s immunotherapy Keytruda was gaining prominence within a class of medicines known as checkpoint inhibitors, which act by lifting natural restraints on the immune system so it can better attack tumors. “What Keytruda taught the world was that, yes, there is an immune recognition of cancer, but cancer is clever in putting up barriers, and Keytruda removes those barriers,” Barr said in an interview in late May.

From there, companies including Merck started looking for ways to further intensify immune responses, combining Keytruda with other cutting-edge immunotherapies such as TIGIT inhibitors. “It didn’t work,” Barr said.

Tal Zaks, Moderna’s chief medical officer from 2015 to 2021, had earlier emigrated from Israel in 1996 to work on cancer vaccines at the National Cancer Institute. “We failed back then, and we failed for many years,” Zaks said. However, he believed that mRNA-based technologies, in combination with checkpoint inhibitors and declining costs of genetic sequencing, could create a viable route to success.

Choosing the Right Partner and Target

Although Moderna possessed the core mRNA platform, the young company lacked the resources to independently fund large-scale oncology trials. Bancel said Moderna explored working with multiple companies that had checkpoint inhibitors, but ultimately favored Merck, citing Merck’s extensive experience running Keytruda studies.

Merck’s Li describes Keytruda as a “miracle drug,” noting its use against 20 different types of cancerous tumors and 45 types and stages of cancer. Yet the precise tumor characteristics that Keytruda targets, and the reasons certain patients experience greater benefit than others, remain unclear.

Messenger ribonucleic acid, or mRNA, resides in every cell, where it delivers genetic instructions from the cell nucleus to the cellular machinery that produces specific proteins. The new vaccine, called intismeran autogene, is designed to train the immune system to recognize and attack cancer cells by focusing on mutations that are unique to each patient’s tumor.

Previous cancer vaccines generally attempted to direct the immune system toward one or two tumor-specific mutations and failed to demonstrate efficacy. Moderna and Merck chose melanoma as their first target indication, drawn by the cancer’s relatively high number of mutations and the established record of benefit from checkpoint inhibitors in this disease.

They also focused on individuals with early-stage melanoma whose tumors had been surgically removed. This strategy provided the time required to manufacture a customized vaccine based on the patient’s tumor profile and allowed additional time for the immune system to mount a response.

With mRNA technology, the partners were able to incorporate dozens of tumor mutations into a single personalized vaccine. Moderna co-founder and MIT scientist Robert Langer said via email, “You have many, many more shots on goal and therefore a much greater chance to succeed.”

How the Combination Works

The therapeutic concept rests on pairing the tailored vaccine with Keytruda. Keytruda helps activate T-cells – the immune system’s targeted killers of abnormal cells – while the vaccine provides the specific instructions for which mutations to attack.

“The whole special thing about Keytruda was that it would unlock the dogs of war,” Li said. According to Li, the vaccine supplies 34 tumor-specific targets for those immune “dogs” to track, and success requires only one of those targets to trigger an effective response. “With the personalized cancer treatment, the dog has your scent.”

Regulatory Outlook and Strategic Stakes

Both Moderna and Merck could see major financial and strategic benefits if regulators approve the vaccine. U.S. authorization could arrive as early as next year.

For Merck, the program comes at a critical time, as the company faces the loss of patent protection for Keytruda later this decade. For Moderna, the cancer vaccine effort provides a new growth avenue as demand for COVID-19 shots declines, along with a potential boost to the company’s public image.

The article notes that U.S. Health Secretary Robert F. Kennedy Jr. has challenged the safety and effectiveness of mRNA vaccines used against infectious diseases, “without evidence,” and has “cut $500 million in related projects.”

Moderna’s share price, which had fallen around 90% from its COVID-era peak, has climbed more than 130% since the melanoma vaccine data were announced. Wall Street analysts expect the product to generate more than $1 billion in sales by 2030 and $3 billion by 2035, according to LSEG data.

Beyond Melanoma: Next Frontiers

The next phase for the partners is to test whether the same personalized mRNA-plus-checkpoint-inhibitor strategy will work in cancers that typically harbor fewer mutations, such as lung, kidney, and pancreatic tumors.

In the shorter term, Moderna and Merck intend to scrutinize the melanoma trial results in depth to identify ways of improving the vaccine.

“I don’t think this is our last version of intismeran,” Bancel said.