Success after a century of failures: Inside Moderna and Merck's cancer vaccine breakthrough

Stephane Bancel, CEO of Moderna MRNA.O, was at a Lebanese restaurant celebrating a friend’s birthday late on August 13 when he got the call. An mRNA cancer vaccine the company had been developing with Merck MRK.N had hit its mark — the first success of a therapeutic cancer vaccine in late-stage testing after more than 100 years of failed attempts. Cancer experts hailed it as the beginning of an era of custom-made vaccines that train the immune system to fight an individual patient’s cancer. In a trial of more than 1,000 patients with localized melanoma, the vaccine kept tumors from coming back or spreading. With full trial details pending, Wall Street is already estimating billions of dollars in sales. Bancel likened news from that call to the day in late 2020 that Moderna announced its COVID-19 vaccine trial results. "It was a moment that we'd worked really hard toward. We knew what was at stake for the planet with COVID," Bancel said in an interview. It's the same with cancer, he said, adding that the disease touches nearly everybody at some point. That moment of joy was brief. "I went right away into, 'OK, what are all the things we have to do?'" For Dean Li, president of Merck Research Laboratories, it was largely the same. When Eliav Barr, Merck's head of global clinical development, called Li, he already had a list of urgent tasks: ready the data for presentation at an international cancer meeting, turn to the U.S. FDA review, and apply the study's strengths to other ongoing trials. "It isn't hallelujah," Li recalls. "It's boom." For Merck and Moderna, it was a moment built over 10 years, according to eight current and former company executives. When they announced a partnership in 2016 to develop a cancer vaccine, the companies had been working for over a year on a separate vaccine venture. For the cancer collaboration, Merck paid $200 million upfront in 2016 and another $250 million in 2022. The companies share costs and profits. At that time, Merck's Keytruda was emerging as a powerhouse in a new class of drugs called checkpoint inhibitors that could unleash the immune system to fight cancers by removing a natural brake. "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," Merck's Barr said during an interview in late May. Next, he said, companies, including Merck, looked for ways to further rev up the immune system, testing Keytruda with next-generation immunotherapy drugs such as TIGIT inhibitors. "It didn't work," Barr said. Tal Zaks, who served as Moderna's chief medical officer from 2015-2021, immigrated to the U.S. 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. But he thought new technologies based on mRNA plus checkpoint inhibitors, as well as cheaper genetic sequencing, might open a path toward success. Moderna had the mRNA technology, but as a young company, expensive cancer trials were out of reach. Bancel said Moderna spoke with companies that had checkpoint inhibitors, but knew Merck well and was swayed by its experience mounting Keytruda trials. Keytruda, which Merck’s Li calls a "miracle drug," is used against 20 different kinds of cancerous tumors and 45 types and stages of cancer. But exactly what aspects of the tumor the drug targets, and why some patients respond better than others, remains a mystery. Messenger ribonucleic acid, or mRNA, is present in every cell of the body. Its job is to carry genetic instructions from the cell nucleus to parts that make specific proteins. The vaccine, known as intismeran autogene, trains the immune system to attack cancer cells by targeting mutations unique to each patient's tumors. Prior cancer vaccines that attempted to train the immune system to target one or two specific tumor mutations failed. The companies decided to test the vaccine in melanoma, which has among the highest number of mutations of any cancer and against which checkpoint inhibitors had a record of success. They also decided to test it in patients with early-stage melanoma following surgical removal of their tumors. That gave the companies critical time to create a customized vaccine based on a patient's tumor and additional time for their immune systems to respond. With mRNA technology, the companies were able to target dozens of mutations. "You have many, many more shots on goal and therefore a much greater chance to succeed," Moderna co-founder and MIT scientist Robert Langer said via email. The companies paired the vaccine with Keytruda’s ability to activate the body's immune system T-cells that hunt down abnormal cells. "The whole special thing about Keytruda was that it would unlock the dogs of war," Li said. The vaccine provides 34 patient-specific cancer targets for those dogs to recognize, he said, and only one needs to work. "With the personalized cancer treatment, the dog has your scent." Both companies stand to benefit significantly if the vaccine is approved. U.S. approval could come as soon as next year. Merck later this decade faces the patent expiration of Keytruda, until recently the world's top-selling drug. For Moderna, it offers a lifeline amid sagging COVID shot demand, and a reputational boost. U.S. Health Secretary Robert F. Kennedy Jr. has criticized the safety and efficacy of mRNA vaccines for infectious disease, without evidence, and cut $500 million in related projects. Moderna's shares, which had fallen around 90% from their COVID peak, are up more than 130% since the vaccine results were announced. Wall Street analysts see sales topping $1 billion by 2030 and $3 billion by 2035, according to LSEG data. The next test is finding whether the approach can work in cancers with fewer mutations, including lung, kidney and pancreatic cancers. In the near term, the companies plan to dig into the melanoma data to see if they can improve the vaccine. "I don't think this is our last version of intismeran," Bancel said.

Success after a century of failures: Inside Moderna and Merck's cancer vaccine breakthrough

A breakthrough after decades of failures

How Merck and Moderna built the partnership

Why the approach worked and what comes next

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