A few months ago, Georgina Long received a message asking her to call a collaborator at Merck & Co. She feared the worst.
The Sydney cancer researcher had spent years leading studies into an experimental approach designed to teach the immune system to recognize and destroy cancer. She worried the pivotal trial had come up short.
“Don’t tell me. Don’t tell me it’s negative,” she recalled saying as she returned the call.
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The results were quite the opposite.
Adding a personalized vaccine developed by Merck and Moderna Inc. to standard immunotherapy cut patients’ risk of cancer recurrence or death after surgery by 42%. Long, the study’s global principal investigator, was ecstatic.
When Long began treating patients two decades ago, advanced melanoma was among the most feared diagnoses in oncology. Once it spread, patients typically had months to live. But there was a tantalizing mystery: in extraordinarily rare cases, the cancer disappeared without treatment. Scientists suspected the immune system was responsible.
Long has spent much of her professional life finding ways to harness the immune system against melanoma. Now the medical director of Melanoma Institute Australia and a professor at the University of Sydney, she presented results from the first late-stage trial to show that a personalized cancer vaccine designed from a patient’s tumor could reduce the risk of cancer recurrence or death at the European Society for Medical Oncology meeting on Oct. 24 in Madrid.
The auditorium was packed, with some attendees sitting on the floor to hear Long present the findings.
“It’s a penicillin moment,” she said.
Her excitement extends beyond the cancer vaccine itself to mRNA as a platform that can carry different biological instructions. “The mRNA is the platform,” she said in an interview. “It is the code which now enables you to print off what you need to print.”
Still, the findings leave some important questions unanswered.
The trial involved patients whose visible melanoma had been surgically removed, so it doesn’t show whether the treatment can attack tumors that are still present or work as well against cancers that are harder for the immune system to recognize.
The benefit was also somewhat smaller in preventing melanoma from spreading to distant parts of the body, a point highlighted by analysts after details of the study leaked. Because such spread generally takes longer to occur than a recurrence, Long said more follow-up is needed to understand the treatment’s full effect. It’s also too soon to know whether the treatment will help patients live longer.
Moderna shares have whipsawed as investors assessed the findings and what they could mean for the treatment’s broader potential.
The stock surged 171% when the companies first announced the trial had succeeded in August and climbed further in subsequent weeks. It fell 18% on Oct. 22 after the detailed results leaked and investors focused on a smaller benefit in preventing the cancer from spreading elsewhere. Even after the drop, the shares remained more than three times their pre-announcement level.
A spokesperson for Long said she couldn’t comment on the market response.
Tumor Fingerprint
The treatment at the center of the breakthrough, called intismeran autogene, isn’t a conventional vaccine. Rather than being mass-produced for the broad prevention of disease, it’s made individually for each patient using genetic information taken from their cancer, effectively giving the immune system a personalized picture of what to attack.
Adding the therapy to Merck’s best-selling immunotherapy drug Keytruda cut the risk of recurrence or death by 42%, with 82% of patients on the combination remaining free of recurrence after two years, compared with 70% given Keytruda alone. It reduced the risk of distant metastasis or death by 38%. The findings are expected to be published in the New England Journal of Medicine.
Inge Marie Svane, a melanoma specialist at Copenhagen University Hospital who discussed the findings after Long’s presentation, called the results a “crucial moment” for cancer vaccines and said they convincingly showed that intismeran added benefit to Keytruda. She described it as “the first personalized agent designed for each patient using a computer algorithm” to reach this stage of development.
Questions remain about where the treatment would fit into melanoma care. Some patients like those enrolled in the trial can receive immunotherapy before surgery, and clinicians will need guidance on choosing between that approach and vaccination afterward, Svane said. Manufacturing could also be a hurdle because every vaccine must be individually made.
Its role in advanced cancer is even less certain. Existing guidelines recommend a combination of two checkpoint inhibitors for patients with advanced melanoma, and it remains unclear whether the personalized vaccine can match their effectiveness, Svane said.
Whether the approach can be extended to other cancers is “the work to be done,” Long said. “There’s a lot to be discovered and understood yet.”
Building Blocks
Getting to this point took decades. Advances in genetics, molecular biology and immunology gradually transformed scientists’ understanding of the disease and expanded what doctors could offer their patients.
When Long entered the field more than two decades ago, melanoma that had spread to other parts of the body was almost invariably fatal. The standard treatment was chemotherapy, and it rarely helped.
Long told patients the truth: the cancer was incurable. Chemotherapy might extend their lives; clinical trials carried risk but provided the chance to try something new. Little else was on offer. Patients with advanced disease had about a one-in-four chance of surviving a year. Most lived six to nine months.
The grim prognosis led to experimentation among patients desperate to live and doctors willing to try new approaches. The rare cases in which tumors spontaneously disappeared suggested that the immune system might accomplish what medicine couldn’t.
Long first saw progress in 2007 when researchers presented early results for Bristol Myers Squibb Co.’s Yervoy. It belonged to a new class of drugs known as checkpoint inhibitors that release the molecular brakes that restrain the immune system. While few patients responded, the cancer remained under control in some for far longer than expected.
Long returned to Sydney convinced that checkpoint inhibitors could change melanoma treatment.
Then came drugs like Keytruda that targeted another immune checkpoint, PD-1. They worked in more patients, with less toxicity. Over little more than a decade, the conversations Long had with patients facing advanced melanoma had fundamentally changed. A word that once seemed unthinkable had entered the oncologist’s vocabulary: cure.
The experience also changed the ambitions of melanoma researchers. Having seen that the immune system could eradicate the disease in some patients, merely extending survival no longer seemed enough.
‘Taste of Cure’
“We got a taste of cure,” Long said. “We set different standards.”
Long came to medicine by an unusual route. She studied mathematics and chemistry, earned a PhD in organic chemistry and went to the Scripps Research Institute in California on a Fulbright scholarship. Exposure to immunology there helped propel her toward medicine.
That background proved useful when she became involved in 2018 with an unconventional cancer-vaccine project from Moderna, then little known outside biotechnology circles. Long didn’t invent the vaccine. She joined the phase-two study and went on to become global principal investigator and chair of the steering committee for the phase-three trial, involving 1,137 patients at 157 sites.
Her role included helping solve the practical problems of making a personalized treatment work at that scale. Each vaccine requires enough of a patient’s tumor to identify its distinctive mutations. When inadequate samples caused patients at Long’s center to miss out, she worked with pathologists to check the tissue before it was shipped to Moderna. Across the trial, personalized vaccines were ultimately successfully made for more than 99% of patients assigned to receive one.
For all the progress, about half of patients with advanced melanoma still ultimately die from the disease.
Long is already looking further ahead, including at ways to use mRNA to give immune cells new instructions for attacking tumors.
For a researcher who began her career making molecules in a chemistry laboratory, it’s another set of building blocks.
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