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After years of disappointment, cancer vaccines show new promise

The development of therapeutic vaccines for cancer has met repeated disappointment over the years, as treatments aimed at cancers of the brain, lung and kidney have failed in clinical testing.

But now, developers like Moderna, BioNTech and Gritstone Bio are pushing forward with personalized, messenger RNA vaccines that have revitalized hopes these treatments could boost human immunity to keep cancer at bay.

The American Society for Clinical Oncology’s annual meeting, held this week in Chicago, was the latest forum for Moderna and partner Merck & Co. to disclose data for a cancer shot they’re developing, called mRNA-4157. The companies had announced the trial met its goal in December, and presented more detailed results in April.

In the background, Roche and partner BioNTech published early clinical trial data for a pancreatic cancer vaccine last month, and the companies are working toward concluding an early-stage melanoma study sometime this year. Gritstone, meanwhile, expects to have early data in colorectal cancer in early 2024.

The development of messenger RNA-based COVID-19 vaccines has helped accelerate some of these advances, showing how developers can quickly tailor and produce treatments using the genetic material.

“We saw something really amazing since the winter of 2020,” Gavin Dunn, director of the Center for Brain Tumor Immunology and Immunotherapy at Massachusetts General Hospital.

“We’ve seen the high immunogenicity of nucleic acid-based vaccines,” he said. Using mRNA’s speed and applying it to cancer vaccine research, “a lot of the time frames may start to be compressed.”

There are a number of reasons why past cancer vaccines have disappointed. Some haven’t targeted enough of the mutated proteins present in tumor cells to spur an immune response, or they’ve stimulated the wrong kind of immune cells or haven’t been able to overcome cancer’s natural immunosuppression. (One approved treatment, an individualized immunotherapy derived from patients’ blood called Provenge, is considered by some to be a cancer vaccine.)

Cancer vaccines now in development target multiple mutated cancer proteins, called neoantigens, and are tailored to the specific ones present in each individual patient.

“The question is whether we didn’t have good enough vaccine technology or whether we didn’t target the correct antigen,” Olivier Michielin, a medical professor at the University of Geneva, said of past cancer vaccine disappointments in a discussion of Moderna’s data at ASCO.

Moderna is testing its shot, mRNA-4157, together with Merck’s immunotherapy Keytruda in people with melanoma who have had their primary tumors removed. The goal of such “adjuvant” treatment is to prevent cancer from returning.

In December, the company reported the two drugs reduced the relative risk of death or recurrence by 44% over Keytruda alone. The new data came from an analysis of the risk of cancer spreading to distant organs or tissues, or “distant metastasis free survival.”

One-third of patients who receive Keytruda in this setting experience such spread, driving researchers’ work to come up with better options. “We know that patients with distant metastases experience more morbidity and mortality,” said Adnan Khattak, a clinical professor at Edith Cowan University in Australia, who presented the Moderna data at ASCO.

In the combination trial, mRNA-4157 and Keytruda reduced the risk of distant spread or death by 65% compared to Keytruda alone.

BioNTech’s candidate autogene cevumeran, which had the promising data in pancreatic cancer in May, soon could have results from a Phase 2 trial in melanoma in combination with Keytruda, too. The company said the trial has completed enrollment and needs a sufficient number of events in order to measure the shot’s effectiveness.

However, the trial is in previously untreated patients, which could raise the threshold for determining success, SVB analyst Daina Graybosch wrote in a Dec. 8 note to clients. Quoting BioNTech executives, Graybosch wrote, “the bar for success is lower in adjuvant settings, as there are fewer tumor cells” for immune cells to attack.

Gritstone, meanwhile, reported in May that it had enrolled 71 of an initially planned 80 participants in a Phase 2 trial of its personalized neoantigen mRNA vaccine program in colorectal cancer. It is now expanding its planned enrollment to 100. The trial, which involves patients who typically don’t respond to Keytruda, is expected to generate preliminary results in early 2024, executives said.

Aiding the development of these personalized vaccines has been artificial intelligence-aided genetic profiling that helps identify the antigens present in patients and how to better target them. That, in turn, has helped speed clinical testing and, if the vaccines are ever approved, could help meet patient demand, said Christina Corridon, a principal at the consulting firm ZS.

“There’s a limited capacity of human pathologists to be doing all of this work,” she said. “One of the limitations to scaling [personalized vaccines] is human pathologists versus computational pathology.”

Gritstone also has an “off-the-shelf” cancer vaccine technology that targets shared neoantigens, an area where the private Swiss company Nouscom has been working.

The recent progress appears to be shifting the views of researchers and physicians, as they try to build on the cancer immunotherapy advances of the past decade.

“We have clearly a new groundbreaking technology that will open a new era in cancer vaccines,” Michielin said in comments on the Moderna data.