Cambridge-based Merck and Moderna reported in August that adding their mRNA cancer vaccine to an existing treatment slowed the return and spread of melanoma. The industry was “eagerly” awaiting news about the drug, called intismeran autogene, said Karen Knudsen, CEO of the Parker Institute, the research organization founded by technology entrepreneur Sean Parker. The results suggest that the idea of using messenger RNA to train the immune system to attack cancer cells – an approach first conceived decades ago – was ripe for further drug development.
However, a few days later, German pharmaceutical manufacturer BioNTech and its partner Genentech ended a mid-term study of its colorectal cancer vaccine. After carefully studying the initial data from the trial, it became clear that the treatment was not working.
Now, as the industry waits for Moderna and Merck to present detailed data at a European oncology meeting next month, there is the question of what to make of the divergent results.
“I think the real big question is, why does Moderna have good data on melanoma and BioNTech, I guess, doesn’t have good data on colon cancer? asked Jason Luke, a physician and clinical trial researcher who joined mRNA company Strand Therapeutics last year.
When BioNTech announced its trial failure, Wall Street analysts like Cowen’s Yaron Werber were quick to point out one possible explanation: The company had made the bold choice to test its cancer vaccine on a “cold” tumor, an industry shorthand for a tumor that can be difficult for immune cells to penetrate. Colorectal cancer is notoriously immunoresistant. Melanoma, on the other hand, provides a more hospitable environment for immune cells.
Personalized cancer vaccines, like BioNTech/Genentech’s autogenous intismeran and cevumeran, are designed to rally the immune system. These drugs use mRNA to create specific mutated proteins from a patient’s tumor, called antigens, that trigger the immune system, like a research poster for cancer. In the case of autogenous cevumeran, even if the vaccine had placed signs around the body to warn of colorectal cancer, the tumor might still have been able to resist attack.
It’s a natural theory. But it is far too early to draw conclusions, said Georgina Long, an oncologist and medical director of the Melanoma Institute Australia.
Long has worked with BioNTech and Moderna on cancer vaccines, as well as startup Strand, which is developing treatments that use mRNA to produce a specific type of immune cell to attack cancer cells.
There are some signs that intismeran, in particular, may work in patients with “colder” tumors, Long said. During their Phase 2 trial, Merck and Moderna collected a lot of data, including information on how subjects with different levels of immune system markers fared. Although melanoma has long been classified as a “hot” tumor, patients can exhibit a wide range of immune responses on an individual basis. Some melanoma patients may still have low levels of immune activity.
In additional data, patients with lower levels of the immune marker PD-L1 appeared to benefit more from adding intismeran to their treatment.
Comparing recent trials of intismeran and autogenous cevumeran is like comparing apples to oranges, researchers and drug developers said. Intismeran was given at the same time as the drug Keytruda, which reverses cancer cells’ blockade against immune cells and has been shown to be very effective in dozens of cancers. Autogenous cevumeran was administered alone. The fact that the trials produced different results could simply mean that the current generation of drugs doesn’t work as well on their own.
BioNTech is currently testing whether adding autogenous cevumeran to other treatments will help patients with pancreatic ductal adenocarcinoma, another “cold” tumor. BioNTech said in a statement that the decision to stop the colorectal cancer trial did not impact the pancreatic cancer trial. This latest trial is expected to end in 2031.
Strand, meanwhile, is testing how various cancers respond to mRNA treatments alone, even in patients for whom drugs like Keytruda haven’t worked.
The company’s approach differs significantly from that of cancer vaccine developers: Its drugs use mRNA to stimulate production of an immune protein called interleukin-12. This is not about generating a tumor “vaccine,” triggered by specific tumor antigens, as cancer vaccine manufacturers do.
The “low-hanging fruit” in developing this first generation of mRNA drugs for oncology is to start where immunotherapy drugs like Keytruda have worked, said Strand director Luke.
The Boston startup has shown promising results in melanoma and recently launched an early trial in patients with non-small cell lung cancer, among other cancers.
Beyond Strand, there have been promising early trials of therapies for some hard-to-treat “cold” cancers, including glioblastoma and pancreatic cancer. The Parker Institute is also working with start-up Medici Therapeutics, which is planning a trial in Merkel cell carcinoma.
Gn Health
