Merck and Cambridge-based Moderna reported in August that adding their mRNA cancer vaccine to an existing treatment slowed the return and spread of melanoma. The field had been waiting “with bated breath” for the news on the drug, called intismeran autogene, said Karen Knudsen, the CEO of the Parker Institute, the research organization founded by tech entrepreneur Sean Parker. The results suggested that the idea of using messenger RNA to train the immune system to attack cancer cells — an approach first devised decades ago — was ripe for further drug development. Just days later, however, the German drugmaker BioNTech and its partner Genentech ended a mid-stage study of its colorectal cancer vaccine.

After carefully studying the early data coming in from the trial, it had become evident that the treatment wasn’t working. Now, as the field waits for Moderna and Merck to present detailed data at a European oncology meeting next month, it is wrestling with questions about what to make of the divergent outcomes. “I think the really big question is: Why does Moderna have good data in melanoma and BioNTech, I guess, doesn’t have good data in colon cancer?”

asked Jason Luke, a physician and clinical trial investigator who joined mRNA company Strand Therapeutics last year. When BioNTech reported its trial failure, Wall Street analysts like Cowen’s Yaron Werber were quick to point out a possible explanation: The company had made the bold choice of testing its cancer vaccine in a “cold” tumor, industry shorthand for one that can be difficult for immune cells to penetrate. Colorectal cancer is notoriously immune-resistent.

Melanoma, on the other hand, is a more hospitable environment for immune cells. Personalized cancer vaccines, like intismeran and BioNTech/Genentech’s autogene 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 provoke the immune system, like a “wanted” poster for the cancer. In the case of autogene cevumeran, even if the vaccine had plastered signs around the body to warn of colorectal cancer, the tumor may have still been able to resist attacks. It’s a natural theory.

But it’s far too early to draw any 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 signs that intismeran, in particular, can work in patients with “colder” tumors, Long said. During their Phase 2 trial, Merck and Moderna collected reams 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, on an individual basis, patients can have a wide range of immune responses. Some melanoma patients can still have low levels of immune activity. In the supplemental data, patients with a lower level of the immune marker PD-L1 appeared to benefit more from adding intismeran to their treatment. Comparing the recent trials of intismeran and autogene cevumeran is like comparing apples to oranges, researchers and drug developers said. Intismeran was given alongside the drug Keytruda, which overrides cancer cells’ blockades against immune cells and has proven highly effective in dozens of cancers. Autogene cevumeran was given as a standalone treatment.

The fact that the trials produced different outcomes could simply mean the current generation of drugs doesn’t work as well alone. BioNTech is currently testing whether adding autogene cevumeran to other treatments will help patients with pancreatic ductal adenocarcinoma, another “cold” tumor. BioNTech said in a statement that the decision to shut down the colorectal cancer trial doesn’t impact the pancreatic cancer trial.

The latter trial is expected to wrap up 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 notably differs from that of cancer vaccine developers: Its medicines use mRNA to spur production of an immune protein called interleukin-12.

It’s not generating a “vaccine” against the tumor, set off by specific tumor antigens, as cancer vaccine companies are doing. The “low-hanging fruit” in developing this first generation of mRNA medicines for oncology is to start where immunotherapy drugs like Keytruda have worked, said Luke, the Strand executive. The Boston startup has shown promising results in melanoma and recently started an early-stage trial in patients with non-small cell lung cancer, among other cancers. Beyond Strand, there have been promising early-stage trials of therapies for some difficult-to-treat “cold” cancers, including glioblastoma and pancreatic cancer.

The Parker Institute is also working with cancer startup Medici Therapeutics, which is planning a merkel cell carcinoma trial.