In an early trial, a one-size-fits-all vaccine showed promise in preventing hard-to-treat pancreatic cancers from coming back.
Pancreatic cancer is of particular concern. The five-year survival rate is about 13%, and up to 80% of pancreatic cancers may come back.
“If you were to ask me what disease most needs something to prevent recurrences, I’d say this one,” said Dr. Zev Wainberg co-director of the University of California, Los Angeles, gastrointestinal oncology program, who co-led the Phase 1 clinical trial.
The vaccine targets one of the most common genetic drivers of cancer: KRAS gene mutations.
KRAS mutations occur in about one-quarter of all cancers, including as much as 90% of pancreatic cancers and about 40% of colorectal cancers. Their ubiquity makes KRAS mutations a great target for cancer therapies, but the mutations have long been considered impossible to target with drugs.
To accomplish this, the vaccine uses short chains of amino acids called peptides that teach immune cells to recognize and attack cells with KRAS mutations.
“The critical step is engaging an immune response,” Wainberg said.
Cancer vaccines are a growing field of research, but many of these vaccines are personalized to the patient. This means their tumor must be sequenced for a specialized vaccine to be created. The vaccine in the current study, however, doesn’t need to be personalized and would be available off the shelf.
Killing lingering cancer cells
In the Phase 1 trial, published Monday in Nature Medicine, Wainberg and a team of doctors from across the country recruited 20 people with pancreatic cancer and five with colorectal cancer. (They chose to also include a few colorectal cancer patients because KRAS mutations are also a common driver of colorectal cancers, and people whose colorectal cancer is driven by these mutations are more likely to have a recurrence, Wainberg said.)
Everyone in the trial had KRAS mutations and had undergone standard treatment — usually chemotherapy and surgery — to remove the bulk of their tumors.
After surgery, blood tests showed that a smattering of cancer cells remained behind, referred to as microscopic residual disease, which is very common with pancreatic cancer.
“We are talking about cancer that is so microscopic that we can’t see it on scans,” said Dr. Scott Kopetz, a professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center in Houston.
These cells can travel elsewhere in the body and grow into metastasized tumors, prompting an often fatal cancer recurrence. Chemotherapy can kill some of these cells, but some usually remain in the body.
“Realistically, if we want to kill every last cancer cell and really make people cured, you need to engage the immune system,” said Stephanie Dougan, an associate professor of cancer immunology and virology at the Dana-Farber Cancer Institute in Boston. “We’ve just been really bad at getting an immune response in pancreatic cancer.”
Post-surgery, everyone in the trial got up to six priming doses of the experimental vaccine, called ELI-002 2P. Thirteen also received booster shots. The whole process took 6 months.
About 85% — 21 of the 25 participants — mounted an immune response to the KRAS mutations, and about two-thirds of those patients had an immune response that appeared to be robust enough to stave off lingering cancer cells.
What’s more, in nearly 70% of people in the trial, the vaccine appeared to trigger an immune response not just to KRAS mutations, but to other tumor cell targets that were not in the vaccine. A few people were “super-responders” who mounted an abnormally strong immune response to the cells.
“Those people had the best outcomes,” Wainberg said. His team is currently running a randomized Phase 2 trial to test the durability of the vaccine and compare whether the vaccine is more effective than the standard of care, which would usually be monitoring the patient for a recurrence.
In the Phase 1 trial, people with pancreatic cancer survived for an average of 29 months and lived recurrence-free for more than 15 months post-vaccination.
“That far exceeds the rates with resectable cancers,” said Wainberg, referring to cancers that can be removed with surgery.
A growing field
Cancer vaccines have been incredibly difficult to make, in part because cancer cells have a lot of the same proteins as healthy cells, making safe targets difficult to come by. Only recently has medical technology made the strides researchers needed to hone the treatment. Refined mRNA technology and gene sequencing becoming faster and cheaper has put cancer vaccines back into clinical trials, Dougan said.
Personalized mRNA cancer vaccines are showing promise in both pancreatic and colorectal cancers, but a one-size-fits-all cancer vaccine would make treatment faster and cheaper. Past trials using peptide vaccines have failed to prevent cancer recurrences. But the peptides in the new vaccine, called lipophilic peptides, have something past treatments did not — a tail.
“That tail sticks in the lymph nodes where immune cells get activated,” Dougan said. “You need something to get the immune system going, and just injecting killed cancer cells or peptides doesn’t work that well.”
More advanced clinical trials will have to confirm the results of the Phase 1 trial, but promising results have been seen in other cancer vaccine trials as well and could pave the way for major breakthroughs in preventing cancer recurrences. Memorial Sloan Kettering is also working on an off-the-shelf vaccine that targets a gene mutation found in 95% of people with acute myeloid leukemia. The data from the KRAS-targeting vaccine trial published Monday showed it is likely possible to target these mutations with nonpersonalized vaccines, something researchers long thought was impossible.
“The fact that the long-term survival really correlated with T-cell response suggests that the vaccine caused this,” Dougan said, referring to the specific immune cells activated by the vaccine. “The idea that you can target KRAS is really exciting.”
