Research suggests that a type of genetic change called a gene fusion can send signals that the immune system can recognize.
Findings from a single person with cancer can kick-start a major scientific breakthrough. When one person benefits from treatment in an uncommon way, doctors call it an exceptional response. In this era of personalized medicine, exceptional responses offer clues about how a drug or class of drugs works.
In a study published online on April 22 by Nature Medicine, a group of Memorial Sloan Kettering doctors and scientists describes one such exceptional response. The research suggests that in some cancers, genetic changes called gene fusions can occasionally send signals that the immune system can recognize. These signals can boost the effectiveness of immunotherapy drugs called checkpoint inhibitors. Checkpoint inhibitors take the brakes off the immune system and allow it to attack tumor cells.
“This is a great reminder that despite what we know about how immunotherapy and other cancer drugs work, we’re far from understanding all the rules,” says physician-scientist Timothy Chan, one of the paper’s two senior authors.
“What we’ve learned from this one patient has opened a new door,” adds surgeon-scientist Luc Morris, the paper’s other senior author. “Our findings suggest a new way that the immune system can recognize and attack certain types of tumors. But we’re really just at the beginning of knowing how to apply this discovery and target these alterations. We are working on the next steps in the laboratory.”
An Unexpected Outcome
The exceptional response described in the paper was in a teenage girl with a head and neck cancer that had spread to her lungs. She initially saw Dr. Morris, a head and neck cancer surgeon, who began tests to genetically profile the tumor, saving samples in the hopes of learning more about her cancer in the future. She was then treated by MSK pediatric oncologist Leonard Wexler with chemotherapy, which kept the disease stable. When the cancer started growing again, Dr. Wexler decided to try the immunotherapy drug pembrolizumab (Keytruda®).
“Further chemotherapy was unappealing because of the side effects and the limited chance that it would be effective,” Dr. Wexler says. “We also knew that the tumor had some unusual features for a head and neck cancer. We decided to think outside the box about how to treat the patient.”
Only about 12 to 15% of head and neck cancers respond to drugs like pembrolizumab. An initial analysis of this patient’s tumor suggested that she was not likely to be one of them.
There were two reasons for this belief. For one, her tumor had very few mutations. It’s known that the more mutations a tumor has, the more likely it is to respond to checkpoint inhibitors. That’s because having a lot of mutations means a tumor is more likely to produce proteins called neoantigens, which the immune system recognizes as foreign. This discovery was first reported in 2014 by Dr. Chan and his colleagues.
Additionally, her tumor was “cold,” meaning it had little immune activity around the tumor cells. By contrast, tumors described as “hot” — with many immune cells interspersed among the tumor cells — are more susceptible to checkpoint inhibitors. Immune cells can more easily find and attack a cancer when they’re already in the vicinity.
Despite these factors, the girl’s cancer had begun to shrink within five months. After three more months, it had completely disappeared. The MSK team decided to take a deeper dive, studying the tumor in greater detail to figure out why.
A Focus on Neoantigens
After sequencing the entire genome of the patient’s tumor, the MSK team discovered it had a kind of alteration called a gene fusion. Gene fusions occur when a gene from one chromosome breaks off during cell division and attaches to a gene on another chromosome. This new combined gene can make a protein that drives cancer growth.
“The fusion that this patient had was totally unheard of, something that has not been seen before,” Dr. Morris says. “But this gene fusion is probably what caused her cancer.”
The researchers discovered that the protein created by the gene was a neoantigen. “Neoantigens are seen as foreign by the immune system. They’re something that doesn’t belong in the body,” says Dr. Chan, who is Director of MSK’s Immunogenomics and Precision Oncology Platform. “In this case, the neoantigen resulting from the gene fusion made the patient’s cancer susceptible to immunotherapy.”Back to top
Looking for Potential Benefit in More Cancer Types
Although this patient’s particular gene fusion was rare, other fusions are more common in certain cancer types. The investigators analyzed tumors from other people treated at MSK for a type of head and neck cancer with common fusions. They found that immune cells in these people were able to recognize tumor cells with these gene fusions.
“One of the things that our team is doing now is systematically going through every single gene fusion across human cancers and predicting which ones may result in neoantigens that can be seen by the immune system,” Dr. Chan says. “We expect these findings are going to apply broadly to many different types of cancer.”
The original patient completed treatment with pembrolizumab and has remained free of cancer. It has been more than 30 months from when she started immunotherapy.Back to top