Immunotherapy treatments like checkpoint inhibitor drugs have shown to treat many patients of their cancer, even putting several into complete remission. But still a majority of patients do not respond to the drugs, and researchers are searching for the reasons why. A team from the Johns Hopkins Kimmel Cancer Center and the Memorial Sloan Kettering Cancer Center believe they have an answer.
Their study was recently published in the journal Science, and it revealed that in both mouse and human models, tumors most likely to respond to immunotherapy treatments have a higher degree or intensity of microsatellite instability (MSI). This means that they have a higher number of DNA alternations because of repetitive cell divisions over a long period of time.
Specifically, the tumors have a larger number of insertion/deletion (indel), mutations of the DNA compared to other tumors. Indel mutations consist of a series of nucleotides, or genetic “letters” that are either placed into the genetic code or removed during cell division. The mutations can also create neoantigens, which are new proteins in cancer cells that the immune system can see and attack.
These findings could allow researchers to take biopsies of one of the tumors and sequence the DNA, allowing them to search for the level of MSI intensity when they’re coming up with a treatment plan. Rajarsi Mandal, MD, director of the Head and Neck Cancer Immunotherapy Research Program at the Bloomberg-Kimmel Institute for Cancer Immunotherapy, says that “this genetic ‘signature’ potentially could serve as a novel biomarker, akin to a crystal ball, to see which cancer patients may respond to immunotherapy.”
The study is still in its early phases, however, so the researchers can’t make any definitive statements. According to Mandal, at least 14 cancers have this genetic characteristic, and its most common in colorectal, stomach, uterine, and endometrial cancers. It’s also been seen in lung and head and neck cancers.
The team conducted several experiments to test the immunotherapy response in mismatch repair deficient tumors. They discovered a statistically significant increase in infiltrating lymphocytes in the MSI-high tumors after the anti-Pd-1 checkpoint inhibitor therapy.
“Together, our data demonstrate that a range of MSI types exist, and may help identify patients who will benefit from immunotherapy,” said Mandal. “It may be possible to classify responders and nonresponders to anti-PD-1 therapy across mismatch repair deficient cancers by using precise, next-generation sequencing measures of MSI intensity.”
Moving forward, the team will continue to investigate the immune system’s role in the MSI-related immune response.