2023-09-14 17:00:03
The immunotherapy, the treatment that is revolutionizing cancer management, is not effective in all tumors. Now, a study published in ‘Nature‘ explains why immunotherapy does not work in more than half of patients with a certain type of colon cancer.
The deficiency in DNA mismatch repair (MMRd) is a genetic condition often associated with colon cancer. It can occur in normal cells before cancer forms or after a tumor has already formed. This condition makes it difficult for cells to correct errors that occur in DNA copying, which can lead to many mutations within tumors or a high burden of tumor mutations.
Some patients with high TMB respond well to immunotherapy, which uses the body’s own immune system to fight cancer cells, but others do not.
Peter Westcott’s team, Laboratorio Cold Spring Harbor (USA) manufactured new mouse models to study different responses to immunotherapy in MMRd colon and lung cancers. The models had more mutations in their genomes to more accurately reflect the tumors seen in human patients.
For years, researchers thought that the more mutations in cells, the better the immune response in cancer patients because it is easier for their bodies to recognize tumors.
Thus, some doctors see a high TMB as an indication that immunotherapy will work well.
In fact, it is even said that a high TMB level may qualify patients for some immunotherapy treatments.
But when Westcott’s team tested their immune response models, they found none.
«There is no doubt that these tumors are MMRdDNA, but they do not respond. That alone is a deeply interesting negative result.», says Westcott.
Westcott had a hypothesis. Although the tumors had many mutations, they may have been too different from cell to cell to trigger an immune response.
To test this, the team isolated tumors with identical mutations in all cells, or clonal mutations, and tumors with identical mutations in only some cells, or subclonal tumors.
If we can know whether a patient is going to respond to therapy or not, that is extremely important information.
Peter Westcott
Laboratorio Cold Spring Harbor
They found that mice with clonal mutations responded to immunotherapy. Those with subclonal mutations did not.
The team also examined data from two small human clinical trials and the hypothesis held up. These remain the only publicly available human clinical trial data.
However, heThe possible clinical implications are staggering.says Westcott.
“If we can know whether a patient is going to respond to therapy or not, that is extremely important information.”
With more research, he says, this finding could offer a new way to determine whether immunotherapy is a viable treatment option for patients with MMRd.
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