Cancer specialists have attempted to utilize the number of mutations in a tumor, known as the tumor mutation burden (TMB), to forecast a patient's response to immunotherapy, with varying degrees of success. Researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg-Kimmel Institute for
The figure shows the interactions between immune cells and tumor cells harboring persistent mutations in the context of immunotherapy as a chess match captured in 5 snapshots. The piece placement is pulled from a Kasparov vs Deep Blue game. Credit: Christina Kostandi and Valsamo Anagnostou
Immune checkpoints are the immune system’s natural on-and-off switches used to ignite the immune response when it is needed and to turn it off when the job is done. Cancer cells exploit this mechanism, shutting down immune responses targeting cancer cells. Checkpoint blockade is a type of immunotherapy that uses a drug or combination of drugs to block the off switch, releasing the breaks on immune cells so they can work against the cancer.
“These ‘stubborn,’ or persistent, mutations are always there in cancer cells, and these mutations may render the cancer cells continuously visible to the immune system,” she says. “If the cancer cell is seen by the immune system as something foreign, then there is an anti-tumor immune response. In the case of immunotherapy, this response is augmented, and the immune system continues to eliminate cancer cells harboring these persistent mutations over time.
In further analyses, the scientists evaluated whether a higher persistent mutation load was linked with clinical outcomes among patients with previously untreated tumors from the Cancer Genome Atlas. They found a significant association with prolonged overall survival for lung squamous cell cancer, melanoma, and uterine cancer but not for other cancer types studied.
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