Tumor mutation burden (TMB) has become a biomarker used to predict patient response to specific immunotherapies. Now new evidence from researchers at the Johns Hopkins Kimmel Cancer Center has found that a subset of mutations within the TMB – defined as “persistent mutations” – are less likely than others to be excised, making them always visible to the immune system. which makes them more likely to respond to immunotherapies.
The identification of these persistent mutations holds the promise of a more precise biomarker that will allow clinicians to stratify eligible patients for enrollment in clinical trials and also predict patients’ response to a type of immunotherapy called immune checkpoint blockade. Immune checkpoints are the immune system’s signals that either turn the immune system on when needed and then turn it off again when it has eliminated the threat.
“It is very frustrating trying to use tumor mutational burden as a universal predictive biomarker for response to immunotherapy in different cancer types,” said Valsamo Anagnostou, MD, PhD, associate professor of oncology at Johns Hopkins University, a senior author of the published in study naturopathy. “Therefore, it is imperative to identify the most biologically significant subset of mutations within the overall TMB. Our study has shown that such mutations are located in aneuploid regions (regions with additional or missing genetic material) of the genome.”
Cancer cells manipulate the human immune response by turning off the immune system’s response to their presence. Checkpoint blocking drugs are a form of immunotherapy designed to revive the immune system’s response to cancer cells.
In addition, cancer cells are known to be aneuploid, resulting in one copy of some chromosomes or multiple copies of others in cancer cells. The Hopkins team pursued their latest research under the hypothesis that mutations in these genomic regions might be preserved in the development of cancer. Anagnostou said that in genomic regions with one copy, eliminating that copy would kill that cancer cell. But in multicopy cases, it was unlikely that a single chromosomal deletion could remove them all.
She found that these persistent mutations, always present in cancer cells, can continuously make cancer cells visible to the immune system. “If the cancer cell is seen as something foreign by the immune system, then there is an anti-tumor immune response,” Anagnostou said. “In the case of immunotherapy, this response is amplified, and the immune system continues to eliminate cancer cells harboring these persistent mutations over time.”
As part of their research, researchers performed an analysis of 9,000 tumors spanning 31 tumor types included in the Cancer Genome Atlas. “When examining how different persistent mutation is compared to total TMB, we found reclassification rates from high/low TMB tumors to persistent mutation load tumors of up to 53% for individual tumor types and a median reclassification rate. Classification rate of 33% for all tumor types,” said Dr. Noushin Niknafs, a research associate at the Johns Hopkins Kimmel Cancer Center.
Examining regions in the genome with a single copy per cell and two copies per cell, the researchers found that the rate or mutational losses were lower in the single copy regions, supporting their hypothesis that mutations in single copy regions occur Harder to find copy would eliminate. The distribution of persistent mutations also differed compared to TMB overall, with a tumor’s TMB not always being consistent with its persistent mutation load.
In further analyzes using tumors from the Cancer Genome Atlas, the scientists examined whether a higher persistent mutation (pTMB) load was associated with clinical outcomes in patients with previously untreated tumors. They found a significant association with prolonged overall survival for squamous cell carcinoma of the lung, melanoma and uterine cancer, but not for other cancers studied.
The team then sought to determine whether tumors high in pTMB would be susceptible to treatment with immunotherapies. In evaluating the potential of pTMB, multicopy, and single copy mutations to predict response to immune checkpoint blockade in 542 patients with melanoma, non-small cell lung cancer, mesothelioma, and head and neck cancer, the team found that that tumors with high pTMB had higher rates of therapeutic response, while TMB alone was a less optimal measure of treatment response.
Overall, the Hopkins team’s results support the clinical utility of pTMB, and the research indicates the need for large-scale validation of the new results and prospective analysis to further evaluate the role of pTMB in patient selection for immunotherapy .
