In a recent study titled “Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma”, published in The New England Journal of Medicine, a team of researchers from the Memorial Sloan Kettering Cancer Center, led by Timothy A. Chan, M.D., Ph.D., has unveiled mechanistic insights for different clinical responses to the immunotherapeutic drug ipilimumab in melanoma patients.
The team found that patients who respond to ipilimumab have a high number of genetic mutations in their cancer cells, some of which allow the immune system to recognize the tumors in a more efficient manner.
“We are learning that there are few treatments that don’t have some footprint in the cancer genome,” Dr. Chan said in a press release. “For the first time, it might be feasible to develop a reliable diagnostic test to help guide treatment decisions by predicting who will respond.”
Ipilimumab (Yervoy) has been tested in different clinical trials and has produced promising results. This drug is an anti-CTLA-4 receptor antibody, which inhibits the connection of the receptor to its ligand and allows the patient’s immune system to recognize and destroy tumor cells, therefore increasing the naturally occurring immune response.
“We’ve spent much time and effort studying how to target the tumor. And we’ve only recently understood how to have the patient’s immune defenses mobilized to treat the tumor. Immunotherapy is by definition how that happens,” Dr. Wolchok added.
However, while for some patients ipilimumab significantly diminishes the tumor burden and extends survival, for the majority (80%) it does not have the same benefit. Until now, this discrepancy in results did not allow physicians to select which patients could benefit from the immunotherapeutic drug.
“There was a correlation between having an elevated number of mutations, or more DNA changes in a tumor, and benefitting from the treatment with ipilimumab, with benefit being long-term stability or resolution of metastatic disease,” lead author Dr. Snyder Charen explained in the press release.
The research team analyzed samples from 64 melanoma patients who had received ipilimumab or tremelimumab therapy (half the samples were from successfully treated patients). Using whole-exome sequencing, DNA modifications were detected, and researchers found that tumors that are drug-responsive have a particular type of mutation that allows cancer cells to express new antigens recognized by T cells.
“We found that tumors that had responded to the drug had a higher mutational burden, or overall number of DNA changes,” Dr. Charen explained. “But the correlation isn’t perfect. Not all patients with a high mutational burden in their tumors responded to the drug.”
These results will allow for the future development of diagnostic tests that can detect the mutational status of melanoma patients, helping both doctors and patients to make adequate treatment choices.
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