Timothy Chan, MD, PhD, and oncology fellow Alexandra Snyder Charen, MD, at the Memorial Sloan Kettering Cancer Center, are working to advance the way melanoma patients are treated with immunotherapy. The two researchers, along with collaborators from outside universities and companies, proposed a reason why only some patients respond to ipilimumab and reported their results in “Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma,” published in the New England Journal of Medicine.
“For the first time, it might be feasible to develop a reliable diagnostic test to help guide treatment decisions by predicting who will respond,” said Dr. Chan in a news report. The diagnostic test described by Dr. Chan could be in the form of a check for mutations, as the team found that patient responders held a high number of mutations in their cancer cells.
“We found that tumors that had responded to [ipilimumab] had a higher mutational burden, or overall number of DNA changes,” stated Dr. Charen. The team collected tumor samples from 64 melanoma patients and ran whole-exome sequencing to determine any changes in DNA that would affect the production of proteins. Afterwards, they identified a discovery set of patients, with 11 patients responding long-term to either ipilimumab (a CTLA-4 inhibitor) or tremelimumab and 14 patients seeing no clinical benefit.
“There was a correlation between having an elevated number of mutations, or more DNA changes in a tumor, and benefiting from the treatment with ipilimumab, with benefit being long-term stability or resolution of metastatic disease,” said Dr. Charen. “But the correlation isn’t perfect. Not all patients with a high mutational burden in their tumors responded to the drug.”
Commenting on this discrepancy, Jedd Wolchok, MD, PhD, who was also involved in the study, stated, “This made us ask, ‘What is the immune system seeing? What is it about the mutational landscape of a tumor that helps the immune system recognize and attack it?'”
To answer these questions, the team used immunology and computational tools to identify a shared set of mutations that led to cancer cell expression of new antigens recognizable by T-cells of the patients. These antigens, called neoantigens, were part of a landscape present in tumors that respond strongly to CTLA-4 blockade.
This neoantigen signature was validated in a separate set of 39 melanoma patients who were treated with anti-CTLA-4 antibodies. “These advances would not have been made without the generosity of patients who consented to having their tumor tissue collected and analyzed,” noted Dr. Charen. “Dr. Wolchok and his lab members have spent many years banking samples, and it’s an invaluable resource for research.”
The envisioned diagnostic test would determine the presence of mutations in melanoma patients. Based on the results, clinicians could then make a more-informed decision of whether or not to use a certain immunotherapy. “If we know a patient won’t respond to ipilimumab, we may be able to identify other drugs that are more likely to be effective against this person’s tumor,” said Dr. Chan.
Ipilimumab is an attractive option for melanoma immunotherapy because it enhances the body’s own immune response to defend against tumors. It acts by inhibiting CTLA-4, which is an antigen expressed by tumor cells to quiet T-cell-mediated immunity. When impilimumab is administered to patients, T-cells are able to recognize and destroy tumor cells. Its use has been shown to be effective in treating many types of cancers during clinical trials. Its proprietary formulation is called Yervoy, and is licensed to Bristol-Myers Squibb.
