Results from a new study led by researchers at NYU Langone Health and its Perlmutter Cancer Center have provided insights into why some patients with metastatic melanoma do not respond to immune checkpoint inhibitors, a common cancer treatment. The study, published in Nature Medicine, found that genetic differences in mitochondrial DNA, specifically mitochondrial haplogroup T (HG-T), are linked to resistance to these therapies.
The research involved analyzing genetic material from 1,225 patients who participated in the CheckMate-067 phase 3 trial. The findings indicated that patients with HG-T were 3.46 times less likely to respond to checkpoint drugs like nivolumab and ipilimumab compared to those without this haplogroup. Approximately 12 percent of metastatic melanoma patients possess HG-T.
Dr. Tomas Kirchhoff, senior study investigator and associate professor at NYU Grossman School of Medicine, stated: “This research fundamentally changes our understanding of mitochondrial genetics in immune response biology and personalized cancer immunotherapy.” He suggested that variations in mitochondrial DNA might also impact treatments for other cancers.
The study’s co-lead investigator Dr. Kelsey Monson emphasized the significance of identifying HG-T as a marker for predicting treatment resistance: “Our study offers the first scientific evidence of an inherited genetic marker…as a means of identifying those metastatic melanoma patients who are least likely to respond to immunotherapy treatment.”
To validate their results, researchers tested samples from an additional 675 metastatic melanoma patients treated at various cancer centers participating in the International Germline Immuno-Oncology Melanoma Consortium (IO-GEM). This confirmed the link between HG-T and immunotherapy resistance.
The study also noted that HG-T patients had more underdeveloped T cells due to increased resilience to reactive oxygen species (ROS), suggesting a protective effect against T cell attacks on tumors.
Funding for the research came from National Institutes of Health grants and support from Melanoma Research Alliance and Italian Ministry of Health grants. Pharmaceutical company Bristol Myers Squibb sponsored the CheckMate trial and provided patient specimens for analysis.
Researchers involved included Drs. Kirchhoff, Monson, Robert Ferguson, Joanna Handzlik, Leah Morales, Jiahan Xiong among others from NYU Langone. Collaborators came from institutions such as University of Pittsburgh, Memorial Sloan Kettering Cancer Center, Massachusetts General Hospital, National Tumor Institute Fondazione G. Pascale in Italy, Netherlands Cancer Institute among others.
Metastatic melanoma is responsible for nearly 10,000 deaths annually in the United States alone.
