Inherited genetic trait predicts resistance to immunotherapy for deadly skin cancer

(Press-News.org) Tests in 1,225 patients with the most deadly form of skin cancer reveal for the first time a genetic trait among most of those who did not respond to the latest cancer treatments, known as immune checkpoint inhibitors. Metastatic melanoma, as the disease is formally named, kills nearly 10,000 Americans annually.

While the drugs have proven highly successful in treating metastatic melanoma and several other cancers, the therapies are known to not work for almost half of those who are prescribed them, usually after initial chemotherapy or surgery have failed to stem the growth of new cancer cells.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the new study involved a genetic analysis of blood samples from the ongoing landmark CheckMate-067 Phase 3 trial being conducted in over 100 medical centers in 19 countries. Study results showed that patients with a specific type of genetic mutation, called MT haplogroup T (HG-T), were 3.46 times less likely to respond to checkpoint therapy than those without HG-T.

Mutations are changes encoded in the DNA of abnormal or different cells. Researchers found the HG-T changes in immunotherapy-resistant patients’ cell powerhouse structures, or mitochondria. Mitochondrial DNA is unique in that it is passed down only from a mother to her offspring, with no genetic contribution or copy from the father, as is traditionally found in a cell’s control center, or nuclear DNA. Over time, mitochondrial DNA has evolved worldwide into subgroups labeled from A to Z based on their common mutations.

Publishing in the journal Nature Medicine online June 5, the researchers say they decided to focus on mitochondrial DNA not just because of its unique lineage but also due to previous research showing it played a role in immune cell development.

In the CheckMate trial, immunotherapy drugs, such as nivolumab, were used alone or in combination with another checkpoint inhibitor, ipilimumab, in preventing postsurgical recurrence of melanoma. The drugs work by blocking molecules (the checkpoints) that sit on the surface of immune T cells to keep them from attacking cancer cells like they would invading viruses or bacteria. The body normally uses checkpoints to recognize healthy cells, but in cancer, tumor cells have hijacked and turned off the checkpoints to evade immune system detection. Immunotherapies block checkpoints, making cancer cells more “visible” and vulnerable again to immune cells.

To validate their CheckMate findings, researchers then checked their initial results against samples from 397 metastatic melanoma patients of similar age and gender, whose immunotherapy treatment records were stored at NYU Langone as part of the International Germline Immuno-Oncology Melanoma Consortium (IO-GEM). Results again revealed the same link of immunotherapy resistance to HG-T.

“Checkpoint immunotherapy has become the mainstay in cancer care in the past decade, especially for those with metastatic melanoma, but until now it has never been clearly explained why nearly half will not respond to treatment,” said study co-lead investigator and epidemiologist Kelsey Monson, PhD.

“Our study results offer the first scientific evidence of a genetic biomarker, or presence of a mitochondrial mutation known as MT haplogroup T, to help explain why and identify those metastatic melanoma patients who are most likely to not respond to immunotherapy for the disease,” said study co-lead investigator and molecular biologist Robert Ferguson, PhD.

“Our findings make possible future testing for the presence of MT haplogroup T to determine which metastatic melanoma patients are most likely to not respond to checkpoint therapy, so other treatment options can be considered, which in turn could improve overall outcomes,” said senior study investigator Tomas Kirchhoff, PhD.

“These study results also raise the possibility that other mitochondrial haploid variants could influence which patients respond to other immune therapies,” said Kirchhoff, an associate professor in the Department of Population Health at NYU Grossman School of Medicine and a member of the Perlmutter Cancer Center.

Among the study’s other key findings was that treatment-resistant HG-T patients had more underdeveloped T cells than nonresistant patients without HG-T. Researchers traced this poor differentiation to increased resilience to reactive oxygen species (ROS), chemicals commonly linked to inflammation, suggesting that HG-T conferred some form of ROS protection that stunted T cell attack.

Kirchhoff says that further experiments are needed to determine the precise role played by mitochondrial genetics, ROS metabolism, and antitumor T cell immunity in cancer therapy. The more immediate next step is a prospective clinical trial to assess whether non-HG-T patients fare better on immunotherapy than patients with HG-T, and whether this applies to other mitochondrial haplogroups and cancers.

Funding for the study was provided by National Institutes of Health grants R01CA227505, F99CA274650, P50CA225450, and P30CA008748, with additional support from Melanoma Research Alliance grant MRA-686192. Further funding support was provided by Italian Ministry of Health Ricerca Corrente grants M2/2 and L1-2. Both drugs used in the CheckMate trial are manufactured by the pharmaceutical company Bristol Myers Squibb, which sponsored the trial and provided the patient specimens and data used in the analysis.

Besides Monson, Ferguson, and Kirchhoff, NYU Langone researchers involved in this study are co-investigators Joanna Handzlik, Leah Morales, Jiahan Xiong, Vylyny Chat, Sasha Dagayev, Alireza Khodadadi-Jamayran, Danny Simpson, Esther Kazlow, Anabelle Bunis, Chaitra Sreenivasaiah, Malid Ibrahim, Iryna Voloshyneya, Yuting Lu, Yongzhao Shao, Michelle Krogsgaard, Janice Mehnart, and Iman Osman.

Other study co-investigators are Wouter Ouwerkerk and Rosalie Luiten, at Amsterdam University Medical Center in the Netherlands; Mariaelena Capone, Gabriele Madonna, and Paolo Ascierto, at the National Tumor Institute Fondazione G. Pascale in Naples, Italy; Anna Pavlick and Hao Tang, at Weill Cornell Medicine in New York; John Haanen, at the Netherlands Cancer Institute in Amsterdam; Sonia Dolfi and Daniel Tenney at Bristol Myers Squibb in Princeton, New Jersey; Thomas Gajewski, at the University of Chicago; Stephen Hodi and Osama Rahma, at Dana-Farber Cancer Institute in Boston; Keith Flaherty and Ryan Sullivan, at Massachusetts General Hospital and Harvard University in Boston; Kasey Couts and William Robinson, at the University of Colorado in Aurora; Igor Puzanov, at Roswell Park Comprehensive Cancer Center in Buffalo, New York; Marc Ernstoff, at the National Cancer Institute in Bethesda, Maryland; Michael Postow, at Memorial Sloan Kettering Cancer Center in New York; and Jason Luke, at the University of Pittsburgh in Pennsylvania.

 

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