Cancer immunotherapy drugs known as “checkpoint inhibitors” are powerful new tools for treating metastatic melanoma, but physicians struggle to predict which patients will benefit from a given drug and which may suffer unnecessary toxicity. Scientists at Dana-Farber Cancer Institute, however, have discovered genetic markers for resistance to ipilumumab, the first checkpoint inhibitor approved by the Food & Drug Administration for the disease, according to a new report in the Journal Cell.
Checkpoint inhibitors target surface proteins on T cells that can act as switches preventing these immune-system cells from attacking tumors. Ipilimumab targets a protein known as CTLA-4 and was the first checkpoint inhibitor approved (on the basis of work from another Dana-Farber investigator and close collaborator on this project, F. Stephen Hodi, MD). Drugs from another class of checkpoint inhibitors that target a protein called PD-1 are also given for metastatic melanoma, sometimes in combination with ipilimumab.
Dana-Farber computational biologist Sachet Shukla, PhD, and medical oncologist Pavan Bachireddy, MD, supervised by medical oncologist Catherine Wu, MD, studied RNA expression in tumors from 146 melanoma biopsies collected by four clinical studies of checkpoint inhibitors. They found a genetic signature for resistance to ipilimumab that was not present for nivolumab, a PD-1 inhibitor.
More surprisingly, the most highly expressed genes in patients that did not benefit from ipilimumab were from a sub-family of genes known as MAGE-A that has been targeted in numerous immunotherapy clinical trials. “Our work suggests that MAGE-A genes themselves actually can suppress critical factors needed to stimulate effective responses to therapy, and may be good targets for drug development efforts,” said Wu, who is senior author on a paper in Cell about the research.
“If the findings about MAGE-A genes are validated in larger studies, they may point toward the development of clinical tools that help to select which patients should receive ipilimumab rather than other treatments,” said Shukla.
The team validated their findings by analyzing tumor samples from a prospective, randomized clinical trial that studied whether or not the order in which nivolumab and ipilimumab are given is clinically important to these patients. The researchers additionally examined a set of patients treated with anti-PD-1 therapy alone as well as genetic data from over 400 melanoma samples collected by The Cancer Genome Atlas program. The scientists again discovered that high expression of MAGE-A genes correlated with resistance to ipilumumab, but they didn’t see a similar correlation for nivolumab.
“Collectively, these results are consistent with the notion that the CTLA-4 and PD-1 pathways occupy biologically and clinically distinct niches,” said Bachireddy.
Previous work by other groups had revealed a connection between MAGE-A genes and the cell housekeeping process called autophagy, in which cells degrade certain of their own internal contents. Some cancer chemotherapies end up boosting autophagy, and other drug candidates designed specifically to heighten the process are in clinical trials. If these drug candidates prove useful, it may make sense to try combining them with ipilumumab to treat melanoma, the authors suggested.
The team acknowledged their support from collaborators. “This was a group effort, integrating our nearest neighbors like Dr. Hodi and Eliezer Van Allen, MD, both at Dana-Farber, as well as overseas colleagues in Germany and Switzerland,” emphasized Shukla and Bachireddy.
The wealth of immunotherapy clinical trials underway for melanoma will offer many further opportunities to mine genomic data to better understand which drugs work for which patients, and why, Wu added.
Other Dana-Farber authors included Rupert Langer, Patrick Lee, Daniel Gusenleitner, Derin Keskin, Clyde Bango, Zachary Cartun, Diana Miao, Ying Huang, Levi Garraway and Donna Neuberg. Contributors also included Bastian Schilling and Dirk Schadendorf of the University Duisburg-Essen; Christina Galonska of the Max Planck Institute for Molecular Genetics; Rupert Langer of the University of Bern; Qian Zhan, Christine Lian and George Murphy of Brigham and Women's Hospital; Mehrtash Babadi, Arman Mohammad, Andreas Gnirke, Kendell Clement, Alexander Meissner and Nir Hacohen of the Broad Institute; Alexandra Snyder, Taha Merghoub and Jedd Wolchok of Weill Cornell Medical College; Jeffrey Weber of New York University Langone Medical Center; and Patrick Potts of St. Jude Children's Research Hospital.
Lead funders for the research included the Blavatnik Family Foundation, the National Cancer Institute and the Damon Runyon Cancer Research Foundation.