Mutations Explain Late Progression in Pembrolizumab-Treated Melanoma
medwireNews: Researchers have identified several genetic mutations in metastatic melanoma that are behind acquired resistance to programmed death 1 (PD-1) therapy.
The team examined pairs of biopsy samples taken from four patients before they achieved an objective tumour response to single-agent pembrolizumab therapy and again after they experienced late progression, at an average of 624 days.
After pembrolizumab therapy, two patients acquired a loss-of-function mutation in the interferon receptor-associated JAK1 or JAK2 genes while also losing heterozygosity for the wild-type chromosome.
“Together, these data suggest that the tumors resistant to anti–PD-1 are a relatively homogenous population derived directly from the baseline tumor and that acquisition of the JAK mutations was an early founder event before clonal selection and relapse despite the fact that the mutation was not detected in pretreatment tumor tissue”, the authors write in The New England Journal of Medicine.
Further analysis demonstrated that the loss of JAK1 or JAK2 “selectively blocked” interferon-γ signalling required for cell-growth inhibition, they write.
The third patient was found to have a homozygous frame-shift deletion in the beta-2-microglobulin component of major histocompatibility complex (MHC) class I, resulting in loss of outer-membrane localisation.
“This finding is in line with the role of beta-2-microglobulin in proper MHC class I folding and transport to the cell surface, and its deficiency has long been recognized as a genetic mechanism of acquired resistance to immunotherapy”, explain Antoni Ribas, from Jonsson Comprehensive Cancer Center at UCLA, USA, and co-authors.
The researchers did not find any genetic mutations in the fourth patient that could explain acquired resistance to T cells. However, they note that cancer cells at both baseline and relapse did not express programmed death ligand 1 (PD-L1) despite being near T cells and PD-L1 expressing stroma.
“These findings suggest possible nongenetic mechanisms of altered expression of interferon-inducible genes”, they hypothesise.
The team concludes: “Understanding the molecular mechanisms of acquired resistance by focused comparison of biopsy samples from paired baseline and relapsing lesions may open options for the rational design of salvage combination therapies or preventive interventions and may guide mechanistic biomarker studies for the selection of patients, before the initiation of treatment, who are unlikely to have a response.”
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