Genome Sequencing Explains Resistance to CTLA-4 and PD-1 Inhibitors in Metastatic Melanoma
Researchers assessed tumor samples to better understand why CTLA-4 and PD-1 inhibitors are only effective in some patients with melanoma.
Whole-exome sequencing of tumor biopsies from metastatic melanoma taken before, during, and after treatment with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) revealed loss of multiple tumor-suppressing genes. These genes affect the immune response to immunotherapy and lead to resistance to CTLA-4 and PD-1 inhibitors.1
Researchers assessed tumor samples from 56 patients to better understand why CTLA-4 and PD-1 inhibitors are only effective in 20% to 30% of patients. Results suggest analysis of loss of blocks of the genome could serve as a novel predictive indicator for response to therapy.
Although the researchers report no obvious correlation between mutations in cancer genes or other genes and immune response in these patients, they discovered genomic patterns that could be indicative of therapeutic response.
Melanoma tumors with higher mutational load could provide more targets on which the immune system can act and could make such tumors more sensitive to immune checkpoint inhibition. Combining mutational load and copy number loss could improve predictive models of patient response.
Next, the researchers stratified a different set of patients by low or high copy number and by low or high mutational load. In total, 11 of 26 patients with high mutational load and low copy loss experienced clinical benefit from immune checkpoint inhibition. Only 4 of 26 patients with low mutational load and high copy loss experienced therapeutic benefit.
In this trial, patients first received the immune checkpoint inhibitor ipilimumab, which inhibits CTLA-4 on T cells allowing them to attack the cancer.
Patients with disease refractory to CTLA-4 inhibition received the anti-PD-1 nivolumab, which inhibits a second checkpoint on T cells.
Genomic analysis of 9 biopsies from patients refractory to both drugs revealed high copy number loss. Specifically, these tumors had repeated loss of blocks of chromosomes 6, 10, and 11. These blocks contain 13 known tumor-suppressor genes.
Analysis revealed that treatment with ipilimumab, even when it fails, improves the chances that a patient will respond to nivolumab. In a group of 8 patients treated with ipilimumab, 3 who later responded to nivolumab showed T-cell activation after ipilimumab. Only 1 of the 5 refractory patients showed similar T-cell activation.
1. Roh W, Chen PL, Reuben A, et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med. 2017 Mar 1. doi: 10.1126/scitranslmed.aah3560 [Epub ahead of print]