Promising clinical responses in patients with various cancer types have recently been achieved with checkpoint blockade immunotherapies, which work by reawakening the immune system’s response to tumours. Five new studies published in this week’s Nature expand the number of cancers now known to respond to this type of therapy and provide some insight into the tumour characteristics that correlate with effective responses.
Immune checkpoints are inhibitory pathways that dampen or block ongoing immune responses. Immune checkpoint blockade therapies are designed to block or inhibit these inhibitory pathways. Targeting one such inhibitory pathway, the PD-1 pathway (by blocking the PD-1 receptor itself or the protein it recognizes, the PD-L1 ligand) leads to disinhibition of a type of immune cell called T cell, allowing it to attack and kill cancer cells.
Two papers, by Thomas Powles and colleagues and Roy Herbst and colleagues, describe data from phase one clinical trials with an antibody that blocks the PD-L1 ligand. The Powles group shows that this treatment is effective in patients with metastatic urothelial bladder cancer, for which there have been no major treatment advances in the past 30 years. Herbst and colleagues demonstrate that checkpoint blockade produces durable responses in patients with forms of lung, skin and kidney cancer, among other tumour types, and identify biomarkers linked to treatment responses. A separate study by Antoni Ribas also identifies biomarkers to predict treatment response by analysing samples of tumour tissue taken during treatment with an antibody blocking the PD-1 receptor. Tumours that express PD-L1, and tumours that have attracted CD8 T cells and other immune cells expressing PD-1 and PD-L1, are shown to have enhanced sensitivity to checkpoint blockade with these antibodies.
Two more papers, by Lélia Delamarre and colleagues and Robert Schreiber and colleagues show that, in mouse models, the infiltrating T cells responding to the cancer often recognize proteins in the tumour that have been altered by mutations (making them look ‘foreign’ and ‘dangerous’ to T cells which have otherwise learned not to respond to ‘self’). Both studies devise strategies by which mutant determinants that are recognized by the immune system can be identified. Being able to identify mutant tumour peptide antigens might help identify those subjects more likely to benefit from checkpoint blockade therapies. Mutant peptides might also eventually be used to generate personalized cancer vaccines.
Authors of the scientific papers:
Thomas Powles (Queen Mary University of London, UK) Author paper  DOI: 10.1038/nature13904
Roy Herbst (Yale School of Medicine, New Haven, CT, USA) Author paper  DOI: 10.1038/nature14011
Antoni Ribas (University of California, Los Angeles, CA, USA) Author paper  DOI: 10.1038/nature13954
Lélia Delamarre (Genentech, South San Francisco, CA, USA) Author paper  DOI: 10.1038/nature14001
Robert Schreiber (Washington University School of Medicine, St Louis, MO, USA) Author paper  DOI: 10.1038/nature13988
Jedd Wolchok (Memorial Sloan Kettering Cancer Center, New York, NY, USA) N&V author