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Melanomas that responded to pembrolizumab already contained killer T cells pressed up against tumour cells expressing PD-L1, showing that the drug works by releasing an immune attack that is already there rather than creating a new one.
Tumeh, Ribas and colleagues at UCLA studied tumour biopsies from 46 patients with metastatic melanoma before and during pembrolizumab. Responding tumours had higher densities of CD8 T cells, PD-1 and PD-L1 at the invasive margin and in the tumour before treatment, with T cells and PD-L1 in close proximity, and their T cell receptor repertoires were more clonal and expanded further on treatment. The authors proposed that PD-L1 is induced as an adaptive resistance mechanism in response to interferon from attacking T cells and that pembrolizumab reverses it.
This paper explained why PD-1 antibodies work in some patients and not others and introduced the idea of inflamed versus non-inflamed tumours that now guides combination strategies designed to bring T cells into cold tumours.
This framework is behind the everyday language of hot and cold tumours and the design of combination trials that pair checkpoint inhibitors with treatments meant to draw T cells into the tumour.
This is the standard overview of checkpoint immunotherapy for clinicians and scientists, tying together the trial results and the biology of response and resistance that guide today's combination trials.
Shares Ribas and Wolchok 2018: cancer immunotherapy using checkpoint blockade, Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer, Immune checkpoint, PD-L1.
Shares Binnewies 2018: understanding the tumour immune microenvironment for effective therapy, PD-L1, PD-1.
Shares Tumour-infiltrating lymphocytes (TILs), PD-L1, PD-1.
Shares UCLA Jonsson Comprehensive Cancer Center, PD-1, Pembrolizumab.
Shares PD-L1, PD-1, Melanoma, Pembrolizumab.
Shares Tumour-infiltrating lymphocytes (TILs), PD-L1, PD-1, Pembrolizumab.
Shares Tumour-infiltrating lymphocytes (TILs), PD-L1, PD-1.
Shares Binnewies 2018: understanding the tumour immune microenvironment for effective therapy, Tumour-infiltrating lymphocytes (TILs).