Ribas and Wolchok 2018: cancer immunotherapy using checkpoint blockade
A review by two of the field's leading trialists, written as checkpoint inhibitors reached a dozen cancers, explaining how CTLA-4 and PD-1 blockade work, why only some patients respond, and how resistance arises.
Overview
Ribas and Wolchok summarised the science and clinical results of checkpoint blockade at the point where PD-1 pathway antibodies had been approved across many cancers. They described CTLA-4 blockade as broadening the T cell repertoire and PD-1 blockade as reinvigorating exhausted T cells already in the tumour; reviewed the features of responding tumours, including mutational burden, pre-existing T cell infiltration and interferon-gamma signalling; and catalogued primary and acquired resistance mechanisms such as loss of antigen presentation and interferon signalling defects. They argued for rational combinations based on these mechanisms.
- CTLA-4 blockade acts mainly at T cell priming and broadens the repertoire; PD-1 blockade reinvigorates antigen-experienced T cells in the tumour.
- Response is associated with mutational burden, pre-existing T cell infiltration and intact interferon-gamma signalling.
- Resistance arises through loss of antigen presentation (for example beta-2-microglobulin), JAK-STAT defects and immunosuppressive microenvironments.
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.
- A review; the field has moved on with LAG-3 blockade, neoadjuvant use and new biomarkers.
- Both authors led many of the trials discussed.
Similar pages
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