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Injecting mice with an antibody that blocks the T-cell inhibitory receptor CTLA-4 caused established colon carcinomas and fibrosarcomas to be rejected and protected against re-challenge, the experiment that founded checkpoint immunotherapy.
Allison's laboratory had shown that CTLA-4 is a negative regulator of T-cell activation, opposing the co-stimulatory receptor CD28. This paper tested whether removing that brake would enhance anti-tumour immunity. Mice bearing transplantable 51BLim10 colon carcinoma or fibrosarcoma tumours were treated with anti-CTLA-4 antibodies.
Anti-CTLA-4 treatment led to rejection of established tumours, including those that were poorly immunogenic when combined with a vaccine, and treated mice were immune to a second tumour challenge. The effect did not require engineering the tumour to express co-stimulatory molecules.
The finding was met with industry scepticism, but Medarex developed the human antibody that became ipilimumab, approved for melanoma in 2011 as the first drug to extend survival in metastatic melanoma. Allison shared the 2018 Nobel Prize with Tasuku Honjo.
Every checkpoint inhibitor, from ipilimumab to pembrolizumab, rests on this idea: the immune system can already recognise cancer and just needs its brakes released. It changed the goal of immunotherapy from vaccinating against tumours to unleashing existing T cells.
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