Seminal immunologic discoveries with direct clinical implications: The 2018 Nobel Prize in Physiology or Medicine honours discoveries in cancer immunotherapy

The Nobel Assembly at Karolinska Institutet has awarded the 2018 Nobel Prize in Physiology or Medicine to two immunologists, James P. Allison and Tasuku Honjo, for their discoveries of cancer therapy by inhibition of negative immune regulation. The prize is a testimony to basic research, which in the minds of great scientists has driven clinical translation with unusual speed. In the 1990s, at the University of California, Berkeley, Allison studied the molecule CTLA-4 on T cells, a key molecule that functions as a brake on T cells.1 Having developed an antibody that could block the function of CTLA-4, Allison set out to investigate if anti-CTLA-4 antibodies could unleash restrained T cells, resulting in an attack on cancer cells. In a first set of experiment, mice with cancer were cured by treatment with the antibody.2 Despite limited interest from the pharmaceutical industry, Allison continued his efforts to develop a therapy for humans. Promising results soon emerged, and in 2010, an important clinical study showed striking effects in patients with advanced melanoma.3 In 1992, a few years before Allison's discovery, Tasuku Honjo had identified PD-1, another protein expressed on the surface of T cells.4 Determined to unravel its role, he explored its function and showed that PD-1, similar to CTLA-4, also functioned as a T cell brake. In animal experiments, PD-1 blockade emerged as a promising strategy in the fight against tumors,5 paving the way for utilizing PD-1 as a target in the treatment of cancer patients. Clinical development ensued, and a clear efficacy in patients with different types of cancer following PD-1 blockade has now been shown.6 A remarkable feature of checkpoint blockade is its capacity to induce long-term remission, and maybe even long-term cure, in patients with metastatic cancer. The clinical development is promising for patients with many types of cancers that are difficult to treat, including melanoma, lung cancer and kidney cancer. A major challenge is to understand heterogeneity in patient responses,7 but already now it is clear that checkpoint therapy, utilizing anti-CTLA-4 and/or anti-PD-1 antibodies, has revolutionized cancer immunotherapy and the way we view how cancer can be managed.