Oncology · 2018
Nobel Prize in Physiology or Medicine for cancer immune-checkpoint therapy
For most of the twentieth century, immunotherapy for cancer was a field full of promise and little delivery. Nonspecific immune stimulants, cytokines at toxic doses, and tumor-infiltrating lymphocyte transfers each produced occasional responses but no reliable benefit. The central obstacle, poorly understood at the time, was that tumors actively suppress the immune cells that infiltrate them, exploiting the same molecular brakes the immune system uses to prevent autoimmunity. The work that eventually won the 2018 Nobel Prize in Physiology or Medicine identified two of those brakes and showed that releasing them could turn T cells into effective tumor killers.
James Allison, working at UC Berkeley and later MD Anderson Cancer Center, spent the 1990s investigating CTLA-4, an inhibitory receptor expressed on T cells after activation. Other researchers viewed CTLA-4 as a signal to study; Allison saw it as a clinical target. His group showed in 1996 that injecting anti-CTLA-4 antibodies into tumor-bearing mice caused tumor regression, an observation that was initially met with skepticism by colleagues who had seen many promising murine immunotherapy results fail in humans. Independently, Tasuku Honjo at Kyoto University identified PD-1 in 1992 while studying programmed cell death and later demonstrated that the PD-1/PD-L1 axis serves as a major immune checkpoint, particularly within the tumor microenvironment.
Clinical translation of both mechanisms moved faster than most cancer drug programs. Ipilimumab, the anti-CTLA-4 antibody developed by Bristol Myers Squibb partly on the basis of Allison's work, received FDA approval for metastatic melanoma in 2011, the first agent ever to extend overall survival in that disease. Anti-PD-1 antibodies nivolumab and pembrolizumab followed in 2014, and by the time the Nobel was awarded in 2018, checkpoint inhibitors were approved for more than a dozen tumor types, including non-small cell lung cancer, renal cell carcinoma, bladder cancer, and head and neck squamous cell carcinoma.
The clinical argument for the prize was as compelling as the basic science. Five-year survival in metastatic melanoma rose from under 5% in the pre-ipilimumab era to roughly 20% with single-agent CTLA-4 blockade, and higher with PD-1 inhibitors or combination regimens. Some patients achieved durable remissions lasting years after discontinuing therapy, a pattern not seen with chemotherapy or targeted agents. The Nobel Committee's decision to award the prize just seven years after the first approval was an unusually rapid recognition, reflecting both the novelty of the mechanism and the breadth of the clinical benefit already documented across multiple tumor types.
Autoimmune toxicity emerged as the class's defining side-effect profile: colitis, pneumonitis, endocrinopathies, and hepatitis occur at rates that require systematic monitoring. Managing immune-related adverse events became a new subspecialty competency for oncologists, and protocols for steroid management and drug discontinuation are now embedded in every major cancer center's procedures.
Key People
- James Allison — Discovered CTLA-4 checkpoint blockade; shared 2018 Nobel Prize
- Tasuku Honjo — Discovered PD-1; shared 2018 Nobel Prize
- Alan Korman — BMS immunologist; developed ipilimumab from Allison's discovery
- F. Stephen Hodi — Lead investigator of the melanoma trial that supported ipilimumab approval
Read the original — PubMed Central
Nobel Assembly, Karolinska Institutet, 2018