Tasuku Honjo (Kyoto University, Japan) and James P. Allison (University of Texas MD Anderson Cancer Center, TX, USA) have been awarded the 2018 Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation.
In the 1990’s James P. Allison studied CTLA-4; he was one of several scientists who had made the observation that CTLA-4 functions as a brake on T cells. Allison realized the potential of releasing the brake and thereby unleashing our immune cells to attack tumors. Successful preclinical trials made Allison anxious to translate the concept of CTLA-4 blockade into an anticancer therapy.
In 1992, a few years before Allison’s discovery, Tasuku Honjo discovered the PD-1 protein on immune cells and, after careful exploration of its function, eventually revealed that it also operates as a brake, but with a different mechanism of action. Therapies based on his discovery proved to be strikingly effective in the fight against cancer.
Allison spent two years pitching the CTLA-4 concept to drug companies, until a small pharma company took a chance on the idea. Following testing in nonhuman primates, the antibody was advanced to clinical evaluation and assigned the generic name of ipilimumab.
The first early-stage clinical trials of ipilimumab were conducted in patients with several different tumor types, including prostate cancer, ovarian cancer and advanced melanoma. Initial results were not promising — only 10% of patients exhibited tumor regression — which was not better than any other form of immunotherapy.
Follow-up scans revealed that the response to ipilimumab is frequently delayed and that it can take 6–12 months for the immune system to mount an effective anticancer response. These effects prompted investigators to change the primary measurement of the trial to overall survival.
Promising results soon emerged from several groups and in 2004, the first placebo-controlled, randomized Phase III trial of ipilimumab in patients with metastatic melanoma began. Patients receiving gp100 in combination with ipilimumab or ipilimumab monotherapy lived 4 months longer than patients receiving gp100 alone.
These results made ipilimumab the first treatment to significantly improve survival in patients with advanced melanoma. More importantly, long-term follow-up of 5000 patients with melanoma who received ipilimumab found that 22% survived for at least 10 years. Such remarkable results had never been seen before in this patient group.
Meanwhile Tasuku Honjo and other groups demonstrated in animal experiments that PD-1 blockade was a promising strategy in the fight against cancer.
This paved the way for utilizing PD-1 as a target in the treatment of patients. Clinical development ensued, and in 2012 a key study demonstrated clear efficacy in the treatment of patients with different types of cancer.
Results were dramatic, leading to long-term remission and possible cure in several patients with metastatic cancer, a condition that had previously been considered essentially untreatable. In 2014, the PD-1 inhibitor – Opdivo® (nivolumab) – was approved by the USA FDA.
Going on from this, investigators discovered that combining the two ground-breaking therapies, in other words targeting both CTLA-4 and PD-1, was even more effective, read related news here:
• Nivolumab + ipilimumab combo approved as first-line treatment for advanced renal cell carcinoma
• ASCO15: Ipilimumab/nivolumab combination treatment shows significant improvement in response rates for advanced melanoma
• Checkmate-227: Nivolumab, ipilimumab combination succeeds in Phase III lung cancer trial
Sources: www.nobelprize.org/prizes/medicine/2018/press-release/ ; Hurst, JH, Cancer immunotherapy innovator James Allison receives the 2015 Lasker~DeBakey Clinical Medical Research Award J. Clin. Oncol. 125(10): 3732–3736 (2015)