L: Tasuku Honjo; R: James Allison

Two scientists whose research led to the development of one of the most important therapeutic modalities in cancers have won the Nobel Prize for the their efforts.

James Allison of The University of Texas MD Anderson Cancer Center and Dr. Tasuku Honjo of the Kyoto University School of Medicine will share the Nobel Prize for Physiology or Medicine.

Starting in the 1990s, while at the University of California Berkeley, Allison led a team of scientists who discovered through preclinical research that inhibiting the immune checkpoint CTLA-4 in mice would unlock the ability of T cells to attack cancer cells. Around the same time, Honjo discovered a similar role for another immune checkpoint, PD-1.

Despite CTLA-4 inhibition being curative in the mice, the drug industry initially showed little interest in Allison’s research, but he continued it, and it eventually was shown to be effective in humans as well. Honjo discovered the role of PD-1 a few years earlier, in 1992,

The Food and Drug Administration approved the first CTLA-4 inhibitor, Bristol-Myers Squibb’s Yervoy (ipilimumab), for unresectable or metastatic melanoma in 2011. It subsequently approved Merck & Co.’s Keytruda (pembrolizumab) for melanoma following Yervoy and other drugs. It then approved BMS’ PD-1 inhibitor, Opdivo (nivolumab), in 2015, for a similar melanoma indication as Keytruda plus non-small cell lung cancer following chemotherapy.

Since then, all three drugs have become some of the world’s top sellers. Global 2017 sales of Yervoy and Opdivo were $1.2 billion and $4.9 billion, according to BMS’ annual report. Keytruda had sales of $3.8 billion, according to Merck’s annual report.

Additionally, other immune checkpoint inhibitors have also won approval, particularly PD-L1 inhibitors, including Roche’s Tecentriq (atezolizumab), Pfizer’s Bavencio (avelumab) and AstraZeneca’s Imfinzi (durvalumab). While PD-1 is expressed on the surfaces of activated T cells, PD-L1 is a ligand of PD-1 activated on the surface of macrophages or dendritic cells. AstraZeneca is also developing a CTLA-4 inhibitor, tremelimumab, for use in combination with Imfinzi. Another company, Akrevia Therapeutics, announced last week that it closed a $30 million Series A financing round to develop its own CTLA-4 inhibitor, which it hopes will overcome the immune toxicity of Yervoy.

Photo: III. Niklas Elmehed, Nobel Media