We all know that our body uses our immune system to protect ourselves from various infections but did you know that the same immune system that fights off a nasty winter cold can also be used to cure cancer? That is the rationale behind so-called immuno-oncology drugs such as Merck and Co Inc’s Keytruda and Bristol-Myers Squibb Co’s Opdivo. These drugs, which have already achieved blockbuster sales, fundamentally changed the way we treat cancer. Unlike traditional chemotherapies, which are generally directly toxic to cells and are associated with substantial side effects, immuno-oncology drugs indirectly attack tumor cells by stimulating killer T cells, a type of immune cell which can specifically recognize and kill abnormal cells. However, while the therapeutic effects of these drugs, which can last for many years, are characteristically longer than other types of cancer therapies, unfortunately, a significant proportion of patients still do not respond to the drugs for various reasons.
One of the suspected culprits for resistance to immunotherapy came from a rather surprising place: amino acid metabolism. In fact, the observation that cancers cells have abnormal metabolism was made almost a century ago and was highlighted in 1929 by the German physiologist and doctor Otto Heinrich Warburg, who later went on to win the Nobel prize for this work. More recent advances in our understanding of the role of metabolism and its effect on the immune system led to the discovery that decreases in the level of an amino acid, tryptophan, in a tumor can result in the activation of regulatory T cells, a type of immune cell that inhibits the ability of killer T cells to function. Therefore, researchers hypothesized that inhibiting an enzyme called IDO, which degrades tryptophan in the vicinity of cancers might help to increase the response rates to immunotherapy. Doctors and investors around the world had thus been eagerly awaiting the clinical trial results from the most advanced IDO inhibitor in development, epacadostat (discovered by the U.S. biotech company Incyte Corp). Indeed, the results presented at the annual American Society of Clinical Oncology meeting earlier this month did not disappoint. Across a wide variety of cancers, including certain types of lung and skin cancers, epacadostat was able to improve the clinical response rates compared to historical results seen with Keytruda and Opdivo.
Admittedly, there is still space for improvement. Based on the observation that deprivation of the amino acid arginine in tumors can also reduce T cell activity, Incyte is now conducting early clinical trials to assess whether inhibition of the arginase enzyme (which degrades arginine) could also improve the outcomes of immunotherapy. IDO and arginase inhibitors are also expected to be tested in combination in the future. Given the outstanding results seen from epacadostat, we have high conviction that this drug could become a blockbuster in the future. We further eagerly await the clinical trial results of molecules that modulate metabolic pathways to improve clinical responses to immunotherapy – each of them offering new hopes to cancer patients and attractive opportunities to investors.
Tasuku Kitada Ph.D., Senior Biotechnology Analyst
Servaas Michielssens Ph.D., Senior Biotechnology Analyst