Five years ago, the company developing the medicine epacadostat ended its late-stage clinical trial. This immunotherapy appeared to be ineffective in patients with melanoma, an aggressive form of skin cancer. Daniel Peeper’s research group recognized an interesting link to their own research into the immune system and melanoma. They decided to use their expertise to investigate why this drug failed.
Epacadostat inhibits the IDO1 protein. This serves to protect the immune cells in the tumor, allowing them to eliminate the cancer cells. But as it turned out, the effect of this inhibitor was more complex than expected. Other clinical trials with these types of inhibitors were terminated as well.
The researchers from the Netherlands Cancer Institute have now discovered that the medicine protects not only the immune cells, but also the cancer cells. IDO1 causes a deficiency of the amino acid tryptophan, which inactivates immune cells. IDO1-inhibitors repair this shortage and thereby protect immune cells. But the researchers discovered that tryptophan deficiency also harms cancer cells; thus, the medicine adversely protects the cancer cells, too. This undesirable effect had not been noted before, although scientific papers from the eighties predicted that this could happen.
One interesting player in this process is a protein known as MITF. The activity of this protein correlates with melanoma susceptibility to immune cell killing in cancer patients as well as cultured cells in the lab. MITF could be a new target for a therapy, but there is no specific inhibitor available yet.
Companies and institutes conduct a lot of research into new immunotherapies and combinations of those drugs. Although the investigators do not claim that their finding is the only reason for the trial failure, the new research by Daniel Peeper’s group does underline the importance of investigating thoroughly how such new therapies work.
This research was financially supported by KWF Dutch Cancer Society and Oncode Institute.