IDO1 - An intracellular target for cancer therapy
The mechanism by which IDO1 activity is associated with poor prognosis in cancer may be explained in that T cell function can be suppressed by both tryptophan depletion and by the presence of kynurenine.4 Tryptophan depletion can lead to accumulation of uncharged tryptophan transfer RNA (tRNA). Uncharged tRNA is sensed by the stress response kinase general control nonderepressible 2 (GCN2), which impairs T cell activation in microenvironments with high IDO1 activity.5 In addition to suppression of T cell activation though tryptophan depletion, kynurenine is a key signaling molecule that promotes transcription of immunosuppressive mediators and development of regulatory T cell populations.6
Together, these effects allow cells that overexpress IDO1 to evade immune surveillance. Consequently, developing therapies that target the IDO1 pathway may provide novel anti-cancer treatment options since a significant portion of cancer patients do not respond to traditional therapies.6 Combining an IDO1 inhibitor with a second treatment modality may expand the responsive patient pool since IDO1 inhibitors can enhance the efficacy of other cancer treatments such as chemotherapy, radiotherapy, and immune checkpoint therapy without increasing their side effects.7,8
Unlike cell-surface checkpoint receptor molecules that can be targeted by antibody-based therapeutics, IDO1 and its downstream effectors are intracellular. Additionally, IDO1 is a single chain catalytic enzyme with a well-defined biochemical action and is one of only a few enzymes which catabolize tryptophan.6 Together, these properties make IDO1 a good target for small molecule inhibitors.
The first generation small molecule IDO1 inhibitors have failed to demonstrate significant anti-tumor activity when provided as a monotherapy in patients with advanced cancers.9 However, more significant response has been observed when IDO1 inhibitors have been combined with an immune checkpoint inhibitor, with the most profound responses seen in renal cell carcinoma, squamous cell cancer of the head and neck, non-small cell lung cancer, and melanoma.6 Multiple distinct small molecule IDO1 inhibitors are currently in clinical development.