Preventing tumor cells from evading the immune response
The indoleamine 2,3-dioxygenase (IDO) pathway regulates immune response by suppressing T cell function and enabling local tumor immune escape. NewLink Genetics has two differentiated product candidates that target the IDO pathway. Indoximod is most advanced with multiple phase 2 trials across various cancer indications. Additionally, NLG802, which is a prodrug of indoximod, entered the clinic in 2017.
IDO immune checkpoint
Tumor cells may hide from the immune system by using the IDO pathwayIDO is one of several immune modulators involved in tumor immune escape. Increased IDO expression by antigen-presenting cells (APCs) leads to tryptophan depletion, resulting in antigen-specific T cell anergy and regulatory T cell recruitment.
IDO degrades the essential amino acid tryptophan into kynurenine, which activates regulatory T cells (Tregs) and inactivates effector T cells.
Activated Tregs spread throughout the body and suppress the immune response to tumor antigens.
A lack of activated effector T cells allows the tumors to grow unchecked by the immune system.
IDO checkpoint inhibition
Reprogramming the immune response to cancer4-6
Inhibition of the IDO pathway allows tumors to be “seen” when the immune system is activated by therapies such as anti-PD-1 agents, cancer vaccines, chemotherapy and other anti-cancer agents. IDO pathway inhibitors may therefore prove useful in combination with other therapeutic approaches to cancer.
A Unique Mechanism with a Broad Spectrum of Potential Clinical Utility
The IDO pathway comprises all the functions that lead to IDO transcriptional, translational and post-translational regulation, as well as the tryptophan sufficiency and deficiency sensors and kynurenine sensing mechanisms, shared across multiple immune cells.
lndoximod is an orally available tryptophan mimetic with immuno-activating and anti-neoplastic activities, which inhibits the IDO pathway by:
- • Counteracts immunosuppressive effects of kynurenine.7
- • Activates multiple immune cells (effector cells)8
- • Prevents activation of regulatory T cells (Tregs)5
- • Reprograms Tregs into helper T cells5
1. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. Inhibition of indoleamine 2,3 dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005;11(3):312-319. 2. Munn DH. Blocking IDO activity to enhance anti-tumor immunity. Front Biosci (Elite Ed). 2012;4:734-745. 3. National Institutes of Health. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=indoximod&Search=Search. Accessed October 3, 2015. 4. Sharma MD, Hou D-W, Liu Y, et al. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood. 2009;113(24):6102-6111. 5. Sharma MD, Hou D-W, Baban B, et al. Reprogrammed Foxp3+ regulatory T cells provide essential help to support cross-presentation and CD8+ T cell priming in naive mice. Immunity. 2010;33(6):942-954. 6. Mautino M, Link C, Vahanian N, et al. Synergistic antitumor effects of combinatorial immune checkpoint inhibition with anti-PD-1/PD-L antibodies and the IDO pathway inhibitors NLG-919 and indoximod in the context of active immunotherapy. Poster presented at: American Association for Cancer Research, April 18-22, 2015, Philadelphia, PA. 7. Metz R, et al. Oncoimmunology. 2012;1(9):1460-1468. 8. Holmgaard RB, et al. Cell Reports. 2015;13(2):412-424.