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 is researching two IDO pathway inhibitors—GDC-0919 (in partnership with Genentech)* and indoximod—small-molecule product candidates that have the potential to disrupt mechanisms by which tumors evade the immune system.1-3
IDO immune checkpoint
Tumor cells may hide from the immune system by using the IDO pathwayIDO is one of several immune response checkpoints that may be 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 cancer through checkpoint inhibition4-6
Inhibition of the IDO pathway allows tumors to be “seen” when the immune system is activated by therapies such as chemotherapy, vaccines, and other checkpoint inhibitors. IDO pathway inhibitors may therefore prove useful in combination with other therapeutic approaches to cancer.
NewLink Genetics’ indoximod and GDC-0919* each have a distinct mechanism of action within the IDO pathway and are in phase 1 and 2 clinical trials for a range of cancers, including breast cancer, melanoma, and other solid tumors.7
IDO pathway inhibitors reprogram immune cells, allowing effector T cells to activate and proliferate
|Indoximod interferes with the signaling by tryptophan degradation in effector T cells and Tregs.3|
|GDC-0919 directly inhibits IDO enzymatic activity.|
|· Tregs are transformed into helper-like T cells
· Suppressive dendritic cells are transformed into immunostimulatory dendritic cells3
*Licensed by Genentech, Inc.
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. Data on file. NewLink Genetics.