期刊
CLINICAL CANCER RESEARCH
卷 25, 期 5, 页码 1462-1471出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-2882
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资金
- Incyte Corporation
- Department of Defense Career Development Award [W81XWH-17-1-0265]
- National Cancer Institute [P30CA014599-43S]
- Arthur J Schreiner Family Melanoma Research Fund
- J. Edward Mahoney Foundation Research Fund
- Brush Family Immunotherapy Fund
- Center for Research Informatics of The University of Chicago Biological Science Division
- Institute for Translational Medicine/CTSA [NIH UL1 RR024999]
Significant progress has been made in cancer immunotherapy with checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)-programmed death-ligand 1 signaling pathways. Tumors from patients showing sustained treatment response predominately demonstrate a T cell-inflamed tumor microenvironment prior to, or early on, treatment. Not all tumors with this phenotype respond, however, and one mediator of immunosuppression in T cell-inflamed tumors is the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) pathway. Multiple mechanisms of immuno-suppression may be mediated by this pathway including depletion of tryptophan, direct immunosuppression of Kyn, and activity of Kyn-bound AhR. Indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in Trp catabolism, is the target of small-molecule inhibitors in clinical development in combination with PD-1 checkpoint inhibitors. Despite promising results in early-phase clinical trials in a range of tumor types, a phase III study of the IDO1-selective inhibitor epacadostat in combination with pembrolizumab showed no difference between the epacadostat-treated group versus placebo in patients with metastatic melanoma. This has led to a diminution of interest in IDO1 inhibitors; however, other approaches to inhibit this pathway continue to be considered. Novel Trp-Kyn-AhR pathway inhibitors, such as Kyn-degrading enzymes, direct AhR antagonists, and tryptophan mimetics are advancing in early-stage or preclinical development. Despite uncertainty surrounding IDO1 inhibition, ample preclinical evidence supports continued development of Trp-Kyn-AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.
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