Indolamine 2,3-dioxygenase (IDO) blockade is a new therapeutic strategy to enhance cancer immunity. However, IDO blockade alone cannot completely block the immunosuppressive tryptophan-kynurenine (Trp-Kyn) pathway in the tumor microenvironment. Recent studies have demonstrated that Trp 2,3-dioxygenase (TDO) is an alternative enzyme employed by various tumors that can be used as a target for the Trp-Kyn pathway; therefore, here we developed an orally available dual inhibitor that targets IDO and TDO.
Small-molecule inhibitors for IDO and TDO were synthesized and screened by in vitro IDO/TDO enzyme and cell-based assays. CT26 colon or 4T1 breast tumor-bearing mice were treated with CB548 either alone or in combination with an anti-PD1 antibody. We monitored tumor growth and analyzed the tumor microenvironment using flow cytometry, qPCR, and confocal microscopy.
A lead compound, CB548, showed potent inhibition of IDO and TDO in the enzyme and cell-based assays with various human and murine cancer cell lines. Oral administration of CB548 revealed a good pharmacokinetic profile, and the conversion of Trp to Kyn in tumors was effectively suppressed. Moreover, the CB548 monotherapy revealed a dose-dependent inhibition of CT26 colon or 4T1 breast cancer growth as well as markedly increased CD8+ T cell infiltration in the tumor microenvironment. Additionally, the combination immunotherapy of CB548 and anti-PD1 antibody suppressed tumor growth to a greater extent than did the monotherapy, and led to durable tumor regression. There was no significant systemic toxicity with the CB548 treatment.
Overall, our study demonstrates that CB548, a novel IDO/TDO dual inhibitor, can elicit a robust anti-cancer immunity and synergistically inhibit cancer progression in combination with an immune checkpoint inhibitor.
Clinical trial identification
Legal entity responsible for the study
CHA Bundang Medical Center.
This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science & ICT of Republic of Korea.
J.S. Kim: Employee of the CMG Pharmaceutical. All other authors have declared no conflicts of interest.