Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

2077 - An oral dual inhibitor of IDO and TDO enhances anti-cancer immunity and synergizes with immune checkpoint blockade

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Topics

Clinical Research

Tumour Site

Presenters

Chan Kim

Citation

Annals of Oncology (2018) 29 (suppl_8): viii400-viii441. 10.1093/annonc/mdy288

Authors

C. Kim1, N.K. Lee2, J.S. Kim3, W.R. Kim4, D.H. Kim5, D.J. Kim6, J.S. Oh5, S.K. Chang7, J.W. Kim4, H.J. Chon2

Author affiliations

  • 1 Medical Oncology, Bundang Cha Medical Center, 13496 - Seongnam/KR
  • 2 Medical Oncology, Bundang Cha Medical Center, Seongnam/KR
  • 3 Research Department, CMG pharmaceutical, Seongnam/KR
  • 4 Surgery, CHA Bundang Medical Center, Seongnam/KR
  • 5 Internal Medicine, CHA Bundang Medical Center, Seongnam/KR
  • 6 Radiology, CHA Bundang Medical Center, Seongnam/KR
  • 7 Radiation oncology, Bundang Cha Medical Center, Seongnam/KR
More

Resources

Abstract 2077

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Funding

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.

Editorial Acknowledgement

Disclosure

J.S. Kim: Employee of the CMG Pharmaceutical. All other authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.