Targeting the Aryl Hyrdrocarbon Receptor (Ahr) as a Novel Immunotherapy for the Treatment of Cancer
Current approved cancer immunotherapy treatments focus on stimulating anti-tumor T cell responses with antibodies against PD1/PD-L1 and CTLA4. However, tumor cells can also evade immune responses by upregulating tryptophan-degrading enzymes like indole-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO2) to generate the immunosuppressive metabolites kynurenine (KYN) and kynurenic acid (KA). KYN and KA bind and activate the aryl hydrocarbon receptor (AhR), which is expressed in many cell types and is well known for its broad immunosuppressive effects. Targeting the AhR with an inhibitor may therefore provide a novel immunotherapeutic approach for enhancing anti-tumoral immune responses and treating cancer.

Here we describe for the discovery and functional characterization of the first-in-class small molecule AhR inhibitor BAY 2416964. BAY 2416964 is a novel, selective and potent inhibitor of AhR that inhibits nuclear translocation of AhR and its ensuing transcriptional activity. In vitro, BAY 2416964 stimulates the pro-inflammatory activity of human T cells and KA-suppressed monocytes. In vivo, BAY 2416964 treatment inhibits tumor growth in CT26 and B16-OVA syngeneic tumor models, the latter demonstrating increases in CD8+ T cells and NK cells, and decreases in suppressive myeloid cells, in the tumor microenvironment.

Based on promising pre-clinical data, a first-in-human phase I clinical trial was initiated in 2019 in patients with advanced solid malignancies to investigate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of BAY 2416964 (CT.gov NCT04069026). Exploratory analyses include assessment of human PK; evaluation of target engagement; assessment of immune cell markers in the tumor microenvironment and profiling of an AhR gene signature. Dose escalation of BAY 2416964 is currently ongoing.
Date: 2 February 2021, 12:00 (Tuesday, 3rd week, Hilary 2021)
Venue: Venue to be announced
Speaker: Ilona Gutcher (Bayer AG)
Organisers: Elodie Siney (BioEscalator), Sheena Lee (MSD Business Partnerships Office)
Organiser contact email address: sheena.lee@medsci.ox.ac.uk
Hosts: Elodie Siney (BioEscalator), Sheena Lee (MSD Business Partnerships Office)
Part of: Industry Insight Seminar Series
Booking required?: Required
Booking url: https://www.eventbrite.co.uk/e/industry-insights-seminar-series-tickets-131313804123
Cost: Free
Audience: Members of the University of Oxford and the Biotech/Pharma industry
Editors: Sheena Lee, Elodie Siney