AhR Antagonist Program

To thwart the effects of kynurenine and other immunosuppressive aryl hydrocarbon receptor (AhR) agonists, IDEAYA has generated a series of highly potent and selective AhR small-molecule antagonists. In vivo, our AhR antagonists demonstrate significant tumor growth inhibition in syngeneic mouse models accompanied with:

  • Reduction in tumor associated macrophages;
  • Decrease in tumor FoxP3+CD4+ T-cells;
  • Increase in tumor infiltrated activated CD8 T-cells.

In vitro, our antagonists potently inhibit AhR-driven expression of CYP1A1 and CYP1B1 in human PBMCs and mouse splenoyctes. Inhibition of AhR is accompanied with enhanced production of IFNg and TNFa by human PBMCs. On-going studies to further define the specific immune cell subsets and pathways modulated by IDEAYA’s AhR antagonists are currently underway.

AhR Biology

The aryl hydrocarbon receptor (AhR) is a helix-loop-helix ligand-activated transcription factor that mediates biological responses to chemically diverse aromatic hydrocarbons. In absence of a ligand, AhR is localized in the cytoplasm in a complex with chaperones such as HSP90. Upon binding to agonist ligand, AhR translocates to the nucleus and forms a heterodimer with aryl hydrocarbon receptor nuclear translocator (ARNT). Formation of the AhR/ARNT complexes subsequently enables binding to xenobiotic response element (XRE) to regulate gene transcription AhR can also activate a non-XRE dependent protein-protein interaction pathway.

Through its XRE-dependent and independent activity, AhR modulates numerous critical innate and adaptive immune responses (Gutiérrez-Vázquez et al, 2018). Chief among those responses, AhR agonists promote development of IL-17 producing T-helper cells (Th17) and regulatory T-cells (Tregs). AhR activation further induces trans-differentiation of Th17 cells to Tregs and enhances the suppressive activity of Tregs. Studies have also demonstrated that AhR agonism results in suppression of innate inflammatory responses mediated by macrophages (e.g. reduced LPS-induced IL-1b, IL-6, IL-12 and TNFa expression) and dendritic cells (DCs) (inhibits activation of DCs and promotes expression of IL-10).

The Kynurenine Pathway and Immune Escape

AhR and Cancer

Cancer cells utilize a variety of genetic and environmental pathways to generate an immune permissive growth environment and evade the host anti-tumor immune response. A critical pathway involves increased metabolism of amino acids such as tryptophan (Trp) and arginase resulting in dampening T-cell activity via activation of amino acid sensing receptors and generation of immuno-modulating metabolites, a process referred to as immuno-metabolism.

Production of T-cell inhibitory Trp metabolites, kynurenine (KYN) and kynurenic acid, via up-regulation of indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO2), has recently been demonstrated to down-regulate generation of a productive anti-tumor immune response. Recent data has revealed that KYN and related TRP metabolites are bone fide AHR agonists and that AHR function is required to elicit KYN immunosuppressive effects in infiltrating lymphoid and myeloid cells. Through AhR activation, KYN both directly and indirectly, via stimulation of regulatory T-cells (Tregs), dendritic cells (DCs) and tumor-associated macrophages (TAM), modulates CD8+ and CD4+ T-cell function resulting in potent inhibition of anti-tumor immunity. Inhibition of AhR activation therefore represents a novel approach to blocking the inhibitory immuno-metabolic effects of Trp metabolites generated by endogenous IDO1 and TDO2. An antagonist of the AhR pathway would therefore block the AhR-dependent immune evasion mechanisms employed by malignant cells and restore effective anti-tumor immunity across a broad range of cancer indications.

The importance Trp-dependent immuno-metabolism towards potentiation of immune check point therapy has recently been highlighted in clinical trials of IDO1 inhibitors INCB024360 (NCT01195311) and BMS-986205 (NCT02658890). However, analysis of pharmacodynamic data in both trials revealed a maximum reduction in circulating KYN levels of ~50% with INCB024360 or BMS-986205, suggesting that other enzymes such as TDO2 may be critical for generation of KYN in the cancer setting. TDO2 has been observed across numerous cancer types and is often but not always co-expressed with IDO1. A recent publication demonstrated that ~40% of tested colorectal cancer samples co-expressed both IDO1 and TDO2 (Chen et al, 2016).

Because KYN acts directly on AhR to modulate anti-tumor immunity, by inhibiting AhR we can fully block the effects of KYN, irrespective of the source of Trp metabolism (e.g. IDO1, TDO2, bacterial enzymes). AHR antagonism also has the potential to block the immune suppressive effects of non-Trp derived AhR agonists. Through this approach, we can therefore expect a more effective release of the break on the anti-tumor immune response in IDO1+, TDO2+ and IDO1+/TDO2+ tumors.

Combination with Other IO Agents

Recent insights into tumor immunobiology has revealed that malignant cells employ a composite of immune-evasion mechanisms. Blocking or enhancing these mechanisms through a combination of therapeutic applications such as immune check point inhibition and vaccines has been demonstrated pre-clinically and clinically to provide an optimal restoration of the anti-tumor immune response. While it is expected that AhR antagonism in monotherapy will restore anti-tumor immunity, a combination of an AhR antagonist with a check point inhibitor and/or vaccine is predicted to work in concert with other therapeutics to potentiate the immunotherapeutic response.