FEB 27, 2023 3:00 AM PST

Safety of an AHR Inhibitor Demonstrated in Early Phase Clinical Trial

WRITTEN BY: Katie Kokolus

A study presented in November at the Society for Immunotherapy of Cancer 37th Annual Meeting and published in the Journal for Immunotherapy of Cancer shows early data from a phase 1a/b trial evaluating a new therapeutic regimen.  The study looked at the efficacy of an aryl hydrocarbon receptor (AHR) inhibitor called IK-175 administered alone as a monotherapy and combined with the immune checkpoint inhibitor (ICI) nivolumab

AHR, a transcription factor found in many cell types throughout the body, plays a vital role in the immune response.  Upon binding to ligands, such as kynurenine , a metabolite of the amino acid tryptophan, AHR activation regulates genes that promote suppression of the immune response.  Thus, preventing binding between AHR and kynurenine would promote immunity.  Researchers have developed the oral drug IK-175 to inhibit AHR binding its ligands with the intention to reduce immunosuppression subsequently. 

The researchers indicated that previous studies had shown high AHR signaling in urothelial carcinoma, the most common type of bladder cancer.  Based on this, urothelial carcinoma patients became a promising cohort to test IK-175. 

The study (NCT04200963) recruited adult patients with unresectable urothelial carcinoma.  All participants had recurrent or metastatic disease that had progressed after receiving standard-of-care treatments.  The urothelial cancer patients enrolled in the study had received several lines of therapy before the study, characterizing them as “heavily pretreated.”  Further, all participants had failed ICI treatment with a PD-1 or PD-L1 inhibitor within 12 weeks of beginning the trial. 

The analysis presented included 22 patients, 11 who received IK-175 monotherapy and 11 who received IK-175 in combination with nivolumab.  Three patients experienced partial responses, which, at the time of publication, had already lasted almost a year.  The authors concluded that patients tolerated IK-175, alone and in combination with PD-1 inhibition, suggesting it is a safe approach for further investigation.  The promising data presented at the meeting has led to ongoing evaluations to validate the efficacy of IK-175 as both a monotherapy and combination therapy. 

In addition to testing IK-175 in urothelial carcinoma patients, the researchers included other patients with solid tumors in the study.  The drug, alone and in combination, also appeared safe in the larger population of the study. 


Sources: Trends Immunol, JITC, clinicaltrials.gov

About the Author
Doctorate (PhD)
I received a PhD in Tumor Immunology from SUNY Buffalo and BS and MS degrees from Duquesne University. I also completed a postdoc fellowship at the Penn State College of Medicine. I am interested in developing novel strategies to improve the efficacy of immunotherapies used to extend cancer survivorship.
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