146P - A Novel Allosteric Oral Immunotherapy Small Molecule Modulates Adenosine 2A Receptor Signaling and Restores Anti-Tumor Immune Responses

Background

Improving survival of cancer patients could be achieved by enhancing anti-tumor immunity which is frequently suppressed. Adenosine, found at high concentrations in most solid tumors, is reported to be a key mediator of immune suppression. Current drugs that target a key immune system switch, the adenosine 2A receptor (A2AR), are confronted with developmental hurdles related to their conventional (orthosteric) molecular mode of action, which cannot modulate A2AR signaling in immunosuppressive solid tumor microenvironment without safety concerns.

Methods

A drug discovery campaign at University of Geneva identified, and improved the potency of, orally bioavailable, non-brain penetrant, small molecule negative allosteric modulators (NAM) of A2AR. Optimized lead drug candidates were evaluated for safety, pharmacokinetics, and pharmacodynamics (target engagement, immune response restoration and tumor growth control) using in vitro, ex vivo, and in vivo models.

Results

A2AR NAMs displayed an excellent safety profile using industry-standard in vitro assays, and when administered to mice. The drug candidates fully restored anti-tumor cytokine secretion in primary human PBMC subsets, outperforming existing A2AR antagonists which have been tested in phase I or II human trials. A2AR NAMs were detected in mouse plasma at therapeutic concentrations after administration via the oral or subcutaneous routes. When tested in high adenosine mouse tumor models such as MC38 and CT26, A2AR NAMs significantly reduced tumor growth as a single agent immunotherapy, outperforming PD-1 immune checkpoint blockade as well as a small molecule A2AR drug candidate currently in Ph-II clinical development.

Conclusions

A2AR NAMs have an excellent safety and efficacy profile in translational assays and biologically relevant mouse tumor models, presumably stemming from their novel allosteric molecular mode of action. The drug candidates represent a next generation approach to A2AR blockade, which are intended to enhance the immune system and favor positive responses in solid tumor patients, especially when used in combination with other standard and immune-based cancer therapies.

Legal entity responsible for the study

University of Geneva.

Funding

Innosuisse.

Disclosure

D. Pejoski, H. Hamed: Financial Interests, Institutional, Member of Board of Directors: Adoram Therapeutics. M. Boujut: Financial Interests, Institutional, Stocks/Shares: Adoram Therapeutics. L. Scapozza: Financial Interests, Institutional, Advisory Role: Adoram Therapeutics. All other authors have declared no conflicts of interest.