P2, N=30, Active, not recruiting, Washington University School of Medicine | Trial completion date: Jun 2030 --> Dec 2030 | Trial primary completion date: Apr 2026 --> Oct 2026

Simultaneous blockade of the downstream effects mediated by both receptor subtypes with a dual inhibitor has the potential to reverse adenosine-mediated suppression of tumor immune surveillance as either a single-agent treatment or in combination with other immunotherapy agents such as anti-PD-1/PD-L1 monoclonal antibodies. This publication describes the discovery and optimization of a novel series of potent and selective dual A2AR/A2BR antagonists, resulting in compound 46 (MK-1088) being identified for progression to human clinical studies.

Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.

The A2AR-SPAK (SPS1-related proline/alanine-rich kinase)-PI3K (phosphoinositide 3 kinase)-Akt (protein kinase B)-NF-κB (a nuclear factor)-ATP1A2 (a Na+,K+-ATPase) pathway was suggested to be instrumental in hydrocephalus development. The clinically important conclusion deriving from this observation was that A2AR blockade by istradefylline, a Food and Drug Administration-approved drug could be introduced into the therapy of human hydrocephalus.

P2, N=10, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=20 --> 10

Single-cell analysis revealed distinct functional subpopulations of macrophages and T cells, highlighting the complexity of immune heterogeneity and the potential for targeting specific immune cell subpopulations to enhance therapeutic efficacy. These findings suggest that the combination therapy of PARPi and A2ARa is a highly promising strategy that overcomes PARPi-induced immune escape by targeting the cAMP/CREB axis, thereby synergistically enhancing antitumor effects and holding promise as an effective treatment for solid tumors.

Correspondingly, their motor activity also improved. These results suggest that AAVrh10-based intrathecal delivery combined with istradefylline provides a promising therapeutic strategy for treating Tay-Sachs disease.

P1/2, N=40, Active, not recruiting, University of Florida | Recruiting --> Active, not recruiting | Trial completion date: May 2026 --> Aug 2026

P1, N=60, Recruiting, Chong Kun Dang Pharmaceutical | Not yet recruiting --> Recruiting

P1, N=40, Recruiting, Janssen Research & Development, LLC

Co-delivery of an ICD inducer (EPI) and an adenosine receptor antagonist (AB928) is realised in a stimuli-responsive nanomedicine to address immunosuppression induced by adenosine, thereby enhancing ICD effects and synergistically reprogramming the immunosuppressive tumor microenvironment.

P2, N=30, Active, not recruiting, Washington University School of Medicine | Trial completion date: Dec 2029 --> Jun 2030 | Trial primary completion date: Oct 2025 --> Apr 2026