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

However, unlike blinatumomab, which tends to induce T cell exhaustion, we showed that the release of PBF-509 from NanoBiTE suppressed the A2AR pathway and substantially improved tumor cell killing induced by NanoBiTE. Moreover, NanoBiTE treatment led to substantially reduced tumor burden in vivo in a humanized mouse model. Our results demonstrate that NanoBiTE is a safe and potent bispecific therapy that can also reduce T cell exhaustion for cancer immunotherapy.

Compound 14a also effectively restored T cell proliferation suppressed by 5'-N-ethylcarboxamidoadenosine (NECA) and exhibited superior T cell-mediated cytotoxicity in coculture systems with A1R- and PD-L1-expressed cancer cells compared with ciforadenant (A2AR antagonist) and etrumadenant (A2AR/A2BR dual antagonist). Moreover, the combination of compound 14a with avelumab, an anti-PD-L1 antibody, resulted in enhanced infiltration of effector T cells and significantly increased the CD8+/Treg ratio in the CT26 syngeneic mouse model, substantially inhibiting tumor growth. Therefore, compound 14a is a promising candidate for multitargeted immunomodulation in cancer immunotherapy.

P1/2, N=227, Completed, Arcus Biosciences, Inc. | Active, not recruiting --> Completed | Trial completion date: Mar 2026 --> Sep 2025

P1, N=60, Not yet recruiting, Chong Kun Dang Pharmaceutical

Furthermore, overexpression of PNP or using taminadenant, a A2aR-targeting inhibitor used in clinical trials, significantly enhances the EGFR-targeted therapeutic response in vitro, as well as in patient-derived organoids, cell-derived xenografts and mouse models bearing human EGFR-driven spontaneous lung tumor. Overall, our findings clarify the role of inosine metabolism in TKI resistance, highlighting a potential therapeutic strategy-targeting the inosine/A2aR axis-to counteract EGFR-TKI tolerance in LUAD treatment.

P2, N=20, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2025 --> Sep 2027 | Trial primary completion date: Sep 2025 --> Sep 2027

P2, N=43, Recruiting, Weill Medical College of Cornell University | Trial primary completion date: Dec 2025 --> Dec 2026

P2, N=151, Completed, Arcus Biosciences, Inc. | Active, not recruiting --> Completed

P1/2, N=227, Active, not recruiting, Arcus Biosciences, Inc. | Trial completion date: Aug 2025 --> Mar 2026 | Trial primary completion date: Jul 2025 --> Oct 2025