ciforadenant (CPI-444)

P1/2, N=314, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Nov 2026 --> Nov 2025

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=50, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=24 --> 50

SHP099, an allosteric inhibitor for Src-homology domain-containing protein tyrosine phosphatase-2 (SHP2), and CPI-444, a selected inhibitor for adenosine A2AR receptor, were co-encapsulated in a T cell-targeting nanoparticle (SCNP/αCD8). The enhanced anti-tumor immunity in vivo is also ascribed to improved infiltration of effector CD8+ T cells in tumor tissues. These findings suggest that concurrent blockade of A2AR and SHP2 immune checkpoint signaling pathways with small molecule inhibitors offers a promising alternative strategy to enhance T cell functions for enhanced cancer immunotherapy.

AMD3100 (CXCR4 antagonist) and CPI-444 (adenosine 2A receptor inhibitor) were formulated into micelles, denoted as AMD@iNPDBCO and CPI@iNPN3, respectively. Furthermore, the nanoplatform remarkably amplifies immuno-radiotherapy by potently evoking cytotoxic CD8+ T cell priming, and synergized with immune checkpoint blockade by delaying CD8+ T cell exhaustion. Our work highlights the potential of the in situ assembly nanoplatform tailored for delivery of extracellular-targeted therapeutic agents for boosting GBM immunotherapy.

P1/2, N=314, Active, not recruiting, Hoffmann-La Roche | N=675 --> 314

Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1hi-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1hi-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.

P1/2, N=675, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Jun 2026 --> Sep 2025 | Recruiting --> Active, not recruiting | Trial completion date: Sep 2027 --> Nov 2026

P1/2, N=24, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1/2, N=24, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

P1/2, N=675, Recruiting, Hoffmann-La Roche | N=470 --> 675 | Trial completion date: Nov 2026 --> Sep 2027 | Trial primary completion date: Aug 2025 --> Jun 2026

P1/2, N=24, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2 | N=15 --> 24