Ciforadenant Shows Promise in Overcoming Immunotherapy Resistance in Prostate Cancer
核心洞察
New data suggests ciforadenant, an adenosine A2A receptor (搜索) antagonist, can overcome resistance to anti-PD1 immunotherapy in metastatic castration-resistant prostate cancer (mCRPC (搜索)).
Studies reveal the role of the adenosine pathway and SPP1+ myeloid cells in the immunobiology of mCRPC (搜索), highlighting potential therapeutic targets.
In a murine model, ciforadenant reduced immunosuppression and enhanced sensitivity to anti-PD1 therapy, suggesting a shift to a less immunosuppressive myeloid environment.
Corvus Pharmaceuticals announced new data highlighting the potential of ciforadenant, an adenosine A2A receptor (搜索) antagonist, to overcome resistance to anti-PD1 immunotherapy in the treatment of metastatic castration resistant prostate cancer (搜索) (mCRPC (搜索)). The data was presented at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting.
Myeloid Cells and Immunotherapy Resistance
Previous studies have indicated that mCRPC (搜索) is often resistant to immune checkpoint inhibitors. Researchers identified SPP1+ myeloid cells as potential mediators of this resistance. Single-cell RNA expression profiling of tumor biopsies revealed that SPP1+ macrophages were more prevalent in mCRPC patients compared to those with early localized or metastatic hormone-responsive prostate cancer.
Murine Model Findings
A murine model confirmed that SPP1+ macrophages were associated with suppressed immunity to prostate cancer and shortened overall survival. Further analysis revealed the involvement of adenosine signaling through the adenosine 2A receptor. Ciforadenant was used to inhibit adenosine signaling in this model, with key findings including:
- Reduced immunosuppression and enhanced sensitivity to anti-PD1 therapy
- Reduced SPP1+ macrophage infiltration in tumors
- Elevation of the Adenosine Gene Signature in SPP1+ macrophages
Clinical Trial Data
Results from the model were consistent with data from a Phase 1b/2 clinical trial of ciforadenant in patients with mCRPC (搜索). The trial included 35 patients with advanced mCRPC, with 11 receiving ciforadenant monotherapy (100 mg twice daily) and 24 receiving ciforadenant (100 mg twice daily) in combination with atezolizumab (840 mg every two weeks). A PSA partial response, defined as PSA reductions >30%, was observed in 5 of 24 patients (21%) receiving combination therapy, compared to 1 of 11 patients (9%) receiving monotherapy.
About Ciforadenant
Ciforadenant (CPI-444) is an investigational small molecule, oral checkpoint inhibitor designed to disable a tumor's ability to subvert attack by the immune system by blocking the binding of adenosine to immune cells in the tumor microenvironment. By blocking the immunosuppressive effects of myeloid cells, ciforadenant has demonstrated synergy with anti-PD1 and anti-CTLA4 antibodies in preclinical studies.