Corvus Pharmaceuticals announced new data highlighting the potential of ciforadenant, its adenosine A2A receptor antagonist, to overcome resistance to anti-PD1 immunotherapy in metastatic castration-resistant prostate cancer (mCRPC). The data were presented at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting.
Myeloid Cells and Immunotherapy Resistance
Previous studies have indicated that mCRPC is often resistant to immune checkpoint inhibitors. This new research identifies SPP1+ myeloid cells as potential key mediators of this resistance. Lawrence Fong, M.D., and his team used single-cell RNA expression profiling of tumor biopsies to measure SPP1+ cell levels in patients with early localized or metastatic hormone-responsive prostate cancer compared to those with mCRPC. The results indicated that SPP1+ macrophages were more prevalent in mCRPC patients as the cancer progressed.
Murine Model Findings
To confirm the role of SPP1+ macrophages, the researchers created a murine model. The 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 then used to inhibit adenosine signaling in this model. Key findings included:
- Ciforadenant treatment was associated with reduced immunosuppression and enhanced sensitivity to anti-PD1 therapy.
- Ciforadenant treatment reduced SPP1+ macrophage infiltration in the tumors, suggesting a shift to a less immunosuppressive myeloid environment.
- The Adenosine Gene Signature, a biomarker reflecting adenosine-induced immunosuppression in the tumor, was elevated in SPP1+ macrophages.
Clinical Trial Data
These preclinical results align with data from a Phase 1b/2 clinical trial of ciforadenant in patients with mCRPC. 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 intravenously every two weeks). A PSA partial response, defined as a PSA reduction >30%, was observed in 5 of 24 patients (21%) receiving combination therapy, compared to 1 of 11 patients (9%) receiving monotherapy.
Implications for Treatment
"These studies reveal important details on the role of the adenosine pathway on the immunobiology of mCRPC, including the importance of myeloid cells and the adenosine gene signature," said Richard A. Miller, M.D., co-founder, president, and chief executive officer of Corvus. "The mechanism is consistent with and builds on results from our clinical trials in renal cell cancer and prostate cancer, along with the potential for the adenosine gene signature to select patients most likely to respond. This could be an important advancement for patients with tumors that are resistant to checkpoint inhibitors, and is supportive of our ongoing clinical trial of ciforadenant in combination with ipilimumab and nivolumab in front line renal cell cancer."
