Corvus Pharma Unveils Data on Ciforadenant's Potential to Combat Prostate Cancer Therapy Resistance

Corvus Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company, recently unveiled promising new data on ciforadenant, its adenosine A2A receptor antagonist, with potential to counteract resistance to anti-PD1 immunotherapy in treating metastatic castration-resistant prostate cancer (mCRPC). The findings were shared at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), where the abstract presented by Dr. Aram Lyu was selected as one of the Top 100 abstracts.

Dr. Lyu, a postdoctoral fellow at Fred Hutch Cancer Center and Parker Scholar at the Parker Institute for Cancer Immunotherapy, highlighted the role of the adenosine pathway in the immunobiology of mCRPC, emphasizing the influence of myeloid cells and the adenosine gene signature. Richard A. Miller, M.D., President and CEO of Corvus, underscored the significance of these findings, which align with results from their clinical trials in renal cell cancer and prostate cancer. He noted the potential of the adenosine gene signature to identify patients who are more likely to respond to the treatment, marking a significant advancement for those with tumors resistant to checkpoint inhibitors. This supports their ongoing clinical trial combining ciforadenant with ipilimumab and nivolumab in frontline renal cell cancer.

Key data from the SITC oral presentation revealed that mCRPC typically shows resistance to immune checkpoint inhibitors. Previous studies had identified tumor-associated macrophages as contributors to immunosuppression within the tumor microenvironment. This research identified SPP1+ myeloid cells as a potential crucial mediator of resistance. Dr. Lawrence Fong's team at Fred Hutch used single-cell RNA expression profiling of tumor biopsies to observe levels of these cells in patients with varying stages of prostate cancer. They found that SPP1+ macrophages were more prevalent in mCRPC patients.

Dr. Fong, scientific director of the Immunotherapy Integrated Research Center at Fred Hutch and a professor in the Translational Sciences and Therapeutics Division, led the research. The team developed a murine model that demonstrated the association of SPP1+ macrophages with suppressed immunity to prostate cancer and reduced overall survival. Further genetic pathway analysis pointed to the involvement of adenosine signaling through the adenosine 2A receptor. The use of ciforadenant to inhibit adenosine signaling in this model produced key findings, including:

- Ciforadenant treatment reduced immunosuppression and increased sensitivity to anti-PD1 therapy.
- It also decreased SPP1+ macrophage infiltration in tumors, indicating a shift towards a less immunosuppressive myeloid environment.
- The Adenosine Gene Signature was elevated in SPP1+ macrophages, reflecting adenosine-induced immunosuppression.

These results were consistent with data from a Phase 1b/2 clinical trial of ciforadenant in mCRPC patients, including 35 individuals with advanced mCRPC. Among them, 11 received ciforadenant alone, while 24 received it in combination with atezolizumab. Notably, 21% of patients receiving the combination therapy experienced partial PSA responses.

Corvus Pharmaceuticals, a company at the forefront of developing ITK inhibition for a range of cancers and immune diseases, has ciforadenant (CPI-444) as one of its key investigational drugs. This oral checkpoint inhibitor is designed to block the binding of adenosine to immune cells within the tumor microenvironment, preventing the tumor from evading immune system attacks. Studies have shown that it can mitigate the immunosuppressive effects of myeloid cells present in tumors and work synergistically with anti-PD1 and anti-CTLA4 antibodies, as evidenced by preclinical studies published in 2018.

The adenosine gene signature serves as a biomarker of adenosine-induced immunosuppression in tumors, indicating the presence of chemokines that recruit myeloid cells, which are believed to mediate resistance to anti-PD-(L)1 treatments.