On November 09, 2024 Corvus Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company, reported new data highlighting the potential of ciforadenant, the Company’s adenosine A2A receptor antagonist, to overcome resistance to anti-PD1 immunotherapy in the treatment of metastatic castration resistant prostate cancer (mCRPC) (Press release, Corvus Pharmaceuticals, NOV 9, 2024, View Source [SID1234648056]).
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The data were presented today in an oral session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 39th Annual Meeting by Aram Lyu, Ph.D., a postdoctoral fellow at Fred Hutch Cancer Center, University of California, San Francisco and Parker Scholar at the Parker Institute for Cancer Immunotherapy. Dr. Lyu’s abstract, titled "Identification and therapeutic target of myeloid-mediated mechanisms of immunotherapy resistance in prostate cancer" was selected as a Top 100 abstract by SITC (Free SITC Whitepaper).
"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."
SITC Oral Presentation Overview and Key Data
Previous studies have shown that mCRPC is resistant to therapy with immune checkpoint inhibitors. While tumor associated macrophages are known to contribute to immunosuppression with the tumor microenvironment, this study identified SPP1+ myeloid cells as a potential critical mediator of resistance to immunotherapy. The team led by Lawrence Fong, M.D. used single cell RNA expression profiling of tumor biopsies to measure levels of these cells in patients with early localized or metastatic hormone responsive prostate cancer compared to patients with mCRPC. The results showed that SPP1+ macrophages were more prevalent as cancer progresses to mCRPC patients.
Dr. Fong is the scientific director of the Immunotherapy Integrated Research Center at Fred Hutch, where he is also a professor in the Translational Sciences and Therapeutics Division and a Bezos Family Distinguished Scholar in Immunotherapy.
The researchers created a murine model that confirmed that SPP1+ macrophages were associated with suppressed immunity to prostate cancer and shortened overall survival. Further analysis of the related genetic pathways revealed involvement of adenosine signaling through the adenosine 2A receptor. The researchers utilized ciforadenant to inhibit adenosine signaling in this model and the key findings demonstrating its potential to overcome this resistance to immunotherapy include:
Ciforadenant treatment associated with reduced immunosuppression and enhanced sensitivity to anti-PD1 therapy in the model
Ciforadenant treatment associated with reduced SPP1+ macrophage infiltration in the tumors, supporting a shift to a less immunosuppressive myeloid environment
The Adenosine Gene Signature, a biomarker that reflects adenosine induced immunosuppression in the tumor, was elevated in SPP1+ macrophages
Results from the model were consistent with data from the Phase 1b/2 clinical trial of ciforadenant in patients with mCRPC, which included data from 35 patients with advanced mCRPC, including 11 who received ciforadenant as a monotherapy (100 mg twice daily) and 24 that received ciforadenant (100 mg twice daily) in combination with atezolizumab (840 mg delivered intravenously every two weeks). 5 of 24 (21%) receiving combination therapy had PSA partial responses defined as PSA reductions >30%, compared to 1 of 11 (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 present in the tumor microenvironment. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2a receptor present on immune cells and block their activity. Ciforadenant has been shown to block the immunosuppressive effects of myeloid cells present in tumors and preclinical studies published in 2018 demonstrated synergy with combinations of anti PD1 and anti-CTLA4 antibodies.