Prostate cancer, particularly in its advanced, metastatic castration-resistant stage (mCRPC), has long been considered a “cold” tumor, meaning it’s largely invisible to the body’s immune system and resistant to typical immunotherapy approaches like checkpoint inhibitors. This resistance has puzzled researchers and presented a formidable challenge in the fight against this prevalent disease. However, recent research presented at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting suggests that this “cold” nature might be a blessing in disguise, offering valuable insights into novel immunotherapy strategies.

The Role of SPP1+ Macrophages in Immunotherapy Resistance

A critical finding highlighted in the study led by Dr. Lawrence Fong at the Fred Hutch Cancer Center is the role of SPP1+ myeloid cells, specifically macrophages, in driving immunotherapy resistance in mCRPC. These cells become more prevalent as prostate cancer progresses, contributing to a suppressed immune response within the tumor microenvironment. In simpler terms, these macrophages act like shields, protecting the cancer cells from immune system attacks.

Adenosine: The Signal of Suppression

Further investigation into the mechanisms behind this immune suppression pointed to the involvement of adenosine signaling through the adenosine 2A receptor. Adenosine, a naturally occurring molecule, can accumulate in the tumor microenvironment and bind to these receptors on immune cells, effectively putting them to sleep. This finding unveiled a crucial target for potential therapeutic intervention.

Ciforadenant: Awakening the Immune System

Corvus Pharmaceuticals has developed ciforadenant, a drug that specifically blocks the adenosine 2A receptor, essentially preventing adenosine from suppressing the immune response. Preclinical studies using a mouse model of prostate cancer demonstrated the potential of ciforadenant to reverse this immunosuppression and enhance the effectiveness of anti-PD1 therapy, a common type of immunotherapy.

Promising Clinical Trial Results

Early clinical trial data in mCRPC patients further supports the potential of ciforadenant. When combined with atezolizumab, another immunotherapy drug, ciforadenant resulted in a 21% partial response rate (PSA reduction >30%) compared to 9% in patients receiving ciforadenant alone. While these results are preliminary, they provide a glimmer of hope for patients with advanced prostate cancer who haven’t responded to other treatments.

The Adenosine Gene Signature: A Roadmap for Treatment

The identification of the Adenosine Gene Signature, a biomarker reflecting adenosine-induced immunosuppression, offers a potential tool for selecting patients most likely to benefit from ciforadenant treatment. This signature essentially identifies tumors with high levels of adenosine signaling, making them prime candidates for ciforadenant’s immune-awakening effects.

Why “Cold” Can Be Good News

The fact that prostate cancer’s “cold” nature is primarily driven by a specific, targetable mechanism like adenosine signaling is a positive development. It means that instead of trying to broadly stimulate a weak immune response, researchers can focus on disrupting this suppressive pathway with drugs like ciforadenant. This targeted approach holds promise for developing more effective and personalized immunotherapies for mCRPC patients.

In conclusion, while the “cold” nature of prostate cancer has posed a significant challenge to immunotherapy, the identification of SPP1+ macrophages and the adenosine signaling pathway as key drivers of this resistance opens new doors for treatment. Ciforadenant, with its ability to reverse adenosine-induced immunosuppression, represents a promising new avenue for improving outcomes for patients with advanced prostate cancer. The ongoing research and clinical trials in this area are crucial steps towards unlocking the potential of immunotherapy for this challenging disease.

Source.

Clinical trial.