Corvus Pharmaceuticals Inc. (CRVS) has unveiled promising new data underscoring the potential of their adenosine A2A receptor antagonist, ciforadenant, in overcoming resistance to anti-PD1 immunotherapy in treating metastatic castration-resistant prostate cancer (mCRPC).
Historically, it has been noted that mCRPC exhibits resistance to immune checkpoint inhibitors. Although tumor-associated macrophages have been implicated in fostering immunosuppression within the tumor microenvironment, this particular study identifies SPP1+ myeloid cells as potentially key mediators of this resistance to immunotherapy.
Conducted under the leadership of Dr. Lawrence Fong, the research employed single-cell RNA expression profiling of tumor biopsies. This technique was used to assess these myeloid cells' levels across different patient groups: those with early localized prostate cancer, metastatic hormone-responsive prostate cancer, and mCRPC. The findings revealed that SPP1+ macrophages tend to be more prevalent as prostate cancer progresses to the metastatic, castration-resistant stage, according to the company.
To provide further insights, the researchers developed a murine model that corroborated the association of SPP1+ macrophages with diminished immunity against prostate cancer and reduced overall survival. Genetic pathway analyses pointed to adenosine signaling via the adenosine 2A receptor as a contributing factor. By utilizing ciforadenant to inhibit this adenosine signaling within the model, key discoveries emerged, showcasing its potential to counteract immunotherapy resistance. Notable findings include: ciforadenant treatment correlating with decreased immunosuppression and enhanced sensitivity to anti-PD1 therapy; a decrease in SPP1+ macrophage presence within tumors, indicative of a shift toward a less immunosuppressive myeloid environment; and an elevated Adenosine Gene Signature—an indicator of adenosine-induced immunosuppression—within SPP1+ macrophages.
The company's findings from the model align with data derived from the Phase 1b/2 clinical trial involving ciforadenant in mCRPC patients. This trial encompassed 35 advanced mCRPC patients, 11 of whom received ciforadenant as a standalone treatment (100 mg twice daily), while 24 received a combination of ciforadenant (100 mg twice daily) and atezolizumab (840 mg administered intravenously biweekly). Of those receiving combination therapy, 5 out of 24 demonstrated PSA partial responses, defined by PSA reductions exceeding 30%, compared to only 1 out of 11 undergoing monotherapy.
