A2ARs Receptor Agonist Combo May be Synergistic in Clear Cell RCC

Kathryn Beckermann, MD, PhD, indicated that there are several reasons why the mechanisms of ipilimumab (Yervoy), nivolumab (Opdivo), and ciforadenant (previously CPI 444) may provide value to patients with advanced clear cell renal cell carcinoma (RCC) in their first line of treatment.

In an interview with CancerNetwork® during the 2023 Kidney Cancer Research Summit (KCRS), Beckermann, an assistant professor of medicine in the Department of Medicine at Vanderbilt University Medical Center, discussed how adenosine triphosphate (ATP) can impact cancer and immune cells within the tumor microenvironment, as well as the preclinical findings that provided the rationale for assessing the aforementioned combination.

Ciforadenant is an investigational small molecule that binds to A2ARs on T lymphocytes and other immune cells. As RCC metabolism can be quite glycolytic and needs to send out ATP to create cancer cell proliferation and adenosine had been known to elicit immune suppressive effects, it is theorized that the combination may be efficacious in this patient population.

This laid the groundwork for a phase 1b/2 trial (NCT05361720) assessing ipilimumab, nivolumab, and ciforadenant in those with advanced clear cell RCC.

Transcript:

We do think there are several mechanistic reasons that this [regimen] might have added value for patients in the first-line setting. First of all, we know that adenosine is a signaling molecule that exists at high levels in the tumor microenvironment. Clear cell RCC is driven by a metabolic switch that comes with the loss of VHL which generates a lot of ATP, which ultimately gets processed to adenosine. Adenosine in and of itself as a signaling molecule can affect the cancer cells; it can also affect the immune cells in the tumor microenvironment.

There has been some preclinical work by multiple labs that have shown that adenosine being high in the tumor microenvironment recruits immune suppressive components. Hence, we designed a trial to say if we can block adenosine signaling that should have an effect on killing the cancer cells as well as perhaps enhancing the immune response. There are preclinical data that it is synergistic with ipilimumab and nivolumab. That was the rationale.

Reference

Beckermann K, Rini B, Haas N, George D, Jonasch E. Phase 1b/2 trial of Ipilimumab, nivolumab, and ciforadenant(INC) (adenosine A2a receptor antagonist) in first-line advanced renal cell

carcinoma. 2023 Kidney Cancer Research Summit (KCRS); July 13-14, 2023; Boston, Massachusetts. Abstract 87.