7:46 PM
 | 
Mar 23, 2018
 |  BioCentury  |  Product Development

Optimism for A2A

Why two negative readouts haven't dimmed hope for A2A in cancer

Once considered solely a neurology target, the adenosine pathway has attracted interest in immuno-oncology based on its ability to control whether immune cells adopt a stimulatory or suppressive phenotype. The early results from A2A receptor antagonists first developed for neurological disease are a mixed bag. But several companies are persevering with new approaches intended to boost efficacy.

Sosei Group Corp. EVP and Chief R&D Officer Malcolm Weir told BioCentury the presence of A2A receptors on immune cells had been known for over a decade, but “it was with the advent of checkpoint inhibitors that the potential for clinical significance of this mechanism flourished.”

When adenosine binds to the adenosine A2A receptor (ADORA2A), CD8+ T cells and other lymphocytes decrease production of pro-inflammatory cytokines and increase production of immunosuppressive ones.

A2A receptor activation also up-regulates other immune checkpoints on T cells, such as PD-1, and increases forkhead box P3 (FOXP3) expression in CD4+ T cells, which steers them toward an immunosuppressive Treg phenotype.

“It was with the advent of checkpoint inhibitors that the potential for clinical significance of this mechanism flourished.”

Malcolm Weir, Sosei

At least five companies, including Sosei, are developing A2A receptor inhibitors for cancer.

The first signs of efficacy in the clinic came from Corvus Pharmaceuticals Inc.’s CPI-444 at the American Association for Cancer Research (AACR) meeting last April. The company reported initial efficacy data from an ongoing open-label Phase I/Ib trial showing one partial response in each of three cohorts in renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and colorectal cancer.

The trial is testing CPI-444 as monotherapy, and in combination with PD-L1 inhibitor Tecentriq atezolizumab from the...

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