LONDON - Iteos Therapeutics SA has joined the growing band of companies seeking to reverse tumor immune evasion by blocking the anti-inflammatory effects of adenosine signaling, with dosing of the first cohort of patients in a phase I/Ib study of its lead compound, EOS-100850, now complete.

The second cohort is due to start dosing this week, and Michel Detheux, Iteos co-founder and CEO, told BioWorld the initial indications are that these patients "should get excellent target coverage."

While other small-molecule adenosine A2A receptor antagonists initially were developed for disorders of the central nervous system, in particular Parkinson's disease, Gosselies, Belgium-based Iteos designed EOS-100850 from the ground up for use in cancer immunotherapy.

That avoids potential neurological side effects of products that cross the blood-brain barrier and means EOS-100850 achieves a higher degree of A2A receptor inhibition. As a result, the compound is effective in the face of the high levels of extracellular adenosine found within the tumor microenvironment.

"We believe we have a potential best-in-class compound, which was carefully designed with differentiating features to maximize the therapeutic window," Detheux said. For example, he claims EOS-100850 is 100-fold to 300-fold more potent than Astrazeneca plc's A2A receptor antagonist, AZD-4635 (formerly HTL-1071).

There is a growing pile of preclinical evidence, and now a trickle of clinical data, indicating the anti-inflammatory effects of adenosine are critical to tumor immunosuppression and that this is a potential cause of resistance to anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors. It has been shown that blocking adenosine receptors can turn cold tumors hot, making them receptive to anti-PD-1/PD-L1 and to chemotherapy.

Within solid tumors, adenosine released in response to hypoxia binds to G protein-coupled adenosine receptors, leading to the down-regulation of cytotoxic T cells directed against the cancer. The most potent immunosuppression effects are mediated by A2A receptors expressed on T cells. The A2B receptor, expressed on dendritic cells and macrophages, also compromises T-cell activation.

In preclinical studies, EOS-100850 restored T-cell activity and promoted antitumor immune responses. In addition, it showed a synergistic effect with several immune checkpoint inhibitors and with chemotherapy. As an orally available small molecule, it could readily be combined with other types of therapy.

The phase I/Ib monotherapy trial started in Belgium and will expand to the U.K. and the U.S. A total of 72 patients with advanced solid tumors will be enrolled. The study has an adaptive design, in which biopsies taken pre- and post treatment will be analyzed to identify and confirm the presence of certain biomarkers and inform onward clinical development.

Adenosine has a very short life and cannot readily be measured directly; the aim is to identify a molecular signature of adenosine release and signaling that can be used to select patients who are likely to respond to A2A receptor inhibition, and to monitor response to therapy.

Adenosine in immuno-oncology

The only other product in development specifically designed for immuno-oncology indications is Arcus Biosciences Inc.'s AB-928, which is an antagonist of both A2A and A2B receptors. The compound currently is being tested in a phase I/Ib program in combination with Arcus' anti-PD-1 antibody, AB-122, and with doxorubicin and FOLFOX chemotherapy.

Last November, Haywood, Calif.-based Arcus published details of a phase I trial in 85 healthy volunteers, which showed AB-928 was well-tolerated up to the highest dose tested. There were no safety concerns and the pharmacokinetics were linear.

At the end of March, Astrazeneca presented phase I/Ib data on AD-4635 at the American Association for Cancer Research meeting in Atlanta, showing it prevents adenosine-mediated immunosuppression. Early signs of clinical activity have been observed with AD-4635 monotherapy and in combination with Imfinzi (durvalumab), Astrazeneca's anti-PD-1 antibody, in metastatic castration-resistant prostate cancer.

Another adenosine A2A antagonist to have shown signs of clinical activity in phase I/Ib is Corvus Pharmaceuticals Inc.'s ciforadenant (CPI-444), which the company said had an effect in non-small-cell lung cancer and renal cancer patients whose tumors did not respond to anti-PD-1/PD-L1.

The rights to ciforadenant came from Vernalis Research of Cambridge, U.K., which previously developed it to treat Parkinson's disease and attention deficit hyperactivity disorder. In the phase I/Ib cancer program, Burlingame, Calif.-based Corvus is testing the drug in combination with Tecentriq (atezolizumab), Genentech Inc.'s anti-PD-L1 antibody, and also in combination with a CD73-targeting antibody, CPI-006, which inhibits production of adenosine.

Two other companies working on de novo discovery of adenosine inhibitors tailored for use in immuno-oncology are Exscientia Ltd., of Dundee, Scotland, and Evotec SE, of Hamburg, Germany, which are collaborating on the design of a selective A2A receptor antagonist and also a bispecific molecule capable of blocking A2A receptors and inhibiting production of adenosine.

Iteos' Detheux noted that having been designed for treating Parkinson's disease, AZD-4635 and ciforadenant are not honed to act in the tumor microenvironment. "They are suboptimal, but still showing clinical activity," he said.

In particular, the response in prostate cancer, which is "cold" and does not usually respond to immunotherapy is "a very good surprise," said Detheux, adding, "We believe we have a compound that is very different from the competitors and can address the specific [requirements] in immuno-oncology," he said.