targeting adenosine to enhance immune response
A critical mechanism of cancer immune evasion is the generation of high levels of immunosuppressive adenosine within the tumor microenvironment (TME). Research suggests that the TME has significantly elevated concentrations (100-500 fold) of extracellular adenosine. Engagement with adenosine receptors A2A and A2B triggers a dampening effect on the immune response, suppressing effector cell function and stabilizing immunosuppressive regulatory cells.
Over-expression of the A2A and A2B receptors leads to poor prognosis in multiple cancers, including prostate cancer, colorectal cancer and lung adenocarcinoma, driven by a reduced ability to generate an immune response against the tumor. These findings have made A2A and A2B high-priority targets for immunotherapeutic intervention. Portage is advancing four first-in-class adenosine inhibitors which together represent the full suite of adenosine-targeting approaches and will enable a comprehensive exploration of how targeting the adenosine pathway could improve response in multiple cancer and non-cancer indications:
- PORT-6 (TT-10): Adenosine receptor type 2A (A2A) inhibitor to treat A2A expressing solid tumors
- PORT-7 (TT-4): Adenosine receptor type 2B (A2B) inhibitor to treat solid tumors
- PORT-8 (TT-53): Dual inhibitor of adenosine receptors 2A and 2B (A2A/A2B) to treat solid tumors
- PORT-9 (TT-3): An A2B inhibitor to treat colorectal and gastrointestinal cancers
Previous research provides evidence of a broad array of indications that show high expressions of A2A, A2B and dual adenosine receptors, and also suggests that high expression of these receptors can vary by tumor type1. In preparation for entering clinical trials for the adenosine programs, Portage will conduct an examination of which solid tumor types have a high expression of receptors A2A and A2B, and enrich for patients that have high expression and therefore have potential to benefit most from treatment.
¹https://www.nature.com/articles/s41571-020-0382-2/
