On September 10, 2019 Omeros Corporation (Nasdaq: OMER) reported a new approach to cancer immunotherapy that targets inhibition of GPR174, a member of the family of G protein-coupled receptors (GPCRs), which can be combined with and significantly improve the tumor-killing effects of adenosine pathway inhibitors. GPR174-targeting immunotherapy is expected to be applicable to all solid tumors (e.g., breast, lung, pancreas, colon, brain, etc.) (Press release, Omeros, SEP 10, 2019, View Source [SID1234539410]).
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The new cancer-immunotherapy approach is based on a series of discoveries by Omeros related to GPR174, which include:
The identification of cancer-immunity pathways controlled by GPR174
The identification of phosphatidylserine (PS) as a potent natural ligand for GPR174
A collection of novel small-molecule inhibitors of GPR174
A dramatic and synergistic enhancement of "tumor-fighting" cytokine production by T cells following the combined inhibition of both GPR174 and the adenosine pathway (e.g., A2A and/or A2B), another key metabolic pathway that regulates tumor immunity
GPR174 and A2A/A2B Adenosine Receptors
Like GPR174, A2A/A2B adenosine receptors are GPCRs. Central components of the adenosine pathway, A2A/A2B receptors are being targeted for cancer immunotherapy by several companies. GPR174 and A2A/A2B receptors share certain features. First, each of them increases intracellular cyclic adenosine monophosphate (cAMP), which is well known for suppressing the type of immune response necessary for killing tumor cells. Second, these receptors are activated by molecules (i.e., PS and adenosine, respectively) that are highly enriched in the tumor microenvironment. Strikingly, in experiments with total human peripheral blood mononuclear cells (PBMCs) where PS and adenosine are naturally abundant, GPR174 inhibitors synergized with A2A/A2B inhibitors to increase T-cell responses dramatically. Findings include the following:
A2A/A2B inhibition alone yielded, on average, 2-fold increases in both interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) and smaller increases in granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-2 (IL-2)
GPR174 inhibition alone averaged increases of 2.8-fold for IFN-γ, 2.7-fold for TNF, 1.7-fold for IL-2, and 1.4-fold for GM-CSF
Combining a GPR174 inhibitor with A2A and/or A2B inhibition increased the average IFN-γ and TNF levels 8- to 9-fold and the average IL-2 and GM-CSF levels nearly 3-fold, with maximum increases reaching 25-fold for IFN-γ and TNF and over 4-fold for IL-2 and GM-CSF
"Our GPR174-related discoveries open a wholly new approach to targeting the tumor microenvironment for cancer immunotherapy," said Marc Gavin, Ph.D., Omeros’ director of immunology who previously pioneered research on cAMP signaling in regulatory T cells and initiated and led Amgen’s groundbreaking IL-2 mutein program. "The adenosine pathway has been a focus of immunotherapy drug development efforts across the pharmaceutical industry. We have now shown that a relatively modest boost in cytokine production by T cells observed with inhibition of the A2A or A2B receptors, singly or together, is synergistically augmented when combined with GPR174 inhibitors. Furthermore, the discovery that PS itself stimulates an immunosuppressive GPCR – namely GPR174 – on all lymphocytes represents a significant advancement in our understanding of how PS regulates tumor immunity. New animal data from our group support these collective findings, and I look forward to clinical studies with GPR174 inhibitors, which could potentially become a treatment for most or all solid malignancies."
Relevance of Findings
Omeros’ findings are also particularly relevant for patients resistant to checkpoint inhibitors, such as anti-PD-1 (e.g., Keytruda and Opdivo) and anti-CTLA-4 (Yervoy), and to emerging cellular therapies such as CAR-T cells and adoptive T-cell therapy. Checkpoint inhibitors are only effective in a minority of patients, and high levels of adenosine-generating molecules have been observed in non-responding patients. Furthermore, overcoming natural immunosuppression in solid tumors represents a major hurdle for cellular therapies. Because PS and adenosine are both products of cell stress and death in solid tumors, it is expected that patients resistant to checkpoint inhibitors or cellular therapies would benefit greatly from the combined inhibition of the GPR174 and adenosine pathways.
"Our team’s discovery of the GPR174-controlled cancer-immunity pathways and their interrelationships with the adenosine pathway have been methodically elucidated and defined," said Gregory A. Demopulos, M.D., Omeros’ chairman and chief executive officer. "Simply put, Omeros has discovered that there are two feet on the cAMP brake pedal restraining immunity against the tumor and, to enable effective tumor-killing activity, both GPR174 and the adenosine pathway must be inhibited. We are optimizing our small-molecule GPR174 inhibitors with the objective of moving orally available therapeutics into the clinic as rapidly as possible. We look forward to providing physicians and patients with a new and broadly applicable option in cancer immunotherapy."
Omeros is preparing a manuscript for publication detailing its GPR174-related discoveries and data and plans to present these same discoveries and data beginning this year at upcoming oncology international congresses.
Omeros is establishing an expansive and exclusive intellectual property position directed to GPR174 inhibitors as well as to inhibition of the GPR174 receptor, both alone and in combination with other cancer therapies, for the treatment of any tumor or malignancy.