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The response to Immune Checkpoint Inhibitors (ICI) treatment can be limited by the implementation of resistance mechanisms by the tumor to escape from the host immune system surveillance. Combination strategies with agents designed to shut down these resistance pathways are highly desirable to generate a better anti-tumor efficacy and, of course, long-lasting complete responses.
Elevated levels of Prostaglandin E2 (PGE2), an eicosanoid synthesized from arachidonic acid by the inducible cyclooxygenase-2 (COX-2), exert strong immunosuppressive effect in the tumor microenvironment. Also, upregulation of COX-2 was shown in several types of tumors. Counteracting this immunosuppressive pathway have the potential to synergize with the anti-tumor effects of ICI. As the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors (Coxibs) in cancer proved to be non applicable due to safety concerns, there is a need to develop safer alternatives, especially by inhibiting downstream targets. PGE2 immunosuppressive effects are largely mediated by the EP4 receptor, expressed on multiple immune cells. The development of antagonists of the EP4 receptor is thus a promising strategy to inhibit the PGE2-induced immunosuppression in the tumor microenvironment and to restore anti-tumor immunity.
Phase Ia clinical candidate DT-9081, a selective EP4 receptor antagonist, was designed to counteract the PGE2-immunosuppressive effects in the TME and to synergize with ICI. DT-9081 in vivo efficacy, in combination with ICI in murine syngeneic models, is presented.
High levels of prostaglandin E2 (PGE2) in tumors suppress anti-tumor immunity in the tumor microenvironment and contribute to tumor escape and disease progression. This effect of PGE2 is mediated through the activation of EP4R, a Gs protein coupled receptor activating cAMP signaling expressed by immune cells.
DT-9081 is a new small molecule, orally administered, highly selective antagonist of EP4R developed to overcome the immune-suppressive effects of PGE2, and to reverse the resistance to immune checkpoint blockers.
DT-9081 has demonstrated significant anti–tumor activity as monotherapy and in combination with immunotherapeutic agents in several syngenic murine cancer models (CT26 colorectal tumor model and MCA205 sarcoma model). These data are presented in poster #814:
”DT-9081, a selective EP4 receptor antagonist which synergizes with immune checkpoint inhibitors to induce complete responses in syngeneic murine
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