Abstract 1333: Dual blockade of the EP2 and EP4 PGE2 receptors with TPST-1495 is an optimal approach for drugging the prostaglandin pathway
Authors: Francica Brian , Lopez Justine , Holtz Anja , Freund Dave , Wang Dingzhi , Enstrom Amanda , Dubois Raymond , Kipper Francielle , Panigrahy Dipak , Whiting Chan , Whiting Sam , Dubensky Thomas W. 
Published: June 2022

Abstract
Prostaglandin E2 (PGE2) is a bioactive lipid produced by tumor cells that drives disease progression through stimulating tumor proliferation, enhancing angiogenesis and suppressing immune function in the TME1, 2. PGE2 is also a mediator of adaptive resistance to immune checkpoint inhibitor therapy via the upregulation of cyclooxygenase-2 (COX-2). While the role of PGE2 signaling in cancer is clear, how best to inhibit PGE2 for cancer treatment remains under investigation. Inhibition of COX-1 and/or COX-2 has shown promising results in observational studies and meta-analyses, but inconsistent results in prospective studies. PGE2 signals through four receptors, EP1-4, that are variably expressed on tumor and immune cells and have distinct biological activities. The EP2 and EP4 receptors signal through cAMP and drive pro-tumor activities, while the EP1 and EP3 receptors signal through calcium flux and IP3 and drive immune activation and inflammation. While COX-2 and single EP inhibitors continue to be developed, the nature of PGE2 signaling supports our rationale to inhibit PGE2 by dual antagonism of the pro-tumor EP2/EP4 receptors, while sparing the pro-immune EP1/EP3 receptors. To our knowledge, TPST-1495 is the first clinical-stage dual inhibitor of both the EP2 and EP4 receptors. In mouse and human whole blood assays, dual blockade of EP2 and EP4 receptors with TPST-1495 reversed PGE2-mediated suppression of LPS-induced TNF-α, while single receptor antagonists were unable to block suppression at higher PGE2 concentrations. Similarly, in murine and human T cells in vitro, TPST-1495 inhibited PGE2-mediated suppression, resulting in a significant increase of IFN-γ production in response to stimulation with cognate peptide antigen. In vivo, TPST-1495 monotherapy significantly reduced tumor outgrowth in CT26 tumor-bearing mice and correlated with increased tumor infiltration by NK cells, CD8+ T cells, AH1-specific CD8+ T cells, and other anti-tumor myeloid and adaptive immune cell populations. The relative contribution of increased immune infiltration may be simultaneously dependent on the immunogenicity of the tumor model and on the direct antitumor effect of TPST-1495, because we also observed significant tumor regression in metastatic burden in the LS174T xenograft model in NSG mice as well as CT26 tumors in RAG2-/- animals, both of which are deficient in immune cell development. To that end, TPST- 1495 monotherapy significantly decreased the tumor burden compared to COX2 inhibition and EP2 or EP4 single antagonism in the Adenomatous Polyposis (APCmin/+) model, a model that is hypo-responsive to PD-1 monotherapy. TPST-1495 is currently being evaluated in an ongoing Phase 1 first-in-human study (NCT04344795) to characterize PK, PD, safety, and to identify a recommended phase 2 dose for expansion cohorts in key indications and biomarker-selected patients.
Citation Format: Brian Francica, Justine Lopez, Anja Holtz, Dave Freund, Dingzhi Wang, Amanda Enstrom, Raymond Dubois, Francielle Kipper, Dipak Panigrahy, Chan Whiting, Sam Whiting, Thomas W. Dubensky. Dual blockade of the EP2 and EP4 PGE2 receptors with TPST-1495 is an optimal approach for drugging the prostaglandin pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1333.