Background Elevated prostaglandin E2 (PGE2) in the tumor microenvironment mediates tumor proliferation, angiogenesis and immune evasion, in the last instance by inhibiting myeloid and lymphoid cell effector functions and inducing immune suppressive populations. These activities are associated with PGE2 binding to E-prostanoid receptors 2 and 4 (EP2 and EP4) and downstream signaling characterized by cAMP production. TPST-1495 is a novel, exquisitely specific dual-antagonist of EP2 and EP4 being assessed in a Phase I trial as a single agent and in combination with pembrolizumab in advanced solid tumor patients (NCT04344795). To characterize TPST-1495 pharmacodynamic activities, we quantified biomarkers associated with EP2 and EP4 blockade in pre- and post-treatment specimens.
Methods TPST-1495 was dosed at 15, 25 or 50 mg BID or QD (continuous or days 1–5 every 7 days) as monotherapy or QD continuously in combination with pembrolizumab 200 mg IV q3 weeks. To assess inhibition of PGE2-mediated immune suppression by TPST-1495, whole blood samples collected prior to and 2- and 4-hours following the first dose were incubated with LPS in the presence or absence of exogenous PGE2 after which supernatants were assayed by TNF-α ELISA (Invitrogen, Inc.). PGE2 catabolism was measured by quantifying PGE2 metabolite (PGEM) in urine using a validated mass spectrometry assay. Biopsies were assessed for quantities of T cells, granzyme B+ cells, and cyclooxygenase-2 (COX-2) positive cells by immunohistochemistry (CellCarta, Inc.).
Results Patients receiving TPST-1495 as a single agent at 25 or 50 mg exhibited statistically higher median TNF-α recovery through PGE2 suppression than those receiving 15 mg (p<0.05 by Wilcoxon’s pair-wise analysis). Patients treated with 25 or 50 mg also demonstrated significant elevations in baseline-normalized urinary PGEM above those receiving 15 mg on day 2 (p<0.05 by Wilcoxon’s paired test) with trends of dose-dependent increases on days 8 and 22. Immunohistochemical analysis revealed COX-2 expression levels > 10% in 3 of 11 baseline biopsies; two were from patients with best objective responses of stable disease, one, a patient with endometrial cancer, exhibited tumor shrinkage of -22% and 2-fold increases in tumor-infiltrating CD8+ and granzyme B+ T cells in an on-treatment biopsy.
Conclusions The pharmacodynamic activities observed in patients receiving TPST-1495 are consistent with blockade of PGE2 signaling through EP2 and EP4 receptors. Elevated baseline COX-2 levels may be a predictive biomarker of response in patients. Currently, the combination of TPST-1495 and pembrolizumab is being assessed in endometrial cancer patients, a malignancy expressing comparatively high levels of EP2, EP4 and COX-2.
Trial Registration Phase 1a/1b Study of TPST-1495 as a Single Agent and in Combination With Pembrolizumab in Subjects With Solid Tumors. NCT04344795
Ethics Approval The study was conducted with adherence to the ethical principles based on the Declaration of Helsinki, International Council for Harmonisation guidelines for current Good Clinical Practice and the applicable national and local laws and regulatory requirements. Before the study began, the protocol, the informed consent form, other written materials provided to participants, and any other relevant study documentation was approved by each Clinical Site Institutional Review Board. All participants provided written informed consent before any study procedures were performed.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.