Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors

• DOI: 10.1186/s40425-018-0363-5
• Publication Date: 2018-06-14T01:23:29Z
• Authors: Edward Hammond; Nicole M. Haynes; Carleen Cullinane; Todd V. Brennan; Darryn Bampton; Paul Handley; Tomislav Karoli; Fleur Lanksheer; Liwen Lin; Yiping Yang; Keith Dredge
• Keywords: PG545; Male; Immunomodulatory; Programmed Cell Death 1 Receptor; Sustainable Development Goals; 610; Adenocarcinoma; tumor-associated macrophage; 03 medical and health sciences; Tumor-associated macrophage; Humans; NK cell; immunomodulatory; RC254-282; SDG 3; 0303 health sciences; pixatimod; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; 600; Saponins; 3. Good health; Pancreatic Neoplasms; Pixatimod; Female; Dendritic cell; Research Article

<h3>Background</h3> Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas immunostimulatory activity DCs through MyD88-dependent TLR9 pathway. recently completed Phase Ia monotherapy trial in advanced cancer patients. <h3>Methods</h3> To characterize safety administered by intravenous (IV) infusion, one month toxicology study was conducted support clinical trial. The relative exposure (AUC) across relevant species determined and influence route administration evaluated. Finally, potential utility combination PD-1 inhibition investigated using syngeneic 4T1.2 breast model. <h3>Results</h3> nonclinical profile revealed that main toxicities are elevated cholesterol, triglycerides, APTT, decreased platelets other changes symptomatic modulating immune system such as pyrexia, WBC subsets, inflammatory liver, spleen kidney. Though adverse events fever, cholesterol triglycerides were reported trial, none considered dose limiting compound well tolerated up 100&nbsp;mg via IV infusion. Exposure proportional some accumulation upon repeated dosing, phenomenon noted study. independent it enhanced effectiveness poorly immunogenic tumor <h3>Conclusions</h3> modulates innate but enhances T cell anti-PD-1 therapy. PK supports ongoing development Ib for cancer/pancreatic adenocarcinoma checkpoint inhibitor nivolumab (Opdivo®). <h3>Trial registration</h3> ClinicalTrials.gov Identifier: NCT02042781. First posted: 23 January, 2014 - Retrospectively registered.