- Title
- Immunomodulatory activities of pixatimod: Emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors
- Creator
- Hammond, Edward; Haynes, Nicole M.; Cullinane, Carleen; Brennan, Todd V.; Bampton, Darryn; Handley, Paul; Karoli, Tomislav; Lanksheer, Fleur; Lin, Liwen; Yang, Yiping; Dredge, Keith
- Relation
- Journal for ImmunoTherapy of Cancer Vol. 6, Issue 54, p. 1-13
- Publisher Link
- http://dx.doi.org/10.1186/s40425-018-0363-5
- Publisher
- BioMed Central
- Resource Type
- journal article
- Date
- 2018
- Description
- Background: Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients.Methods: To characterize the safety of pixatimod administered by intravenous (IV) infusion, a one month toxicology study was conducted to support a Phase Ia monotherapy clinical trial. The relative exposure (AUC) of pixatimod across relevant species was determined and the influence of route of administration on the immunomodulatory activity was also evaluated. Finally, the potential utility of pixatimod in combination with PD-1 inhibition was also investigated using the syngeneic 4T1.2 breast cancer model. Results: The nonclinical safety profile revealed that the main toxicities associated with pixatimod are elevated cholesterol, triglycerides, APTT, decreased platelets and other changes symptomatic of modulating the immune system such as pyrexia, changes in WBC subsets, inflammatory changes in liver, spleen and kidney. Though adverse events such as fever, elevated cholesterol and triglycerides were reported in the Phase Ia trial, none were considered dose limiting toxicities and the compound was well tolerated up to 100 mg via IV infusion. Exposure (AUC) up to 100 mg was considered proportional with some accumulation upon repeated dosing, a phenomenon also noted in the toxicology study. The immunomodulatory activity of pixatimod was independent of the route of administration and it enhanced the effectiveness of PD-1 inhibition in a poorly immunogenic tumor model. Conclusions: Pixatimod modulates innate immune cells but also enhances T cell infiltration in combination with anti-PD-1 therapy. The safety and PK profile of the compound supports its ongoing development in a Phase Ib study for advanced cancer/pancreatic adenocarcinoma with the checkpoint inhibitor nivolumab (Opdivo).
- Subject
- pixatimod; PG545; immunomodulatory; tumor-associated macrophage; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1454471
- Identifier
- uon:44951
- Identifier
- ISSN:2051-1426
- Rights
- © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Language
- eng
- Full Text
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