Abstract
Abstract Background: Treatment approaches that engage both the innate and adaptive immune response have the potential to transform anti-cancer therapy, especially in settings of checkpoint inhibitor insensitivity or acquired resistance. Toll-like receptors (TLRs) are a class of targets that mediate the initial cellular response to external pathogens or endogenous alarmins, activating downstream pro-inflammatory cascades and leading to the activation and recruitment of key innate subsets. TLR2 is a cell surface receptor, expressed predominantly on macrophages, dendritic cells (DC), neutrophils and subsets of NK and T cells. TLR2 signaling plays important role in NK and T cell cytolytic cell functions, as well as DC and macrophage activation. AXA-042 is a novel synthetic TLR2/6 agonist designed for systemic delivery to re-engage the innate immune response to help overcome tumour immune escape. Methods: In vitro potency and selectivity of AXA-042 was assessed across a panel of human and mouse HEK-blue TLR reporter assays. AXA-042 activity was profiled relative to other TLR agonists in human PBMC cytokine release assays. AXA-042 in vivo efficacy was evaluated in the EMT6 and CT26 syngeneic tumour models. The Nanostring nCounter™ Mouse PanCancer Immune Profiling Panel was used to identify AXA-042 tumour-localized and peripheral response signatures. Results: AXA-042 demonstrated potent and selective activity in murine and human TLR2/6 reporter assays and a differential PBMC cytokine release profile relative to other TLR agonists in vitro. Systemic delivery (QW, IV or IP) of AXA-042 significantly inhibited EMT6 and CT26 tumour growth, which was accompanied by an increase in circulating plasma levels of IL6, IL12 and CXCL10. Combination with anti-PD-1 Ab further potentiated anti-tumour response, resulting in approximately 30-40% tumour regressions. AXA-042 anti-tumour effects were accompanied by increased activation of the tumour-infiltrating myeloid cells, including DCs and macrophages, and a reduction in the M2 TAM subset. Nanostring analysis confirmed TLR and IFNγ pathway engagement and revealed an induction of gene signatures associated with macrophage, DC and NK functions. Longitudinal studies to characterize whole blood biomarkers associated with response are currently in progress. Conclusion: AXA-042 was well tolerated in vivo and demonstrated innate response engagement and anti-tumour efficacy as monotherapy and in combination with anti-PD-1 immunotherapy. AXA-042 has completed GLP toxicology studies and initiation of Phase 1/1b trial is planned for early 2022. Citation Format: Anna V. Galkin, Francesca Mercuri, Nicholas West, Ping Zhang, Weiguang Zeng, Grant McLachlan, Michael Bettess, Ian Holmes, David Jackson, Chris Smith, Christophe Demaison, Tobias Bald, Phil Kearney. AXA-042 - a novel systemic TLR2/6 agonist for anti-tumor therapy [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 3502.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have