Synergy Of Tlr4 Agonist Gsk1795091, An Innate Immune Activator, With Agonistic Antibody Against Co-Stimulatory Immune Checkpoint Molecule Ox40 In Cancer Immunotherapy.

12055 Background: GSK1795091 (aka, GSK’091) is a synthetic glycolipid toll-like receptor 4 (TLR4) agonist. TLR4 is a Pattern Recognition Receptor for host defense against bacterial infection, expressed on innate immune cells monocytes, macrophages, dendritic cells. GSK’091 is a potent and selective TLR4 agonist and is being evaluated for use in combination with other immunotherapies to treat cancer Methods: To understand the antitumor activity and pharmacologic effects of intravenously administered GSK’091, in vivo studies were performed in murine syngeneic tumor models. Pharmacodynamic (PD) effects of GSK’091 was examined in peripheral and tumor infiltrating lymphocytes (TILs) using multicolor flow cytometry assays. Additionally, TCRβ sequencing, Nano string and multiplex cytokine assays were employed to understand the molecular and cellular mechanisms induced by this molecule Results: GSK’091 potently activated the immune system and modulated the tumor microenvironment by inducing an array of proinflammatory cytokines, enhancing antigen presentation, activating T cells, and reducing T regulatory cells. At doses sufficient to induce systemic cytokines in mice, GSK’091 inhibited tumor growth and resulted in long term survival in tumor model. When administrated with OX86, a murine surrogate OX40 agonist monoclonal antibody (mAb), the combination induced a robust PD response as demonstrated by a significant increase in Th1 cytokines, expression of interferon regulated genes, higher tumor infiltration by leucocytes, increase in T cell activation , proliferation and increase in the CD8: Treg ratio. Additionally, GSK’091 when combined with anti-OX40 induced clonal expansion of T-cells and drove synergistic interferon and T-cell dependent anti-tumor response Conclusions: The current study demonstrated that GSK’091 activates key initiating immune pathways and can induce robust anti-tumor efficacy when combined with agonistic antibodies directed against the OX40 receptor. This novel combination provides a strong rationale and supports evaluation of GSK’091 in combination with immuno-oncology agents in clinical trials