LAUSR

Despite the recent breakthrough of checkpoint blockade antibodies targeting T cells to combat cancer, it has become apparent that the majority of patients are not fully responsive. Engaging innate immune cells is a promising way to fully exploit the anti-cancer potential of the immune system. Our strategy is to stimulate TOLL-like receptors (TLRs) with MEDI9197, a potent TLR7 and TLR8 agonist, which stimulates the release of interferon-alpha (IFN-α) from plasmacytoid dendritic cells (pDCs) and interleukin-12 (IL-12) and other cytokines from myeloid DCs. While several compounds including MEDI9197, CpG and STING agonists can induce the production of IFN-α, we show that only MEDI9197 is able to induce high levels of interferon-gamma (IFN-γ) and IL-12p70 in human PBMCs, a hallmark of TLR 7/8 agonists. We also demonstrate in vitro that MEDI9197 upregulates activation markers on both innate and adaptive human immune cells, repolarizes macrophages and skews immunity from a Th2 towards a Th1 phenotype in a PHA assay, thereby increasing the functional activity of NK and cytotoxic CD8 cells. MEDI9197 is an imidazoquinoline with a unique lipid tail and formulation designed for intratumoral (IT) dosing and retention at the site of injection to minimize unwanted systemic exposure. Mass spectrometry imaging of MEDI9197 in mouse tumors and whole-body autoradiography in rats confirm local retention of MEDI9197, with Citation Format: Stefanie R. Mullins, John Vasilakos, Katharina Deschler, Iwen Grigsby, Song Ren, Matthew J. Elder, Simon J. Dovedi, Andrew J. Leishman, Patricia Ryan, Zachary Cooper, James Elvecrog, Ronald Herbst, Rakesh Kumar, Mark Tomai, Robert W. Wilkinson. Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 711.