RT Journal Article SR Electronic T1 Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP 244 DO 10.1186/s40425-019-0724-8 VO 7 IS 1 A1 Stefanie R. Mullins A1 John P. Vasilakos A1 Katharina Deschler A1 Iwen Grigsby A1 Pete Gillis A1 Julius John A1 Matthew J. Elder A1 John Swales A1 Elina Timosenko A1 Zachary Cooper A1 Simon J. Dovedi A1 Andrew J. Leishman A1 Nadia Luheshi A1 James Elvecrog A1 Ashenafi Tilahun A1 Richard Goodwin A1 Ronald Herbst A1 Mark A. Tomai A1 Robert W. Wilkinson YR 2019 UL http://jitc.bmj.com/content/7/1/244.abstract AB Background Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically “cold” tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated.Methods The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models.Results Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models.Conclusion Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.Abbreviations:APCAntigen presenting cellCRSCytokine release syndromedLNAxilliary and brachial lymph nodesFPFusion proteinICBImmune checkpoint blockadeIMIntramuscularIPIntraperitonealITIntratumoralmAbsMonoclonal antibodiesmDCMyeloid dendritic cellsMECMinimum effective concentrationMLRMixed lymphocyte reactionmo-DCMonocyte-derived DCNKNatural killerPDPharmacodynamicpDCPlasmacytoid dendritic cellsQRAQuantitative radiochemical analysisQWBAQuantitative whole-body autoradiographySCSubcutaneousSTINGStimulator of interferon genesTILsTumor infliltrating lymphocytesTLRToll-like receptorTMETumor microenvironment