PT - JOURNAL ARTICLE AU - Müller, Louise M. E. AU - Holmes, Matthew AU - Michael, Joanne L. AU - Scott, Gina B. AU - West, Emma J. AU - Scott, Karen J. AU - Parrish, Christopher AU - Hall, Kathryn AU - Stäble, Sina AU - Jennings, Victoria A. AU - Cullen, Matthew AU - McConnell, Stewart AU - Langton, Catherine AU - Tidswell, Emma L. AU - Shafren, Darren AU - Samson, Adel AU - Harrington, Kevin J. AU - Pandha, Hardev AU - Ralph, Christy AU - Kelly, Richard J. AU - Cook, Gordon AU - Melcher, Alan A. AU - Errington-Mais, Fiona TI - Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21 AID - 10.1186/s40425-019-0632-y DP - 2019 Dec 01 TA - Journal for ImmunoTherapy of Cancer PG - 164 VI - 7 IP - 1 4099 - http://jitc.bmj.com/content/7/1/164.short 4100 - http://jitc.bmj.com/content/7/1/164.full SO - J Immunother Cancer2019 Dec 01; 7 AB - Background The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible.Methods This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment.Results An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response.Conclusion This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.Abbreviations:AMLAcute myeloid leukemiaAPCAntigen presenting cellCTLCytotoxic T lymphocyteCVA21Coxsackievirus A21DAFDecay accelerating factorDAMPsDamage-associated molecular patternsDCDendritic cellsHDACHistone deacetylaseHSVHerpes simplex virusICAM-1Intercellular adhesion molecule 1mDCMyeloid –derived DCMMMultiple myelomaNK cellNatural killer cellsOVOncolytic virusOVTOncolytic virotherapyPAMPsPathogen-associated molecular patternsPBMCPeripheral blood mononuclear cellspDCPlasmacytoid DCTAATumor-associated antigenVPAValproic acidVSVVesicular stomatitis virus