TY - JOUR T1 - Intratumoral delivery of engineered recombinant modified vaccinia virus Ankara expressing Flt3L and OX40L generates potent antitumor immunity through activating the cGAS/STING pathway and depleting tumor-infiltrating regulatory T cells JF - bioRxiv DO - 10.1101/2021.10.31.466698 SP - 2021.10.31.466698 AU - Ning Yang AU - Yi Wang AU - Shuaitong Liu AU - Joseph M. Luna AU - Gregory Mazo AU - Adrian Y. Tan AU - Tuo Zhang AU - Jiahu Wang AU - Wei Yan AU - John Choi AU - Anthony Rossi AU - Jenny Zhaoying Xiang AU - Charles M. Rice AU - Taha Merghoub AU - Jedd D. Wolchok AU - Liang Deng Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/11/01/2021.10.31.466698.abstract N2 - Intratumoral (IT) delivery of immune-activating viruses can serve as an important strategy to turn “cold” tumors into “hot” tumors, resulting in overcoming resistance to immune checkpoint blockade (ICB). Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus that has a long history of human use. Here we report that IT recombinant MVA (rMVA), lacking E5R encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase (cGAS), expressing a dendritic cell growth factor, Fms-like tyrosine kinase 3 ligand (Flt3L), and a T cell co-stimulator, OX40L, generates strong antitumor immunity, which is dependent on CD8+ T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and STAT1/STAT2-mediated type I IFN signaling. Remarkably, IT rMVA depletes OX40hi regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Taken together, our study provides a proof-of-concept for improving MVA-based cancer immunotherapy, through modulation of both innate and adaptive immunity.One Sentence Summary Intratumoral delivery of recombinant MVA for cancer immunotherapyCompeting Interest StatementMemorial Sloan Kettering Cancer Center filed a patent application for the use of recombinant MVAΔE5R-Flt3L-OX40L as monotherapy or in combination with immune checkpoint blockade for solid tumors. L.D., J.D.W., T.M., N.Y. Y.W. are authors on the patent, which has been li-censed to IMVAQ Therapeutics. L.D., J.D.W., T.M., W.Y., J.C., N.Y. are co-founders of IMVAQ Therapeutics and C.M.R. is a member of the scientific advisory board of IMVAQ Thera-peutics. ER -