Summary
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 immunotherapy
Competing Interest Statement
Memorial 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.