Interleukin $($IL$)-15$ is a pleiotropic cytokine with multiple roles that improve immune responses to tumor cells. Oncolytic viruses $($OV$)$ specifically lyse tumors and activate immune responses. Systemic administration of IL$-15$ or its complex with the IL$-15$R and chimeric antigen receptor $($CAR$)$ natural killer $($NK$)$ cells are currently being tested in the clinic. Here we generated

a herpes simplex $1-$based OV expressing human IL$-15/$IL$-15$R sushi domain fusion protein $($named OV$-$IL$15$C$),$ as well as off$-$the$-$shelf EGFR$-$CAR NK cells, and studied their monotherapy and combination efficacy in vitro and in multiple glioblastoma $($GBM$)$ mouse models. In

vitro, soluble IL$-15/$IL$-15$R complex was secreted from OV$-$IL$15$C$-$infected GBM cells, which promoted GBM cytotoxicity and improved survival of NK and CD$8+$ T cells. Frozen, readily available off$-$the$-$shelf EGFR$-$CAR NK cells showed enhanced killing of tumor cells compared