**9. Orchestrating Anti-Cancer Innate Immune Cells in the Absence of Functional HLA**

A great strength of oncolytic viruses is that they are fully customizable drugs that can be fine-tuned to accomplish the tasks at hand. Where adaptive immunity is unlikely to be harnessed, arming elements targeting cancer vaccine approaches can be swapped out for those targeting the innate immune system. NK cells have been directly implicated in enhancing the efficacy of oncolytic viruses in experimental models [83]. Arming oncolytic viruses with IL-15 [84] is likely to augment NK activation, while strategies based on CCL5 chemotaxis [85] have been used to attract them in to tumors. Expression of SIRPa-Fc antagonists from oncolytic viruses can block the CD47 "don't eat me" signals on cancer cells and facilitate macrophages to attack them directly [86]. Building on the BiTE principle, it is now possible to develop bispecific killer cell engagers (BiKEs) that crosslink cancer cell surface antigens with CD16 on NK cells, or better still, trispecific TriKEs that included further functionality through integrating IL-15 [87,88]. Equivalent approaches using BiMEs (bispecific macrophage engagers) to activate macrophages have also been reported [89]. Like all arming approaches to activate the adaptive immune system, strategies for exploiting innate cells will benefit from selective expression in the tumor microenvironment provided

by oncolytic viruses. Careful design of the innate immune cell stimulation is required in order to avoid the premature and unwanted elimination of virus-infected cells.
