Genetic therapies, including transfected immune cells and viral vectors, continue to show clinical responses as systemically deliverable and targeted therapeutics, with the first such approaches having been approved for cancer treatment. The majority of these employ cytokine transgenes. However, expression of cytokines early after systemic delivery can result in increased toxicity and nonspecific induction of the immune response. In addition, premature immune-mediated clearance of the therapy may result, especially for viral-based approaches. Here, it was initially verified that cytokine (interleukin (IL)2) or chemokine (CCL5) expression from a systemically delivered oncolytic virus resulted in reduced oncolytic activity and suboptimal immune activation, while IL2 also resulted in increased toxicity. However, all these limitations could be overcome through incorporation of exogenous regulation of cytokine or chemokine transgene function through fusion of a small and externally controllable destabilizing domain to the protein of interest. Regulation allowed an initial phase without cytokine function, permitting enhanced delivery and oncolytic activity before activation of cytokine function and a subsequent phase of enhanced and tumor-targeted immunotherapeutic activity. As a result of this exogenous regulation of cytokine function, both oncolytic and immune-mediated mechanisms of action were optimized, greatly enhancing therapeutic activity, while toxicity was significantly reduced.