Assessment of current virotherapeutic application schemes: "hit hard and early" versus "killing softly"?

Over the past two decades, a considerable amount of oncolytic vector families has entered numerous clinical trials. However, to this date, the field has not yet been able to come to a common understanding regarding the best possible ways to administer oncolytic viruses to cancer patients. This is mainly due to the fact that so far clinical trials being designed for head-to-head comparisons (such as using two different virotherapeutics originating from two distinct virus families being applied via identical routes in the same types of cancer) are still missing. Hence, there is no consent (i) on the best route of virotherapeutics administration (e.g., systemic versus intratumoral), (ii) on the virus dosages to be applied, (iii) on dosing intervals, and (iv) on the numbers of repetitive courses of virus administration. As the detailed comparison of clinical virotherapy trial regimens is time-consuming and complex, we here present an overview of current state-of-the-art virotherapeutic application schemes. Notably, our comprehensive assessment culminates in raising two rough classifications of virotherapeutic strategies, i.e., "hit hard and early" versus "killing softly". In order to find out which one of these two gross alternatives might be most successful for each and every tumor entity, we here suggest the implementation of phase 1/2 studies, which primarily aim at a repetitive sampling and analysis of tumor samples in cancer patients treated with oncolytic viruses reading out (i) virus-specific, (ii) tumor-specific as well as (iii) immunotherapeutic parameters. On this basis, a rational design of significantly improved virotherapeutic application schemes should be possible in the future.