Background and Objective <p>Oncolytic viruses (OVs) are a growing immuno-oncology therapeutic class that rely on their capability to activate the dormant endogenous anti-tumor immune response in order to control or eradicate tumor cells. Given their intrinsic mechanisms of action and their biological nature, development of antidrug antibodies (ADA) represents an important aspect to consider during clinical evaluation. ADAs can potentially affect viral kinetics and/or dynamics, ultimately resulting in reductions or even loss of drug efficacy. Here, we present a semi-mechanistic pharmacokinetic/pharmacodynamic model characterizing the interplay between V937 and neutralizing ADA in cancer patients receiving the V937 oncolytic virus.</p> Methods <p>The quantitative framework has been developed integrating viral load and ADA titers from 208 cancer patients who received V937 following intratumoral or intravascular administration, in monotherapy or in combination with pembrolizumab.</p> Results <p>The model successfully captured both V937 time course and the dynamics of ADAs under the different settings, showing no meaningful impact of ADAs on viral kinetics. Moreover, tumor response was neither affected by the preexistence or development of ADAs, which can be explained by the primary role of the immune system in the response.</p> Conclusions <p>This quantitative and (semi-) mechanistic framework can be expanded to other oncolytic viruses and used to explore under which scenarios a relevant impact could be observed, thus supporting the development of novel oncolytic viral therapies.</p>