Current use of pre-clinical models for evaluation of human adenovirus-based cancer therapeutics

Human adenoviruses (HAdVs) are enjoying a renaissance in interest for the development of cancer therapies following the approval of Adstiladrin (Ferring Pharmaceuticals) for the treatment of bladder cancer, strong phase 3 data from CG Oncology's cretostimogene grenadenorepvec, and many other products in late-stage clinical development. Most therapeutic oncolytic HAdV (oHAdV)-based vectors are engineered to enhance their natural selectivity for human cancer cells and/or to alter their capsid proteins to bias their tropism toward cancer tissues. Furthermore, modern therapeutic oHAdV-based vectors often include transgenes encoding potent immunotherapies. These transgenes have the potential to overcome the relatively modest efficacy that has been observed for non-transgene-bearing viruses, which rely on direct oncolysis of virally infected tumor cells. These modifications, and the highly complex interactions that occur between oHAdVs and the host, make it particularly challenging to develop relevant animal models to investigate acute toxicity, immunity, efficacy, and pharmacodynamics for pre-clinical development of these agents. Here, the experimental options for pre-clinical evaluation of therapeutic oHAdV-based vectors for cancer therapy are reviewed, with a focus on Ad serotype 5 (Ad5), the most common serotype for therapeutic oHAdV-based vector development.