Abstract
Oncolytic adenoviruses (OAd) selectively target and lyse tumor cells and enhance anti- tumor immune responses. OAds have been used as promising cancer gene therapies for many years and there are a multitude of encouraging pre-clinical studies. However, translating OAd therapies to the clinic has had limited success, in part due to the lack of realistic pre-clinical models to rigorously test the efficacy of OAds. Solid tumors have a heterogenous and hostile microenvironment that provides many barriers to OAd treatment, including structural and immunosuppressive components that cannot be modeled in two-dimensional tissue culture. To replicate these characteristics and bridge the gap between pre-clinical and clinical success, studies must test OAd therapy in three-dimensional culture and animal models. This review focuses on current methods to test OAd efficacy in vitro and in vivo and the development of new model systems to test both oncolysis and immune stimulatory components of oncolytic adenovirotherapy.
Highlights
Human adenovirus (Ad) is one of the most studied viruses for cancer therapy and has shown great promise as a cancer treatment owing to its high gene transduction efficiency and genetic stability, as well as our ability to manufacture vectors to a high titer [1,2]
This study indicates that selection and isolation of Oncolytic adenoviruses (OAd) from similar therapeutic environments results in a more potent OAd that is already “primed” towards a solid tumor microenvironment
In order to robustly evaluate their anti-tumor activity, OAd therapy must be tested in humanized mouse models with competent and complete immune systems [86]
Summary
Human adenovirus (Ad) is one of the most studied viruses for cancer therapy and has shown great promise as a cancer treatment owing to its high gene transduction efficiency and genetic stability, as well as our ability to manufacture vectors to a high titer [1,2]. Oncolysis of tumor cells after OAd infection releases pattern and damage-associated molecular patterns (PAMPs and DAMPs) and tumor-associated antigens (TAAs) that stimulate the immune response and enhance anti-tumor activity through epitope spreading or antigen cascade with limited clinical pathologies [6]. In order to model the biology of human OAd infection with the promotion of immunomodulatory effects, in vivo studies are required [11]. Recent studies using 3D cultures and hydrogels to better recapitulate the physical tumor structure and microenvironment in vitro can be combined with advanced in vivo models, such as humanized mouse models, to elucidate the anti-tumor and anti-viral immune responses to OAd. This review will address current efforts to pre-clinically model the efficacy of oncolytic adenovirus against solid tumors and describe new approaches to bridge the gap between preclinical and clinical studies
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