Modeling the Efficacy of Oncolytic Adenoviruses In Vitro and In Vivo: Current and Future Perspectives

Abstract

Oncolytic adenoviruses (OAd) selectively target and lyse tumor cells and enhance antitumor 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. Author Contributions: Conceptualization, M.S.; Writing-Original Draft, M.K.M.; Writing-Review and Editing, M.K.M., A.R.-S. and M.S.; Supervision, M.S.; Funding Acquisition, M.S. All authors have read and agreed to the published version of the manuscript.

Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

“…The ability of the combination treatment using oncolytic viruses with pembrolizumab to enhance anti-cancer potency and induce immunogenic cell death were investigated in vivo. To this aim, we used the C57BL/6 as the immunocompetent mouse model rather than immunodeficient xenograft alternative models [ 53 ] since we aimed to elucidate the involvement and contribution of the immune system to the efficacy of our combination therapy. Syngeneic tumor models (C57BL/6 or BALB/c mice) are the oldest and most commonly utilized preclinical models to evaluate anticancer therapeutics.…”

Developing μSpherePlatform Using a Commercial Hairbrush: An Agarose 3D Culture Platform for Deep-Tissue Imaging of Prostate Cancer

“…Extensive immunohistochemical analysis revealed upregulated expression of PSMA on malignant prostatic epithelia and undetectable levels in normal tissues . The uptake study and selective internalization of bioconjugate 12 in PSMA + LNCaP cells are shown in Figure .…”

“…Estimates suggest that >80% of biologists rely on two-dimensional (2D) culture assays prior to in vivo testing because of their convenience, simplicity, and accessibility . Advantages of employing three-dimensional (3D) culture models over 2D culture include (i) increased interactions between cells and extracellular matrix, (ii) study of site-specific stromal cells in tumor microenvironments, (iii) study of varying cell proliferation zones, and (iv) establishment of oxygen, nutrient, metabolites, and catabolite gradients mimicking the solid tumor environment. , Image-guided tracking of diagnostics in 3D tumor models is a major medical need as it enables the study of the movement of fluorophores in real time .…”

Animal Models in Human Adenovirus Research

“…In vivo studies on adenoviral vectors in general and their use in vaccine- and gene therapy approaches in particular have been extensively reviewed. The same applies to oncolytic adenoviruses in animal models that are not part of this work, but were reviewed by others recently [ 8 , 9 , 10 , 11 , 12 ]. This review outlines the current knowledge on HAdV susceptibility of different animal models, highlighting key features, strengths, and limitations.…”