Preclinical And Clinical Development Of Oncolytic Adenovirus For The Treatment Of Malignant Glioma.

Abstract

Replication conditional oncolytic human adenovirus has long been considered a promising biological therapeutic to target high-grade gliomas (HGG), a group of essentially lethal primary brain cancer. The last decade has witnessed initiation and some completion of a number of Phase I and II clinical investigations of oncolytic adenovirus for HGG in the US and Europe. Results of these trials in patients are pivotal for not only federal approval but also filling an existing knowledge gap that primarily derives from the stark differences in permissivity to human adenovirus between humans and preclinical mouse models. DNX-2401 (Delta-24-RGD), the current mainstream oncolytic adenovirus with modifications in E1A and the fiber, has been shown to induce impressive objective response and long-term survival (>3 years) in a fraction of patients with recurrent HGG. Responders exhibited initial enlargement of the treated lesions for a few months post treatment, followed by shrinkage and near complete resolution. In accord with preclinical research, post-treatment specimens revealed virus-mediated alteration of the immune tumor microenvironment as evidenced by infiltration of CD8+ T cells and M1-polarized macrophages. These findings are encouraging and together with further information from ongoing studies have a potential to make oncolytic adenovirus a viable option for clinical management of HGG. This review deals with this timely topic; we will describe both preclinical and clinical development of oncolytic adenovirus therapy for HGG, summarize updated knowledge on clinical trials and discuss challenges that the field currently faces.