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

Juri Kiyokawa, Hiroaki Wakimoto, Juri Kiyokawa, Hiroaki Wakimoto

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.

Keywords: glioblastoma; glioma; high-grade; immunotherapy; oncolytic adenovirus; pseudo-progression; tumor microenvironment.

Conflict of interest statement

The authors report no conflicts of interest in this work.

© 2019 Kiyokawa and Wakimoto.

Figures

Figure 1
Figure 1
Genomic structure of oncolytic adenoviruses currently used in pre-clinical and clinical studies on high-grade glioma. ITR, inverted terminal repeat. E1AΔ24: a deletion of 24 base pairs within the E1A region. DM: insulator DM-1. E2Fp: E2F-responsive promoter. K: a Kozak sequence. E2F-pal: E2F-responsive palindromes (8 E2F-binding sites). PH20: human sperm PH20 hyaluronidase cDNA. RGD: an RGD integrin-binding motif in the HI loop of the fiber. RGDK: RGDK in the putative heparin sulfate-glycosaminoglycans binding domain KKTK in the fiber shaft. pCMV: the cytomegalovirus promoter. mOX40L: mouse OX40L cDNA. BGH pA: bovine growth hormone poly-adenylation signal. The mOX40L expression cassette replaces the E3 region in Delta-24-RGDOX.
Figure 2
Figure 2
Dynamic changes that occur over time within the tumor microenvironment after oncolytic adenovirus therapy of glioblastoma. Upper, macroscopic and radiographic changes. Lower, microscopic-level changes. (A) Before treatment, the GBM tumor microenvironment is immune-suppressive as characterized by M2-polarized macrophages and few effector T cells. (B) A few days after virus administration, oncolytic adenovirus is actively replicating within the tumor, starting to induce the recruitment of effector T cells and macrophages with a shift from an M2 to M1 phenotype. (C) A few months later, the tumor exhibits an increase in size on magnetic resonance imaging (MRI). At this stage, virus has been cleared, but an active inflammatory reaction persists with the infiltration of immune cells such as T cells and M1-polarized macrophages. Tumor cells are essentially absent (necrosis), despite the worsening of imaging (pseudo-progression). (D) During the follow-up, inflammation gradually subsides and MRI shows progressive regression of the lesion and associated edema, which could take over a year.

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