Synthetic and systems biology principles in the design of programmable oncolytic virus immunotherapies for glioblastoma

Abstract

Oncolytic viruses (OVs) are a class of immunotherapeutic agents with promising preclinical results for the treatment of glioblastoma (GBM) but have shown limited success in recent clinical trials. Advanced bioengineering principles from disciplines such as synthetic and systems biology are needed to overcome the current challenges faced in developing effective OV-based immunotherapies for GBMs, including off-target effects and poor clinical responses. Synthetic biology is an emerging field that focuses on the development of synthetic DNA constructs that encode networks of genes and proteins (synthetic genetic circuits) to perform novel functions, whereas systems biology is an analytical framework that enables the study of complex interactions between host pathways and these synthetic genetic circuits. In this review, the authors summarize synthetic and systems biology concepts for developing programmable, logic-based OVs to treat GBMs. Programmable OVs can increase selectivity for tumor cells and enhance the local immunological response using synthetic genetic circuits. The authors discuss key principles for developing programmable OV-based immunotherapies, including how to 1) select an appropriate chassis, a vector that carries a synthetic genetic circuit, and 2) design a synthetic genetic circuit that can be programmed to sense key signals in the GBM microenvironment and trigger release of a therapeutic payload. To illustrate these principles, some original laboratory data are included, highlighting the need for systems biology studies, as well as some preliminary network analyses in preparation for synthetic biology applications. Examples from the literature of state-of-the-art synthetic genetic circuits that can be packaged into leading candidate OV chassis are also surveyed and discussed.

Oncolytic virotherapy using neural stem cells as a novel treatment option for glioblastoma multiforme

“…IFNAR1/IFNAR2 transduces autocrine and paracrine signals through early IFNs, activating ISGs as well as IRF7 via ISG3 (STAT1/STAT2/IRF9). IFNAR3/IFNAR4 transduces autocrine and paracrine late IFN signals 21,163 . A number of ISGs can inhibit viral replication while also slowing down the host cell's metabolism.…”

“…IFNAR3/IFNAR4 transduces autocrine and paracrine late IFN signals. 21,163 A number of ISGs can inhibit viral replication while also slowing down the host cell's metabolism. Increased levels of IFN are produced by cells when IRF7 is utilized to activate the PRR.…”

Systems neuroimmunology: a review of multiomics methodologies to characterize neuroimmunological interactions in spinal and cranial diseases

“…33 Given how complex these interactions between immune cells and GBM cells are, there has been an increasing appreciation of the need for systems-based approaches to develop new immunotherapies for GBM. 34 Herein, we present use case 3, our second use case based on original work that uses systems neuroimmunology to better understand how the immune system interacts with GBM, in which we aimed to determine potential therapeutic targets for HSV-1-derived oncolytic viruses (OVs) to treat GBM. This use case underscores how proteomic data analysis can generate insights about GBM neuroimmunology.…”

Characterization and Optimization of the Tumor Microenvironment in Patient-Derived Organotypic Slices and Organoid Models of Glioblastoma

“…New therapeutic approaches are desperately needed. In recent years, major progress has been made in developing new immunotherapeutic treatment options such as bispecific T-cell engagers (BiTes) [9,10], chimeric antigen receptors (CAR) T-cell therapies [11][12][13] or oncolytic viruses [14,15].…”