Immune Suppression during Oncolytic Virotherapy for High-Grade Glioma; Yes or No?

Abstract

Oncolytic viruses have been seriously considered for glioma therapy over the last 20 years. The oncolytic activity of several oncolytic strains has been demonstrated against human glioma cell lines and in in vivo xenotransplant models. So far, four of these stains have additionally completed the first phase I/II trials in relapsed glioma patients. Though safety and feasibility have been demonstrated, therapeutic efficacy in these initial trials, when described, was only minor. The role of the immune system in oncolytic virotherapy for glioma remained much less studied until recent years. When investigated, the immune system, adept at controlling viral infections, is often hypothesized to be a strong hurdle to successful oncolytic virotherapy. Several preclinical studies have therefore aimed to improve oncolytic virotherapy efficacy by combining it with immune suppression or evasion strategies. More recently however, a new paradigm has developed in the oncolytic virotherapy field stating that oncolytic virus-mediated tumor cell death can be accompanied by elicitation of potent activation of innate and adaptive anti-tumor immunity that greatly improves the efficacy of certain oncolytic strains. Therefore, it seems the three-way interaction between oncolytic virus, tumor and immune system is critical to the outcome of antitumor therapy. In this review we discuss the studies which have investigated how the immune system and oncolytic viruses interact in models of glioma. The novel insights generated here hold important implications for future research and should be incorporated into the design of novel clinical trials.

A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model

“…Additionally, these approaches are also intriguing options for exploration in combinatorial treatment strategies that utilize other immunotherapeutic agents. Our findings further endorse the likely benefit of this approach, and we encourage further investigation of the synergistic effects of virotherapy and immunotherapy 33, 34…”

A mathematical approach to virus therapy of glioblastomas

“…This model could be extended to be applied to in vivo experiments where, among other effects, the immune response should be also included in the model because it may play a significant role regulating the efficacy of the therapy. In particular, it seems that there is currently no agreement about which approach is better in oncolytic therapy, whether to modify oncolytic viruses to obtain the maximum antitumoral immune response [ 39 ], to transiently suppress the immune response [ 40 ], or to use a combination of both [ 40 ]; future appropriate modeling of the three scenarios might help in tackling this controversy from a different perspective.…”

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

“…Oncolytic virotherapy uses viruses to selectively destroy cancer cells and is gathering momentum as a novel approach for pHGG . Oncolytic viruses confer their antitumor activity through direct cancer cell lysis and by induction of both the innate and adaptive antitumor immune responses . A small number of studies have focused on oncolytic virotherapy for pHGG …”

“…74,75 Oncolytic viruses confer their antitumor activity through direct cancer cell lysis and by induction of both the innate and adaptive antitumor immune responses. 74,76 A small number of studies have focused on oncolytic virotherapy for pHGG. 74,75 Herpes simplex virus-1 G207 has been delivered by continuous infusion via intratumoral catheters to pediatric patients with recurrent malignant supratentorial tumors.…”