Development of immunotherapy for high-grade gliomas: Overcoming the immunosuppressive tumor microenvironment

Abstract

The preclinical and clinical development of novel immunotherapies for the treatment of central nervous system (CNS) tumors is advancing at a rapid pace. High-grade gliomas (HGG) are aggressive tumors with poor prognoses in both adult and pediatric patients, and innovative and effective therapies are greatly needed. The use of cytotoxic chemotherapies has marginally improved survival in some HGG patient populations. Although several challenges exist for the successful development of immunotherapies for CNS tumors, recent insights into the genetic alterations that define the pathogenesis of HGG and their direct effects on the tumor microenvironment (TME) may allow for a more refined and targeted therapeutic approach. This review will focus on the TME in HGG, the genetic drivers frequently found in these tumors and their effect on the TME, the development of immunotherapy for HGG, and the practical challenges in clinical trials employing immunotherapy for HGG. Herein, we will discuss broadly the TME and immunotherapy development in HGG, with a specific focus on glioblastoma multiforme (GBM) as well as additional discussion in the context of the pediatric HGG diagnoses of diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG).

Immunotherapy associated central nervous system complications in primary brain tumors

“…Cancer immunotherapy is an exciting and emerging therapeutic field for extracranial malignancies with the promise of forward progress and marked improvement in patient outcomes in several solid tumor malignancies. Yet, in primary brain tumors, failures of later phase clinical trials evaluating immunotherapy treatments have highlighted the ongoing challenges of single agent immunotherapy in the treatment of brain cancer with ongoing and planned trials evaluating combinations of immunotherapeutics including approaches aimed at changing the immunosuppressive tumor microenvironment ( 152 ).…”

Updates in Glioblastoma Immunotherapy: An Overview of the Current Clinical and Translational Scenario

“…As an immunosuppression-associated tumor, GBM negatively affects the local and systemic immune system’s response to both tumor antigens and intrinsic factors [ 23 , 24 ]. While the exact mechanism of these effects remains unknown, numerous theories have been proposed over time.…”

The function of histone methylation and acetylation regulators in GBM pathophysiology

“…In contrast, the SB28 model demonstrates a greater resistance to immune checkpoint blockade, more faithfully recapitulating human glioblastoma immune characteristics ( 213 ). A recent review highlighting the importance of diverse cellular and extracellular components that contribute to the TME found in human glioblastoma adds salience to the need for more robust pre-clinical models ( 214 , 215 ). Additional examples supporting the need for immunocompetent mouse models include, as mentioned earlier, prolonged inhibition of EZH2 leading to a reversion back to a pro-growth state ( 141 ).…”