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).

Keywords: gene therapy; gliomas; immune suppression; immunotherapy; tumor microenvironment.

Figure 1

Strategies to redirect T cells toward tumor cells using TCRs and CARs. T cells can be redirected against TAAs via viral transduction of specific T Cell Receptors (TCRs) or Chimeric Antigen Receptors (CARs), which identify target molecules in the surface of tumor cells independently of MHCI presentation. LTR, Long Terminal Repeat; Fab, fragment antigen-binding region; TM, transmembrane domain.

Figure 2

The immune mediated gene therapy consisting of Ad-TK [plus Ganciclovir (GCV)], and Ad-Flt3L. Glioma cells can be efficiently transduced with Ad-TK, which encodes the conditionally cytotoxic HSV1-Thymidine Kinase (TK). TK can convert the prodrug GCV, a nucleotide analog, to GCV-phosphate, which is further phosphorilated into GCV-triphosphate by intracellular kinases. GCV-triphosphate is a purine analog and can inhibits DNA replication, inducing Immunogenic Cell Death (ICD). Dying cells release Damage-Associated Molecular Patterns (DAMPs), i.e., HMBG1, calreticulin, and ATP. Glioma cells transduced with Ad-Flt3L, express and secret Flt3L that recruits dendritic cells (DC) into the tumor microenvironment, where they uptake tumor associated antigens and get activated by DAMPs. Mature antigen presenting cells (APC) migrate to the regional lymph nodes and prime anti-tumor cytotoxic CD8+ T lymphocytes. Cytotoxic T cells recognize and kill tumor cells. Following T cells exposure to tumor antigen, immunological memory is developed. Memory T cells activate an anti-tumor response leading to inhibition of tumor recurrence.