Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

Abstract

High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.

Keywords: clinical trial; glioma; immune microenviroment; immunotherapy; mouse model.

Figure 1

Current and novel immunotherapeutic strategies for GBM treatment under pre-clinical and clinical investigation. Current immunotherapeutic strategies in GBM include oncolytic viruses that can destroy glioma cells through immunogenic cell death without affecting non neoplastic brain cells, TAM reprogramming and the use of CAR T cells. Activation of immune checkpoint ligands such as PD-1, CTLA-4, and IDO can help tumor cells to escape immune surveillance. Thus, inhibition of them can effectively inhibit glioma progression and improve the response to other active immunotherapeutic strategies, such as DC vaccines and immunostimulant gene therapy. GBM antigens, including IL-13Rα2, HER2/neu and EGFRvIII are present in tumor cells. These tumor-associated antigens are targets of genetically modified CAR-T cells or peptide vaccines. Also, novel strategies are being studied currently in the pre-clinical setting, addressing more efficient ways to cross the blood-brain barrier (BBB), such as nanodiscs, and the modulation of the activity of novel targets. Created with BioRender.com.

Figure 2

Genomic sequencing of glioma patient tumor biopsies could guide the immunotherapy strategies selected based on the mutational profile and clinical status. Tumor biopsies obtained by surgical resection undergo high-throughput genomic sequencing to identify mutations present within the cancer cells. The genetic lesions detected could be used as a decision factor to select which immunotherapy to choose. Patients with primary tumors that express specific tumor antigens can undergo a variety of immune-based treatments that address these driver mutations directly and could be combined with chemotherapeutic agents and other approaches, such as immune checkpoint inhibitors. Patients that present with recurrent or residual glioma could also be treated with gene therapy or virotherapy-mediated approaches that directly target the glioma cells to trigger immune-stimulatory mechanisms.