Current state of immunotherapy for glioblastoma

Abstract

Glioma is the most common primary cancer of the central nervous system, and around 50% of patients present with the most aggressive form of the disease, glioblastoma. Conventional therapies, including surgery, radiotherapy, and pharmacotherapy (typically chemotherapy with temozolomide), have not resulted in major improvements in the survival outcomes of patients with glioblastoma. Reasons for this lack of progress include invasive tumour growth in an essential organ, which limits the utility of local therapy, as well as the protection of tumour cells by the blood-brain barrier, their intrinsic resistance to the induction of cell death, and lack of dependence on single, targetable oncogenic pathways, all of which impose challenges for systemic therapy. Furthermore, the unique immune environment of the central nervous system needs to be considered when pursuing immune-based therapeutic approaches for glioblastoma. Nevertheless, a range of different immunotherapies are currently being actively investigated in patients with this disease, spurred on by advances in immuno-oncology for other tumour types. Herein, we examine the current state of immunotherapy for gliomas, notably glioblastoma, the implications for combining the current standard-of-care treatment modalities with immunotherapies, potential biomarkers of response, and future directions for glioblastoma immuno-oncology.

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

“…5 Inhibition of neddylation pathway by pevonedistat as a potential therapeutic strategy has been validated in both GBM cancer cells in vitro and an orthotopic xenograft mouse model in vivo. [35][36][37] Thus, immunotherapy to counteract immune evasion and suppression has already been underway in a few preclinical and clinical studies in GBM. Although the cytotoxic effects of pevonedistat, including inducing cell-cycle arrest, apoptosis and autophagy, have been well studied, the role of neddylation inhibition in cancer-associated immunity remains largely unknown.…”

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

“…1,39 Furthermore, although glioblastoma creates profound local immunosuppression, evidence is mounting that tumor antigen-specific T cells can both be primed and operate well in the hostile tumor microenvironment. 1,39 Furthermore, although glioblastoma creates profound local immunosuppression, evidence is mounting that tumor antigen-specific T cells can both be primed and operate well in the hostile tumor microenvironment.…”

“…1 Glioblastoma tumor cells also usually lack the rich repertoire of nonsynonymous somatic gene mutations that generate the tumor neo-epitopes capable of eliciting productive if transient antitumor immunity. Glioblastoma tumor cells are hosted by a stroma replete with immunosuppressive myeloid and lymphoid cells but depleted in immunocompetent antigen-presenting cells and lymphocytes.…”

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

“…Immune checkpoint inhibitors have demonstrated little efficacy as monotherapy in GBM, and studies of other immunotherapeutic approaches, including oncolytic viral therapy and dendritic cell vaccination, have generally failed to produce rates of response or stable disease above 20% [4,12,13,25,26]. Immunologically, GBM is characterized by a highly suppressive tumor microenvironment [12], and for most patients, there is scant intratumoral infiltration of effector T cells [27,28].…”

“…Even in GBMs with higher than average TMB, there does not appear to be a resultant influx of CD8+ T cells or increase in PD-1/PD-L1 expression [7]. Furthermore, approaches for increasing intratumoral T cells in GBM, such as vaccines, oncolytic viruses, or chimeric antigen receptor (CAR) T cells, are hindered by a severely immunosuppressive tumor microenvironment [12–14]. An improved understanding of the factors that influence both the infiltration and killing activity of CD8+ T cells in GBM may allow for rational immunotherapeutic targeting in this disease.…”