Abstract
Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential.
Highlights
Glioblastoma multiforme (GBM), the most common malignant primary brain tumor, is highly diffusive and infiltrative in nature
GBM ranks high on the cancer spectrum owing to epigenetic-based prognostic markers, e.g., isocitrate dehydrogenase 1 (IDH1) gene mutations with high global DNA methylation levels and hypermethylation in the O6-methylguanine DNA methyltransferase (MGMT)
IL-2 and α-GalCer (KRN7000, a synthetic glycosphingolipid originally isolated from a marine sponge) from PBMC of healthy donors, type I Natural Killer T (NKT) cell-mediated cytotoxicity was induced by both CD1d-positive glioblastoma cell lines or CD1d-positive patient-derived glioblastoma cells in vitro, with significant increases in the production of IFN-γ, TNF-α, granzyme B, and IL-4 [99]
Summary
Glioblastoma multiforme (GBM), the most common malignant primary brain tumor, is highly diffusive and infiltrative in nature. Several microRNAs (miRNAs) have been identified in GBM and are thought to play important roles in initiation, progression, and response to therapy [4,5,6] Of interest, these miRNAs are often combined with MGMT status to assign patients to high and low-risk groups [7,8]. While preclinical models have advanced our knowledge for ranking GBM in the spectrum of the cancer landscape, they have shown less efficacy on the treatment side Another layer of complexity in GBM relates to microanatomical compartments representing specialized tumor niches within the tumor microenvironment that regulate metabolic needs, immune surveillance, survival, and invasion, as well as maintenance of cancer stem cells [14]. We will decipher the function of NKT cells in GBM and review the prospective of cytokine-induced killer (CIK) cells in GBM, with an emphasis on the role of NKT cells and recent NKT-based innate and adaptive immune therapy in GBM
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