Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers

Abstract

Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood–brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.

Cuproptosis key gene FDX1 is a prognostic biomarker and associated with immune infiltration in glioma

“…Although according to the existing reports and actual clinical manifestations, the benefit of immunotherapy for patients with brain tumors, especially high-grade gliomas, is limited ( 66 , 69 – 73 ). Therefore, we speculate that the heterogeneity of the tumor microenvironment is one of the important factors limiting glioma patients’ benefit from biologically targeted therapies ( 70 – 72 ).…”

Progress in phase III clinical trials of molecular targeted therapy and immunotherapy for glioblastoma

“…The causes of immunotherapy resistance in GBM are complex and may include the following factors: (1) the immunosuppressive microenvironment and overall immune response suppression in patients; (2) heterogeneity during tumor progression, as well as between tumors and patients; (3) low TMB and immunogenicity; (4) the presence of the BBB; (5) pathway redundancy and escape through bypass pathways; (6) a lack of effective biomarkers; and (7) a lack of experimental models [ 107 , 108 , 109 ]. Unlike immunogenic tumors such as lung cancer, GBM has a low level of TMB neoantigens.…”

The Development of Immunotherapy for the Treatment of Recurrent Glioblastoma

“…Some physical ways such as non-invasive micro bubble-enhanced focused ultrasound (MBF), or some biological ways like the up-expression of chemokines, are now proven in their ability to increase the permeability of BBB. And some chemotactic enhancement methods for CAR-T are also stable and feasible in preclinical experiments [63]. Moreover, to avoid consumption in the peripheral blood, direct local injection or intracavitary injection can be useful.…”