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.

Keywords: brain tumors; gliomas; immune checkpoint inhibitors; immunotherapy; ultrasound.

Figure 1

(A) Immune checkpoint inhibitors bind to and inhibit immunosuppressive molecules on either T-cells or tumor cells. This dampens tumor cells′ ability to evade the immune system. (B) (1) In tumor-infiltrating lymphocyte (TIL) therapy, T-cells from the tumor microenvironment are isolated following surgical resection. (2) Isolated T-cells are clonally expanded by using IL-2 stimulation. (3) Expanded T-cells are reintroduced to the patient. (C) (1) In the vaccine approach, a resected tumor biopsy is taken from the patient and sequenced to identify neoantigens. (2) Neoantigens are then delivered via a vaccine. (3) At the site of injection, neoantigens stimulate antigen-presenting cells (APCs). (4) In the lymph node, APCs present T-cells with neoantigens. (5) Activated T-cells attack cancer cells. Created with BioRender.com.

Figure 2

The left panel shows the normal anatomy of the blood–brain barrier in which tight junctions exist between endothelial cells to prevent the passage of most therapeutics into the brain parenchyma. This basic structure is supported by astrocytes and pericytes, which help maintain and regulate these tight junctions. The right panel shows the pathology of the BBB induced by tumor growth. For one, there is increased permeability of the endothelial cells’ tight junctions, permitting tumor cell extravasation. There is an atrophied basal lamina, which contributes to anergic endothelial cells. Finally, pericytes are both fewer and display an abnormal morphology. The combination of these factors can promote tumor migration and growth. Created with BioRender.com.

Figure 3

Cartoon illustrating how microbubbles can induce a focal disruption or opening of the blood–brain barrier (BBB), thus enabling the delivery of a biologic such as a monoclonal antibody. Microbubbles flow through the normal vasculature or vasculature supplying the glioblastoma tumor microenvironment (TME). Only the microbubbles in the vasculature exposed to ultrasound insonation enable BBB/BTB disruption following ultrasound insonation. Created with BioRender.com.