LAUSR

Simple Summary The poor prognosis for glioblastoma (GBM) despite the existence of a standard-of-care treatment of resection, radiotherapy, and adjuvant chemotherapy has necessitated the exploration of other therapeutic avenues. One particularly promising avenue is an immunotherapeutic approach in which the body′s immune system is artificially stimulated to directly identify and attack the tumor cells. A variety of methods including immune checkpoint inhibition, T-cell transfer, vaccination, and a viral approach are being developed for GBM. Barriers such as tumor heterogeneity, the physical blood–brain barrier, the immunosuppressive nature of GBM, and the limited number of identifiable GBM-specific targets have reduced the efficacy of the aforementioned approaches. In the following review, we document the advances in immunotherapy, the barriers to implementation, and the development of a new technology (microbubble-enhanced focused ultrasound) to overcome the physical barriers to immunotherapy. 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.