Immunotherapy for Glioblastoma: Current Progress and Challenges

Abstract

Glioblastoma is a highly lethal brain cancer with a median survival rate of less than 15 months when treated with the current standard of care, which consists of surgery, radiotherapy and chemotherapy. With the recent success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research. Resistance to therapy has been a major challenge across a multitude of experimental candidates and no immunotherapies have been approved for glioblastoma to-date. Intra- and inter-tumoral heterogeneity, an inherently immunosuppressive environment and tumor plasticity remain barriers to be overcome. Moreover, the unique tissue-specific interactions between the central nervous system and the peripheral immune system present an additional challenge for immune-based therapies. Nevertheless, there is sufficient evidence that these challenges may be overcome, and immunotherapy continues to be actively pursued in glioblastoma. Herein, we review the primary ongoing immunotherapy candidates for glioblastoma with a focus on immune checkpoint inhibitors, myeloid-targeted therapies, vaccines and chimeric antigen receptor (CAR) immunotherapies. We further provide insight on mechanisms of resistance and how our understanding of these mechanisms may pave the way for more effective immunotherapeutics against glioblastoma.

Advances in Immunotherapy for Adult Glioblastoma

“…Here, we detailed clinical and preclinical advances in immune checkpoint blockade, vaccination strategies and emerging CAR T cell therapies for the treatment of GBM ( Figure 1 ). Among the major hurdles to clinical efficacy are immense intratumoral heterogeneity [ 6 , 7 ], parallel modes of immunosuppression by tumor cells [ 121 , 122 , 123 ] and low mutational burden in GBM [ 124 ]. With these factors in mind, investigators and clinicians are shifting their focus to combinatorial and personalized treatment strategies to achieve synergistic effects, reduce treatment resistance and overcome immunosuppression.…”

Prognostic value and immune relevancy of a combined autophagy-, apoptosis- and necrosis-related gene signature in glioblastoma

“…Patients with GBM have a very poor prognosis, with an average overall survival of merely 12–15 months [ 5 ]. In spite of recent advances in standard treatment, including surgery, chemotherapy, radiotherapy, and the achievement in targeted therapies and immunotherapies over the past several years, GBM still carries a dismal prognosis with poor survival [ 6 – 10 ]. Therefore, novel prognostic approaches to pick out patients with high risks are warranted to further help therapeutic options for GBM patients.…”

Treatment patterns and outcomes for patients with newly diagnosed glioblastoma multiforme: a retrospective cohort study

“…So far, novel therapies have been associated with, at best, modest improvements in survival in GBM in both methylated and unmethylated study populations [ 4 , 18–20 ]. Increasing the rate of MGMT testing will not only result in better and more appropriate care for patients with methylated MGMT but will also help support research into new therapies for patients with unmethylated MGMT [ 6 , 19 ].…”

“…For example, NCT04396860 is now recruiting patients to investigate the efficacy of immunotherapy compared with standard of care (RT and TMZ) in patients at first diagnosis of unmethylated GBM [ 25 ]. In general, research is ongoing to identify and characterize markers in the tumor-immune microenvironment to serve as targets for novel therapies, which include drugs, medical devices, vaccines and immune cell therapy [ 19 ].…”