Glioblastoma Immunotherapy: A Systematic Review of the Present Strategies and Prospects for Advancements

Abstract

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to “glioblastomas,” “immunotherapies,” and “treatment.” The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.

Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

“…This resonates with the findings of Liu et al [ 48 ], where ADAM8 causes tumor infiltration of tumor-associated macrophages and overcomes TMZ chemosensitization. The interplay between GSCs and the microenvironment emerges as a critical determinant of therapy response and poses challenges for designing targeted interventions[ 49 , 50 ]. These findings highlight the need for a holistic approach considering the tumor microenvironment in developing therapeutic strategies[ 2 , 5 , 6 ].…”

A Systematic Review of the Metabolism of High-Grade Gliomas: Current Targeted Therapies and Future Perspectives

“…The complex microenvironment of glial tumors has a significant impact on the effectiveness of therapies [5]. However, recent studies have shown that immunotherapy could be a promising strategy to control TME and improve clinical outcomes significantly [49]. Combining conventional treatments with immune checkpoints, vaccines, oncolytic immunovirotherapy, and CAR T-cell therapy has shown great potential for treating HGGs.…”

The need for paradigm shift: prognostic significance and implications of standard therapy-related systemic immunosuppression in glioblastoma for immunotherapy and oncolytic virotherapy

“…Clinical trials of immunotherapies, including vaccines and oncolytic viruses, have demonstrated encouraging efficacy in minor subsets of patients with progressive/recurrent glioblastoma ( 3 – 8 ). Different patient selection criteria, recombinant viruses, protocols for vaccine preparation, and schedules and routes of vaccine or virus administration have been applied in trials.…”