Immunotherapy for recurrent glioblastoma: practical insights and challenging prospects

Abstract

Glioblastoma (GB) is the most common high-grade intracranial malignant tumor with highly malignant biological behavior and a high recurrence rate. Although anti-PD-1/PD-L1 antibodies have achieved significant survival benefits in several kinds of solid tumors, the phase III clinical trial Checkmate 143 demonstrated that nivolumab, which targets PD-1, did not achieve survival benefits compared with bevacizumab in recurrent glioblastoma (rGB) patients. Nevertheless, neoadjuvant anti-PD-1 therapy followed by surgery and adjuvant anti-PD-1 therapy could effectively activate local and systemic immune responses and significantly improve the OS of rGB patients. Furthermore, several studies have also confirmed the progress made in applying tumor-specific peptide vaccination or chimeric antigen receptor-T (CAR-T) cell therapy to treat rGB patients, and successes with antibodies targeting other inhibitory checkpoints or costimulatory molecules have also been reported. These successes inspired us to explore candidate combination treatments based on anti-PD-1/PD-L1 antibodies. However, effective predictive biomarkers for clinical efficacy are urgently needed to avoid economic waste and treatment delay. Attempts to prolong the CAR-T cell lifespan and increase T cell infiltration through engineering techniques are addressing the challenge of strengthening T cell function. In this review, we describe the immunosuppressive molecular characteristics of rGB; clinical trials exploring anti-PD-1/PD-L1 therapy, tumor-specific peptide vaccination, and CAR-T cell therapy; candidate combination strategies; and issues related to strengthening T cell function.

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.…”

Comprehensive transcriptomic characterization reveals core genes and module associated with immunological changes via 1619 samples of brain glioma

“…Although ICB combination therapy has been shown to be effective in preclinical models of glioma, the efficacy in patient needs to be further verified [ 33 ]. Here, we first explored the relationship between the risk score of signature and the well-studied checkpoints.…”

Cancer Stem Cell-Associated Immune Microenvironment in Recurrent Glioblastomas

“…In fact, a Phase III clinical study demonstrated that anti-PD-1 monoclonal antibody Nivolumab was not superior to anti-VEGF monoclonal antibody Bevacizumab from the view of OS [21,22]. Additionally, anti-PD-1 therapy combined with surgical treatment effectively activates local and systemic immune responses to rGBM, but it is still far from eradication [23,24]. These data suggest that both immune checkpoint blockade and antigen presentation augmentation need to be exploited.…”