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.

Fig. 1. Molecular characteristics of different subtypes of GB.

a pro-neural (PN) subtype; b classical (CL) subtype; c mesenchymal (MES) subtype; d neural subtype. Expression degree: Red > Yellow > Blue. m: mutation.

Fig. 2. The tumor microenvironment of rGB.

The immunosuppressive microenvironment of rGB is composed of a variety of immunosuppressive cells and cytokines which outweigh the role of immunostimulatory factors.

Fig. 3. The molecular mechanism of combination strategies for rGB.

a DC vaccination + anti-PD-1/PD-L1 mAb; b CAR T-cell therapy + anti-PD-1/PD-L1 mAb; c anti-PD-1/PD-L1 mAb + checkpoint inhibitor/agonist; d Neoadjuvant anti-PD-1 mAb + surgery/radiation + adjuvant anti-PD-1 mAb.