Advances in Immunotherapy for Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients with GBM have poor outcomes, even with the current gold-standard first-line treatment: maximal safe resection combined with radiotherapy and temozolomide chemotherapy. Accumulating evidence suggests that advances in antigen-specific cancer vaccines and immune checkpoint blockade in other advanced tumors may provide an appealing promise for immunotherapy in glioma. The future of therapy for GBM will likely incorporate a combinatorial, personalized approach, including current conventional treatments, active immunotherapeutics, plus agents targeting immunosuppressive checkpoints.

Figure 1

Mechanism of CTLA-4 and PD-L1 immune checkpoints. The CTLA-4 immune checkpoint (left figure) occurs early during the priming phase of the immune response, acting within secondary lymphoid organs. CTLA-4 is a powerful inhibitory T-cell receptor that can preferentially bind to CD80/CD86 on the surface of APCs, preventing their binding to the T-cell costimulatory receptor CD28, thus leading to decreased T-cell activation and proliferation in the context of antigen-presenting MHC class I. PD-1 signaling takes place during the effector phase of the immune responses within the tumor microenvironment. The inhibitory PD-1 T-cell receptor interacts with one of two currently identified PD-1 ligands: PD-L1 or PD-L2, expressed on the surface of tumor cells. Engagement of PD-1 ligands with the PD-1, in the context of tumor antigen-presenting MHC class I, can decrease the T-cell tumor lytic capacity and induces T-cell anergy. APC: antigen-presenting cell.