Immunotherapy advances for glioblastoma

Abstract

Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation.

Keywords: glioblastoma; immune checkpoint; immunosuppression; immunotherapy; vaccine.

Fig. 1.

Systemic and local (microenvironment) immunosuppressive adaptations elicited by glioblastoma tumors generating a protective shield against potential antitumor immune responses.

Fig. 2.

Immunomodulatory molecules expressed on T cells that provide either a costimulatoryeffect to enhance T-cell activation or a coinhibitory effect to attenuate T-cell activation following interaction of antigen/MHC complex on antigen-presenting cells with the T-cell receptor.

Fig. 3.

Steps involved with T-cell activation as well as its negative modulation by CTLA-4 and PD-1/PD-L1. Note that CTLA-4 and PD-1/PD-L1 act by complementary mechanisms to inhibit T-cell activation. Monoclonal antibody blockade of CTLA-4 or PD-1/PD-L1 relieves immune checkpoint inhibition, thereby restoring T-cell activation.