Advances in Immunotherapy for Adult Glioblastoma

SIMPLE SUMMARY: Therapy failure and disease recurrence are hallmarks of glioblastoma (GBM), the most common and lethal tumor in adults that originates in the brain. Despite aggressive standards of care, tumor recurrence is inevitable with no standardized second-line therapy. Recent clinical studies evaluating therapies that augment the anti-tumor immune response (i.e., immunotherapies) have yielded promising results in subsets of GBM patients. Here, we summarize clinical studies in the past decade that evaluate vaccines, immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells for treatment of GBM. Although immunotherapies have yet to return widespread efficacy for the majority of GBM patients, critical insights from completed and ongoing clinical trials are informing development of the next generation of therapies, with the goal to alleviate disease burden and extend patient survival. ABSTRACT: Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent clinical and preclinical efforts to evaluate vaccination strategies, immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells. Although these modalities have shown long-term tumor regression in subsets of treated patients, the underlying biology that may predict efficacy and inform therapy development is being actively investigated. Common to all therapeutic modalities are fundamental mechanisms of therapy evasion by tumor cells, including immense intratumoral heterogeneity, suppression of the tumor immune microenvironment and low mutational burden. These insights have led efforts to design rational combinatorial therapies that can reignite the anti-tumor immune response, effectively and specifically target tumor cells and reliably decrease tumor burden for GBM patients.