Immunogenetics of glioblastoma: the future of personalized patient management

Abstract

The prognosis of glioblastoma has changed little over the past two decades, with only minor improvements in length of overall survival through the addition of temozolomide (temodal) to standard of care and the recommended use of alternating electric field therapy (optune) to newly diagnosed patients. In an effort to define novel therapeutic targets across molecularly heterogeneous disease subgroups, researchers have begun to uncover the complex interplay between epigenetics, cell signaling, metabolism, and the immunosuppressive tumor microenvironment. Indeed, IDH mutations are now recognized as a defining differential factor not only influencing global hypermethylation and patient prognosis but also degree of immune infiltration within individual tumors. Likewise, next-generation sequencing has defined subgroup-specific transcriptional profiles that correlate with different mechanisms of immune evasion, including increased PD-L1 and CTLA-4 among mesenchymal tumors. Interestingly, sequencing of the T cell repertoire from numerous patient samples suggests that the correlation between mutational burden and enrichment of tumor-specific peptides may be less convincing than originally suspected. While this raises questions over the efficacy of dendritic cell or tumor-lysate vaccines and CAR-T therapies, these avenues continue to be explored. In addition to these active immunotherapies, inhibitors of molecular hubs with wide reaching effects, including STAT3, IDO, and TGF-β, are now in early-phase clinical trials. With the potential to block intrinsic biological properties of tumor growth and invasion while bolstering the immunogenic profile of the tumor microenvironment, these new targets represent a new direction for GBM therapies. In this review, we show the advances in molecular profiling and immunophenotyping of GBM, which may lead to the development of new personalized therapeutic strategies.

Fig. 1

Molecular and immunological characterization of GBM^–

Fig. 2

New trials in GBM (non-exhaustive list)

Fig. 3

Immunogenetics of GBM and future emerging drug targets. a Quantitative analysis of copy number, mutational status, promoter methylation, and deletions are now established genes implicated in the pathophysiology of different GBM subtypes (including EGFR, ATRX, CDK4, CDKN2A/B, and Tert). In addition, longitudinal studies suggest that genetic diversification occurs as tumors evolve and recur. b Emerging NGS analyses has suggested novel signaling, inflammatory, and immune pathways that may vary within tumors of different molecular GBM subtypes. These data, combined with the success of immunotherapies in other cancer types, provide hope for new GBM-based immunovaccines and CAR-T therapies