Concepts in glioma immunotherapy

Abstract

Immunotherapeutic concepts in neurooncology have been developed for many decades but have mainly been hampered by poor definition of relevant antigens and selective measures to target the central nervous system. Independent of the recent remarkable successes in clinical immunooncology with checkpoint inhibitors and vaccines, immunotherapy of brain tumors in general and gliomas in particular has evolved with novel neurooncology-specific concepts over the past years providing new phase 1 approaches of individualized immunotherapy to first phase three clinical trials. These concepts are driven by a high medical need in the absence of approved targeted therapies and refute the classic dogma that the central nervous system is immune-privileged and hence inaccessible to potent antitumor immunity. Instead, measures have been taken to improve the odds for successful immunotherapies, including rational targeting of relevant antigens and integration of immunotherapies into standard of care primary radiochemotherapy to increase the efficacy of antitumor immunity in a meaningful time window. This review highlights concepts and challenges associated with epitope discovery and selection and trial design.

Keywords: CIMT 2015; Checkpoint inhibition; EGFRvIII; Glioblastoma; IDH1; Vaccine.

Fig. 1

EGF receptor (EGFR) is a transmembrane protein with an extracellular N-terminus and intracellular tyrosine phosphorylation sites for signaling. Fusion of exons 1 and 8 results in the constitutively active EGFRvIII, which has a truncated extracellular domain containing a novel glycin residue. This makes EGFRvIII an extracellular antigen, which is accessible for direct antibody binding. The fusion epitope PEPvIII is additionally loaded onto MHC class I and II molecules after proteasomal cleavage within the mutated tumor cell, making it accessible for EGFRvIII-specific T cell responses. PEPvIII is the fusion epitope used for vaccination. Novel glycine residue is shown in red

Fig. 2

IDH1 is a cytosolic protein with enzymatic activity. A point mutation leads t a single amino acid exchange (R132H), resulting in a neomorphic enzymatic function, the production of R-2-HG. IDH1(R132H) is processed in the endosomes and lysosomes within tumor cells and APCs that have taken up the protein from necrotic and apoptotic tumor cells, from where the epitope pIDH1R132H is loaded onto MHC class II. This makes it accessible for IDH1(R132H-specific CD4+ T cells. Amino acid exchange to histidine is shown in red