Immunotherapy for brain tumors checkpoint inhibitors, vaccines and beyond

      The current standard of care for glioblastoma of resection followed by involved-field radiotherapy and concomitant and maintenance temozolomide chemotherapy prolongs survival to a median of 16 months in clinical trial populations, but survival with glioblastoma is still in the range of one year on a population level. Immunosuppression is one of the hallmarks of the glioblastoma microenvironment, prompting the clinical development of various immunotherapeutic strategies that are currently being studied in clinical trials of phase I, II or III. Efforts focusing on the antagonism of glioma-associated immunosuppression alone, e.g., blocking the transforming growth factor (TGF)-β pathway, have not been successful. Similarly, counteracting inhibitory signalling to T cells via cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed death (PD)-1 using various neutralizing antibodies has generated hope not only for several solid cancers outside the brain, but also for glioblastoma, yet, nivolumab was not superior to bevacizumab in the CHECKMATE-143 trial. Various vaccination approaches are also being tested, including dendritic cell-based vaccines, using either crude tumor lysates (DCVax) or tailored mRNA or peptide stimulation (ICT-107). The most advanced approach explored in phase III (ACT IV) was based on the vaccination against a mutant variant of the epidermal growth factor receptor (EGFR), EGFRvIII, which is expressed at different levels in approximately 30% of all primary glioblastomas. This mutation results in inability to bind ligand and constitutive signalling activity. Moreover, EGFRvIII represents a unique tumor antigen exhibiting a novel peptide sequence and is thus considered a true tumor-specific antigen. Phase II trials in glioblastoma patients with EGFRvIII-positive tumors without progression after radiotherapy and concomitant temozolomide chemotherapy treated with the vaccine rindopepimut showed encouraging progression-free and overall survival compared with historical controls, but the double-blind phase III trial, ACT IV, failed to improve overall survival. In contrast, the ReACT trial which explored bevacizumab plus rindopepimut and bevacizumab plus placebo in a non-comparative randomized phase II trial in patients with EGFRvIII-positive recurrent glioblastoma, provided early evidence for efficacy of this vaccine. Further, high-throughput analyses involving genome, transcriptome, and proteome are likely to result in the delineation of novel glioma-specific targets for novel immunotherapy approaches in the near future.
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