New concepts for glioblastoma vaccine immunotherapy

Glioblastoma remains one of the most lethal malignancies, characterized by rapid recurrence, profound intratumoral heterogeneity, and a highly immunosuppressive microenvironment. Among immunotherapeutic strategies, peptide-based vaccines have attracted attention for their safety, specificity, and capacity to elicit tumor-directed T cell responses. Over the past two decades, several platforms targeting tumor-associated or tumor-specific antigens, including EGFRvIII, WT1, and survivin, have advanced into clinical trials. While early-phase studies demonstrated immunogenicity and occasional survival benefits, phase III trials have largely failed to confirm durable efficacy, underscoring the challenges posed by the ongoing complexity of tumor evasion mechanisms among which down regulation of MHC (HLA) expression in tumor cells, lack or reduced tumor antigen expression and a suppressive tumor microenvironment certainly play a role. As far as tumor antigens, recent insights also question the centrality of neoantigens, highlighting instead the immunogenicity of shared tumor-associated antigens, which may provide a more reliable foundation for broadly applicable vaccines in GBM. A major barrier to efficacy remains impaired antigen presentation, particularly the downregulation of MHC-II pathways. In this context, strategies leveraging the transcriptional activator CIITA to restore MHC-II expression hold promise both for reprogramming GBM cells into effective antigen-presenting cells and for the isolation of new families of MHC class II-bound peptides relevant for the triggering of tumor-specific CD4+ T cells. This new approach could pave the way for next-generation peptide vaccines, particularly when integrated with combinatorial modalities such as checkpoint inhibitors, myeloid-targeted therapies, or oncolytic viruses. • Peptide vaccines for glioblastoma are immunogenic but clinically limited • Immune evasion and poor antigen presentation restrict vaccine efficacy • Restoring MHC II expression may enhance antitumor immunity