Person:

Iorgulescu, Julian

Neoantigens, derived from tumor-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses, and can function as bona fide tumor rejection antigens. Here, we demonstrate that a strategy of multi-epitope, personalized neoantigen vaccination, previously tested only in patients with high-risk melanoma, is feasible for tumors such as glioblastoma, which typically have a relatively low mutation load and an immunologically “cold” tumor microenvironment. We immunized patients with newly diagnosed GBM using personalized neoantigen-targeting vaccines following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone, a highly potent corticosteroid frequently prescribed to glioblastoma patients for cerebral edema, generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T-cell responses that were enriched for a memory phenotype, and increased tumor-infiltrating T-cells. Utilizing single-cell T-cell receptor analysis, we provide evidence that neoantigen-specific T-cells from the peripheral blood can migrate into an intracranial glioblastoma tumor. Neoantigen-targeting vaccines thus have the potential to favorably alter the immune milieu of glioblastoma.