The study demonstrates the feasibility of using personalized neoantigen vaccines to generate intratumoral T cell responses in patients with glioblastoma, a tumor type typically associated with a low mutation load and a cold tumor microenvironment. In a phase I/Ib clinical trial, patients newly diagnosed with glioblastoma who underwent surgical resection and conventional radiotherapy were immunized with neoantigen-targeting vaccines. Patients who did not receive dexamethasone, a corticosteroid, generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses, enriched in a memory phenotype, and showed an increase in tumor-infiltrating T cells. Single-cell T cell receptor (TCR) analysis revealed that neoantigen-specific T cells from peripheral blood can migrate into intracranial glioblastoma tumors. The findings suggest that neoantigen-targeting vaccines have the potential to alter the immune milieu of glioblastoma, potentially leading to improved treatment outcomes.The study demonstrates the feasibility of using personalized neoantigen vaccines to generate intratumoral T cell responses in patients with glioblastoma, a tumor type typically associated with a low mutation load and a cold tumor microenvironment. In a phase I/Ib clinical trial, patients newly diagnosed with glioblastoma who underwent surgical resection and conventional radiotherapy were immunized with neoantigen-targeting vaccines. Patients who did not receive dexamethasone, a corticosteroid, generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses, enriched in a memory phenotype, and showed an increase in tumor-infiltrating T cells. Single-cell T cell receptor (TCR) analysis revealed that neoantigen-specific T cells from peripheral blood can migrate into intracranial glioblastoma tumors. The findings suggest that neoantigen-targeting vaccines have the potential to alter the immune milieu of glioblastoma, potentially leading to improved treatment outcomes.