A phase Ib clinical trial evaluated the efficacy of personalized neoantigen vaccines in patients with newly diagnosed glioblastoma. The vaccine, composed of multiple epitopes derived from tumor-specific mutations, was administered to patients following surgical resection and radiotherapy. Patients who did not receive dexamethasone showed increased circulating polyfunctional CD4+ and CD8+ T cell responses, enriched in a memory phenotype, and higher numbers of tumor-infiltrating T cells. Single-cell TCR analysis confirmed that neoantigen-specific T cells from peripheral blood could migrate into the tumor. The vaccine induced intratumoral T cell infiltration, suggesting a favorable immune environment for glioblastoma. Patients with disease progression had increased CD8+ and CD4+ T cells at relapse compared to those who received dexamethasone. TCR sequencing identified neoantigen-specific T cell clones in tumor tissue, indicating successful trafficking of vaccine-induced T cells to the tumor site. Despite these immune responses, all patients eventually died of progressive disease, highlighting the challenges in achieving clinical efficacy. The study demonstrates that neoantigen vaccination is feasible for immunologically cold tumors with low mutational burden, but further optimization of algorithms and combination with immune checkpoint blockade may improve outcomes. The results suggest that neoantigen-specific T cells can be induced and traffic to the tumor, but tumor-intrinsic defects and immunosuppressive factors in the microenvironment remain significant barriers to effective anti-tumor activity.A phase Ib clinical trial evaluated the efficacy of personalized neoantigen vaccines in patients with newly diagnosed glioblastoma. The vaccine, composed of multiple epitopes derived from tumor-specific mutations, was administered to patients following surgical resection and radiotherapy. Patients who did not receive dexamethasone showed increased circulating polyfunctional CD4+ and CD8+ T cell responses, enriched in a memory phenotype, and higher numbers of tumor-infiltrating T cells. Single-cell TCR analysis confirmed that neoantigen-specific T cells from peripheral blood could migrate into the tumor. The vaccine induced intratumoral T cell infiltration, suggesting a favorable immune environment for glioblastoma. Patients with disease progression had increased CD8+ and CD4+ T cells at relapse compared to those who received dexamethasone. TCR sequencing identified neoantigen-specific T cell clones in tumor tissue, indicating successful trafficking of vaccine-induced T cells to the tumor site. Despite these immune responses, all patients eventually died of progressive disease, highlighting the challenges in achieving clinical efficacy. The study demonstrates that neoantigen vaccination is feasible for immunologically cold tumors with low mutational burden, but further optimization of algorithms and combination with immune checkpoint blockade may improve outcomes. The results suggest that neoantigen-specific T cells can be induced and traffic to the tumor, but tumor-intrinsic defects and immunosuppressive factors in the microenvironment remain significant barriers to effective anti-tumor activity.