In preclinical orthotopic glioma models, combining αVEGF therapy with intratumoral epidermal growth factor receptor (EGFR)-targeted cytotoxic therapy and αCD40 immunotherapy normalized the tumor vasculature, promoted lymphatic vessel growth, induced tumor cell killing, increased intratumoral T cells, plasma cells, germinal center B cells, and antigen-presenting and tissue-repair-associated macrophages, while reducing immunosuppression and supporting mature TLS formation with an antitumor immune phenotype. Here, EGFR is linked to central nervous system cancer.