Here, the key innovative point is brain delivery of a-PD-1 and a-CTLA-4, which were never before used with “old” or “unknown” delivery vehicles, and their action in the brain, which may be used for other checkpoint inhibitors and treatments of not only untreatable GBM or brain metastases, but also of Alzheimer’s and other neurodegenerative diseases. Here, PDCD1 is linked to glioblastoma.