The value of EGFRvIII as the target for glioma vaccines.

Malignant brain tumors continue to be rapidly progressive and resistant to most treatments. Even with state-of-the-art standard of care (surgery, chemotherapy, and radiotherapy) long-term survival in the last 80 years improved from 6 to 15 months. Improved imaging has also likely contributed to prolonged survival. Immunotherapy for cancer dates back to publications from 1742. The central idea is that the immune system can detect and eliminate foreign antigens, either from infectious agents or tumors, and thus could be therapeutic in brain tumors. Recent introduction of immune modulators of cytotoxic T-lymphocyte antigen (CTLA)-4 and programmed cell death 1/programmed cell death 1 ligand (PD-1/PDL1) add much excitement to this field. For brain tumors, there are several ongoing phase I and III trials to determine whether any of the current immunotherapy approaches can demonstrate activity in randomized, controlled double-blinded trials-with ongoing and historical trials presented in tables within the manuscript. Immunotherapy has explored the use of various types of antigens (obtained either from homogenates of patients' tumors or synthetically produced), and various immunization procedures and adjuvants. Glioma antigens have also been isolated from the patients' own tumor, then produced in vitro (for example the glioma antigen EGFRvIII), and used to immunize patients directly, or with carriers such as dendritic cells with or without additional adjuvants. Several of these practical approaches are currently in phase III trials. Remaining challenges are how to increase the percentage of complete responses and response duration, and the enigmatic absence of an almost total lack of adverse brain inflammation following immunization of brain tumor patients, as has been observed following immunization against brain antigens in other diseases, such as Alzheimer's Disease.