Gene therapy for brain tumors: basic developments and clinical implementation.
Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM.
Department of Neurosurgery, University of Michigan Medical School, MSRBII, Rm 4570, 1150 Medical Center Drive, Ann Arbor, MI 48109, USA.
Hikmat
H
Assi
Marianela
M
Candolfi
Gregory
G
Baker
Yohei
Y
Mineharu
Pedro R
PR
Lowenstein
Maria G
MG
Castro
D056704:Adaptive Immunity; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002986:Clinical Trials as Topic; D003603:Cytotoxins / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology; D059016:Tumor Microenvironment
D003603:Cytotoxins; D051195:Toll-Like Receptor 2