Cytokine gene therapy for malignant glioma.
Despite advances in surgical and adjuvant therapy, the prognosis for malignant gliomas remains dismal. Malignant gliomas, like other malignancies, are able to overcome host immune defences through a variety of mechanisms that have become increasingly well-characterised over the past decade. However, this 'immunologically privileged' status of the brain is not absolute. Systemic immunisation with brain-specific antigens can induce immune responses that are manifested in the CNS, such as experimental allergic encephalomyelitis. The efficacy of peripheral immunisation against brain tumours has also been demonstrated in preclinical models. Based on these observations, clinical trials of peripheral immunisations with brain tumour-derived antigens have been initiated. A limitation of this approach is that the immunological environment within brain tumours is suboptimal for functions of antitumour immune effector cells. As a means to overcome this issue, delivery of cytokine genes to the tumour site may reverse the inhibitory immunological environment of the brain tumours and enhance the efficacy of peripheral vaccine-induced immune effector cells. The brain tumour environment may also be rendered more immunologically favourable by the delivery of additional antigen-presenting cells that can provide infiltrating effector cells with secondary activation signals. Indeed, the authors' recent data indicate that the injection of intracranial tumours with dendritic cells secreting interferon-alpha enhances the efficacy of peripheral vaccinations with tumour-specific antigens by cross-priming tumour antigen-specific T cells in the cervical lymph nodes. This review highlights the recent literature on cytokine gene therapy for brain tumours, and proposes the effective use of cytokine gene delivery both at the site of vaccines (i.e., the site of antigen presentation) and within the target brain tumours (i.e., the site where the effector cells exert their antitumour immunity). Successful immunogene therapy for brain tumours requires detailed understanding of cytokine functions and the use of them at the appropriate stages/sites of the immunological milieu.
University of Pittsburgh Medical Center/Cancer Institute, Department of Neurological Surgery, Brain Tumor Program, G12.a Research Pavilion at the Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, PA 15213-1863, USA. okadah@upmc.edu
Hideho
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Okada
Ian F
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Pollack
D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000276:immunology; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use; D002478:Cells, Cultured / Q000637:transplantation; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000235:genetics* / Q000493:pharmacokinetics / Q000502:physiology; D003713:Dendritic Cells / Q000637:transplantation; D015316:Genetic Therapy; D005909:Glioblastoma / Q000235:genetics / Q000276:immunology / Q000628:therapy; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000502:physiology; D051379:Mice; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014611:Vaccination
D019496:Cancer Vaccines; D016207:Cytokines; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins