Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials.
The long-term consequences of adenovirus-mediated conditional cytotoxic gene therapy for gliomas remain uncharacterized. We report here detection of active brain inflammation 3 months after successful inhibition of syngeneic glioma growth. The inflammatory infiltrate consisted of activated macrophages/microglia and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and included secondary demyelination. We detected strong widespread herpes simplex virus 1 thymidine kinase immunoreactivity and vector genomes throughout large areas of the brain. Thus, patient evaluation and the design of clinical trials in ongoing and future gene therapy for brain glioblastoma must address not only tumor-killing efficiency, but also long-term active brain inflammation, loss of myelin fibers and persistent transgene expression.
Dewey
R A
RA
Department of Neuropathology, Institute of Psychiatry, Kings College London, DeCrespigny Park, Denmark Hill, London SE5 8AS, UK.
Morrissey
G
G
Cowsill
C M
CM
Stone
D
D
Bolognani
F
F
Dodd
N J
NJ
Southgate
T D
TD
Klatzmann
D
D
Lassmann
H
H
Castro
M G
MG
Löwenstein
P R
PR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000276:immunology; D001483:Base Sequence; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002986:Clinical Trials as Topic; D017931:DNA Primers; D004660:Encephalitis / Q000209:etiology* / Q000276:immunology; D015774:Ganciclovir / Q000009:adverse effects / Q000627:therapeutic use; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors; D005910:Glioma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D008262:Macrophage Activation; D017628:Microglia / Q000276:immunology; D009186:Myelin Sheath / Q000378:metabolism; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics; D019076:Transgenes; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D013937:Thymidine Kinase; D015774:Ganciclovir