Document Detail


Engineered herpes simplex virus expressing IL-12 in the treatment of experimental murine brain tumors.
MedLine Citation:
PMID:  10681459     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Genetically engineered, neuroattenuated herpes simplex viruses (HSVs) expressing various cytokines can improve survival when used in the treatment of experimental brain tumors. These attenuated viruses have both copies of gamma(1)34.5 deleted. Recently, we demonstrated increased survival of C57BL/6 mice bearing syngeneic GL-261 gliomas when treated with an engineered HSV expressing IL-4, as compared with treatment with the parent construct (gamma(1)34. 5(-)) alone or with a virus expressing IL-10. Herein, we report construction of a conditionally replication-competent mutant expressing both subunits of mIL-12 (M002) and its evaluation in a syngeneic neuroblastoma murine model. IL-12 induces a helper T cell subset type 1 response, which may induce more durable antitumor effects. In vitro studies showed that, when infected with M002, both Vero cells and murine Neuro-2a neuroblastoma cells produced physiologically relevant levels of IL-12 heterodimers, as determined by ELISA. M002 was cytotoxic for Neuro-2a cells and human glioma cell lines U251MG and D54MG. Neurotoxicity studies, as defined by plaque-forming units/LD(50), performed in HSV-1-sensitive A/J strain mice found that M002 was not toxic even at high doses. When evaluated in an intracranial syngeneic neuroblastoma murine model, median survival of M002-treated animals was significantly longer than the median survival of animals treated with R3659, the parent gamma(1)34.5(-) mutant lacking any cytokine gene insert. Immunohistochemical analysis of M002-treated tumors identified a pronounced influx of CD4(+) T cells and macrophages as well as CD8(+) cells when compared with an analysis of R3659-treated tumors. We conclude that M002 produced a survival benefit via oncolytic effects combined with immunologic effects meditated by helper T cells of subset type 1.
Authors:
J N Parker; G Y Gillespie; C E Love; S Randall; R J Whitley; J M Markert
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  97     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2000 Feb 
Date Detail:
Created Date:  2000-04-11     Completed Date:  2000-04-11     Revised Date:  2013-04-16    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2208-13     Citation Subset:  IM; X    
Affiliation:
Department of Pediatrics, Brain Tumor Research Laboratories, Division of Neurosurgery, Department of Surgery, University of Alabama, Birmingham, AL 35294-3295, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Therapy
Brain Neoplasms / immunology,  therapy*
CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / immunology
Cercopithecus aethiops
Disease Models, Animal
Female
Gene Expression
Genetic Engineering
Genetic Vectors* / genetics
Glioma / immunology,  therapy*
Herpesvirus 1, Human* / genetics,  pathogenicity
Humans
Interleukin-12 / genetics*,  immunology
Mice
Mice, Inbred A
Neuroblastoma / immunology,  therapy*
Recombination, Genetic
Tumor Cells, Cultured
Vero Cells
Virulence
Grant Support
ID/Acronym/Agency:
N01-AI-62554/AI/NIAID NIH HHS; P01 AI 24009/AI/NIAID NIH HHS; P01 CA 7 1933/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
187348-17-0/Interleukin-12
Comments/Corrections

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