Induction of an antitumor immunological response by an intratumoral injection of dendritic cells pulsed with genetically engineered Semliki Forest virus to produce interleukin-18 combined with the systemic administration of interleukin-12.
OBJECTIVE
The aim of this study was to investigate further immunogene treatment of malignant brain tumor to improve its therapeutic efficacy.


METHODS
Intratumoral dendritic cells pulsed with Semliki Forest virus (SFV)-interleukin-18 (IL-18) and/or systemic IL-12 were injected into mice bearing the B16 brain tumor. To study the immune mechanisms involved in tumor regression, we monitored the growth of implanted B16 brain tumor cells in T cell-depleted mice and IFNgamma-neutralized mice. To analyze the protective immunity created by tumor inoculation, B16 cells were injected into the left thighs of mice that had received an inoculation, and tumor growth was monitored. The local delivery of dendritic cells pulsed with IL-18 bound by SFV combined with the systemic administration of IL-12 enhanced the induction of the T helper type 1 response from tumor-specific CD4+ and CD8+ T cells and natural killer cells as well as antitumor immunity. Interferon-gamma is partly responsible for this IL-18-mediated antitumor immunity. Furthermore, the protective immunity is mediated mainly by CD8+ T cells.


CONCLUSIONS
Immunogene therapy that combines the local administration of dendritic cells pulsed with IL-18 bound by SFV and the systemic administration of IL-12 may be an excellent candidate for the development of a new treatment protocol. A self-replicating SFV system may therefore open a novel approach for the treatment of malignant brain tumor.
Yamanaka
Ryuya
R
Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. ryaman@pop11.odn.ne.jp
Tsuchiya
Naoto
N
Yajima
Naoki
N
Honma
Junpei
J
Hasegawa
Hitoshi
H
Tanaka
Ryuichi
R
Ramsey
Jay
J
Blaese
R Michael
RM
Xanthopoulos
Kleanthis G
KG
D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy / Q000821:virology; D006224:Cricetinae; D017931:DNA Primers / Q000235:genetics / Q000276:immunology; D018076:DNA, Complementary / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D005818:Genetic Engineering / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000276:immunology / Q000628:therapy / Q000821:virology; D007125:Immunogenetics / Q000379:methods; D016233:Immunotherapy, Active / Q000379:methods*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012672:Semliki forest virus / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000637:transplantation
D015703:Antigens, CD; D017931:DNA Primers; D018076:DNA, Complementary; D020382:Interleukin-18; D018664:Interleukin-12