Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki forest virus-mediated tumor complementary DNA.
OBJECTIVE
Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy.


METHODS
Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)-mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset-depleted mice and in interferon (IFN) gamma-neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFN-gamma production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial.


CONCLUSIONS
Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.
Yamanaka
Ryuya
R
Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. ryaman@pop11.odn.ne.jp
Yajima
Naoki
N
Tsuchiya
Naoto
N
Honma
Junpei
J
Tanaka
Ryuichi
R
Ramsey
Jay
J
Blaese
Michael
M
Xanthopoulos
Kleanthis G
KG
D000818:Animals; D000917:Antibody Formation / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D018076:DNA, Complementary / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000627:therapeutic use; D003713:Dendritic Cells / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D007167:Immunotherapy; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000502:physiology; D051379:Mice; D012672:Semliki forest virus / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma