PMID- 12796406
OWN - NLM
STAT- MEDLINE
DCOM- 20040106
LR  - 20121115
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 9
IP  - 6
DP  - 2003 Jun
TI  - Intensification of antitumor effect by T helper 1-dominant adoptive immunogene 
      therapy for advanced orthotopic colon cancer.
PG  - 2357-65
AB  - PURPOSE: T helper (Th) 1/Th2 balance, controlled by Th1 or Th2 cells producing 
      cytokines, plays important roles in antitumor immunity. Interleukin-18 (IL-18) 
      can act together with IL-12 in promoting the generation of IFN-gamma producing 
      Th1 cells. The goal of this study was to determine whether cytotoxic T lymphocyte 
      (CTL) secreted in a murine IL-18-induced Th1-dominant state inhibited the 
      development of primary tumors and synchronous liver metastases in orthotopic 
      colon cancer model. EXPERIMENTAL DESIGN: Murine IL-18 gene was transduced into 
      activated T lymphocytes by an adenovirus vector encoding IL-18 (AdIL-18) liposome 
      complex method. Efficacy of adoptive immunogene therapy using AdIL-18 with or 
      without IL-12 was tested in advanced orthotopic xenograft of murine colon cancer. 
      To elucidate the mechanism responsible for the adoptive immunogene therapy, serum 
      IL-4, IL-6, IFN-gamma, and tumor necrosis factor alpha production in Th1/Th2 
      cytokine balance and quantification of tumor vascularity were investigated. 
      RESULTS: By a modified method of adenoviral gene transduction, T lymphocytes 
      achieved efficient IL-18 production without cell toxicity. Against orthotopic 
      colon cancer, when combined with low dose of recombinant (r) IL-12 
      (AdIL-18-CTL/rIL-12), the therapeutic efficacy showed much smaller tumors with no 
      liver metastases and no disseminated tumors. There was a significant difference 
      in the volume of primary tumors and the number of liver metastases compared with 
      the group treated with AdIL-18-CTL alone or other group (P < 0.01). In addition, 
      the median survival time of the group treated with AdIL-18-CTL was 53.7 +/- 5.8 
      days and that of AdIL-18-CTL/rIL-12 was 78.4 +/- 6.1 days, which was also a 
      significant difference (P < 0.01). These antitumor mechanisms were involved with 
      Th1-dominant response in serum Th1/Th2 cytokine balance and suppression of 
      neovascularization at primary tumor site. CONCLUSION: These data suggest that a 
      strategy of Th1/Th2 balance-based adoptive immunogene therapy might be useful for 
      advanced cancer patients.
FAU - Nakamori, Mikihito
AU  - Nakamori M
AD  - Second Department of Surgery, Wakayama Medical University, School of Medicine, 
      Wakayama 641-8510, Japan.
FAU - Iwahashi, Makoto
AU  - Iwahashi M
FAU - Nakamura, Masaki
AU  - Nakamura M
FAU - Ueda, Kentaro
AU  - Ueda K
FAU - Zhang, Xiaoliu
AU  - Zhang X
FAU - Yamaue, Hiroki
AU  - Yamaue H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Interleukin-18)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Colonic Neoplasms/*therapy
MH  - Female
MH  - *Genetic Therapy
MH  - *Immunotherapy, Adoptive
MH  - Interleukin-18/biosynthesis/*genetics
MH  - Lymphocyte Activation
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Neovascularization, Pathologic/prevention & control
MH  - T-Lymphocytes, Cytotoxic/immunology
MH  - Th1 Cells/*immunology
MH  - Transduction, Genetic
EDAT- 2003/06/11 05:00
MHDA- 2004/01/07 05:00
CRDT- 2003/06/11 05:00
PHST- 2003/06/11 05:00 [pubmed]
PHST- 2004/01/07 05:00 [medline]
PHST- 2003/06/11 05:00 [entrez]
PST - ppublish
SO  - Clin Cancer Res. 2003 Jun;9(6):2357-65.