Gene therapy for cancer using intratumoral injection of dendritic cells genetically modified to express interleukin 12

Research Project

Project/Area Number	12671145
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	General surgery
Research Institution	The University of Tokyo
Principal Investigator	ICHIKAWA Naoya The University of Tokyo, Institute of Medical Science, Research Associate, 医科学研究所, 教務職員 (60251451)
Co-Investigator(Kenkyū-buntansha)	TAHARA Hideaki The University of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (70322071)
Project Period (FY)	2000 – 2001
Project Status	Completed (Fiscal Year 2001)
Budget Amount *help	¥3,300,000 (Direct Cost: ¥3,300,000) Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000) Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywords	gene therapy / viral vector / dendritic cell / OK-432 / interleukin-12 / インターロイキン12
Research Abstract	Dendritic cells (DCs) are potent professional antigen presenting cells and play a key role in cellular immunity. We have previously demonstrated that specific antitumor immune response can be induced with intratumoral (I.t.) injection of bone marrow-derived DCs genetically engineered with interleukin (IL)-12 genes. In this study, we examined whether DCs stimulated with OK-432 could be used in the same manner. In vivo administration of recombinant IL-12 causes NK cells and T cells to secrete IFN-g and enhances the cytolytic functions against tumor cells. These cytokines, however, induce abundant secretion of nitric oxide (NO) from activated macrophages, and appear to suppress cellular immunity in murine system. OK-432 has been clinically used as a potent biological modifiers for treating cancer patients and is known to induce multiple cytokines including IFN-g and IL-12 in vitro. In intradermal tumor modeles using MCA205 into C57BL/6 mice, I.t. injection bone marrow-derived DCs with or without OK-432 showed marginal antitumor effects on day 7 established tumors. However, potent antitumor effects were observed when they are treated with the combination of DCs, OK-432, and N-nitro-L-arginine methyl ester (L-NAME), which inhibits inducible nitric oxide synthase (iNOS)-mediated NO production. Furthermore, tumor specific and potent cytotoxic T lymphocytes (CTLs) could be obtained from the splenocytes of the mice treated with this combination. These results suggested that tumor specific cellular immunity in mice could be strongly suppressed with NO, which is abundantly secreted by macrophages and DCs stimulated with OK-432. Thus, I.t. injection of DCs and OK-432 could be a promisingly cancer immunotherapy if NO production is properly regulated.