Inducing long-term survival with lasting anti-tumor immunity in treating B cell lymphoma by a combined dendritic cell-based and hydrodynamic plasmid-encoding IL-12 gene therapy.
In a previous study we showed that immunization with dendritic cells (DC) pulsed with idiotype (Id) fused with CD40 ligand (CD40L) could break the tolerance to Id which is expressed on B lymphoma cells and restored the responsiveness of T(h) cells, and, subsequently, induced IgG antibody response. However, this treatment had no therapeutic effect. In the present study, we found that using a hydrodynamic transfection-based technique, a high level of IL-12 production was noticed as early as 7 h after administering plasmid encoding IL-12 (pIL-12) and persisted at a detectable level for at least 9 days. In evaluating the efficacy of DC-based and/or IL-12 gene-based therapy in the treatment of 38C13 B cell lymphoma, it was found that either treatment alone was ineffective. However, a combined treatment induced 100% long-term survival. Furthermore, a long-lasting anti-tumor immunity was induced in these mice which resisted further tumor challenge at 58 days after initial inoculation. The surviving mice showed a strong IFN-gamma-producing T(h) cell response and humoral antibody response, but there were no detectable cytotoxic T lymphocytes. The antibody from the immune sera mediated a complement-dependent lysis of tumor cells that was tumor specific. Furthermore, immunization of mice with DC-based vaccine and pIL-12 treatment elicited higher levels of anti-Id IgG titer and an enhanced IgG2a response which increased the efficacy in mediating 38C13 tumor lysis. On examining the mechanism for this isotype change, we found that IFN-gamma production by CD4(+) T cells is not the only determining factor for achieving a successful therapy. DC-based treatment alone could induce the increase of IFN-gamma production, but lacked any therapeutic effect. The deciding factor appears to be the abrogation of IL-4 production that was achieved by combing with IL-12 gene therapy. Our study provides a basis for exploring the combined use of cytokines or cytokine genes in DC-based treatment for achieving effective cancer immunotherapy.
Chen
Hsin-Wei
HW
Immunology Group, National Health Research Institutes, 201 Shih-Pai Road, Section 2, Taipei, Taiwan.
Lee
Yi-Ping
YP
Chung
Yu-Fen
YF
Shih
Yan-Chung
YC
Tsai
Jy-Ping
JP
Tao
Mi-Hua
MH
Ting
Chou-Chik
CC
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015316:Genetic Therapy; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D051379:Mice; D010957:Plasmids
D000906:Antibodies; D000951:Antigens, Neoplasm; C464525:Id tumor-specific protein, mouse; D018664:Interleukin-12