Successful cancer vaccine therapy for carcinoembryonic antigen (CEA)-expressing colon cancer using genetically modified dendritic cells that express CEA and T helper-type 1 cytokines in CEA transgenic mice
Toshiyasu Ojima
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorCorresponding Author
Makoto Iwahashi
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Fax: +81-73-446-6566.
Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8510, JapanSearch for more papers by this authorMasaki Nakamura
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorKenji Matsuda
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorMikihito Nakamori
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorKentaro Ueda
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorTeiji Naka
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorKoichiro Ishida
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorF. James Primus
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
Search for more papers by this authorHiroki Yamaue
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorToshiyasu Ojima
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorCorresponding Author
Makoto Iwahashi
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Fax: +81-73-446-6566.
Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8510, JapanSearch for more papers by this authorMasaki Nakamura
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorKenji Matsuda
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorMikihito Nakamori
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorKentaro Ueda
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorTeiji Naka
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorKoichiro Ishida
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorF. James Primus
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
Search for more papers by this authorHiroki Yamaue
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
Search for more papers by this authorAbstract
This study was designed to determine whether the vaccination of genetically modified dendritic cells (DCs) simultaneously expressing carcinoembryonic antigen (CEA), granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 12 (IL-12) can overcome the peripheral T-cell tolerance to CEA and thereby elicit a therapeutic response in CEA transgenic mice. CEA transgenic mice were immunized once by subcutaneous injection with DCs adenovirally transduced with CEA and T helper-type 1 cytokine genes. The cytotoxic activity of spleen cells against CEA-expressing tumors, MC38-CEA, in the mice immunized with DCs expressing CEA (DC-AxCACEA) was higher than that in those immunized with DCs-AxCALacZ (p < 0.0001), and was augmented by the cotransduction with the GM-CSF/IL-12 gene (p < 0.05). The vaccination with DC-AxCACEA/GM-CSF/IL-12 could elicit a more potent therapeutic immunity than the vaccination with DC-AxCACEA in subcutaneous tumor models (p < 0.0001), and 4 of 5 mice showed a complete eradication of the subcutaneous tumors in these vaccination groups. Even in a large tumor model, this vaccination therapy completely eliminated the subcutaneous tumors in all mice. This antitumor activity mostly vanished with the depletion of CD8+ T cells and NK cells in vivo and was completely abrogated with the depletion of CD4+ T cells. A histopathological examination showed no evidence of an autoimmune reaction. No other adverse effects were observed. This vaccination strategy resulted in the generation of highly efficient therapeutic immune responses against MC38-CEA in the absence of autoimmune responses and demonstrated no adverse effects, and may therefore be useful for future clinical applications as a cancer vaccine therapy. © 2006 Wiley-Liss, Inc.
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