1. ¹Department of Pediatric Surgery, Kyushu University, Fukuoka, Japan
2. ²Pathophysiological and Experimental Pathology, Department of Pathology, Kyushu University, Fukuoka, Japan
3. ³Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
4. ⁴Department of Gene Therapy, Chiba University Graduate School of Medicine, Chiba, Japan
5. ⁵DNAVEC Corporation, Tsukuba, Ibaraki, Japan
6. ⁶Fukuoka Dental College, Fukuoka, Japan
7. ⁷Operating Unit of Clinical Trial of Gene Therapy, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Correspondence: Professor Y Yonemitsu, Operating Unit of Clinical Trial of Gene Therapy, Graduate School of Medical Sciences, Kyushu University, Room 505, Collaborative Research Station II, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yonemitu@med.kyushu-u.ac.jp

Received 16 June 2008; Revised 2 October 2008; Accepted 2 October 2008; Published online 6 November 2008.

Abstract

Dendritic cell (DC)-based immunotherapy has been investigated as a new therapeutic approach to intractable neuroblastomas; however, only limited clinical effect has been reported. To overcome the relatively low sensitivity of neuroblastomas against immunotherapy, we undertook a preclinical efficacy study to examine murine models to assess the combined effects of -irradiation pretreatment and recombinant Sendai virus (ts-rSeV/dF)-mediated murine interferon- (mIFN-) gene transfer to DCs using established c1300 neuroblastomas. Similar to intractable neuroblastomas in the clinic, established c1300 tumors were highly resistant to monotherapy with either -irradiation or DCs activated by ts-rSeV/dF without transgene (ts-rSeV/dF-null) that has been shown to be effective against other murine tumors, including B16F10 melanoma. In contrast, immunotherapy using DCs expressing mIFN- through ts-rSeV/dF (ts-rSeV/dF-mIFN-DCs) effectively reduced tumor size, and its combination with -irradiation pretreatment dramatically enhanced its antitumor effect, resulting frequently in the complete elimination of established c1300 tumors 7–9 mm in diameter, in a high survival rate among mice, and in the development of protective immunity in the mice against rechallenge by the tumor cells. These results indicate that the combination of ts-rSeV/dF-mIFN-DCs with -irradiation is a hopeful strategy for the treatment of intractable neuroblastomas, warranting further investigation in the clinical setting.