Complete elimination of established neuroblastoma by synergistic action of gamma-irradiation and DCs treated with rSeV expressing interferon-beta gene.
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 gamma-irradiation pretreatment and recombinant Sendai virus (ts-rSeV/dF)-mediated murine interferon-beta (mIFN-beta) 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 gamma-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-beta through ts-rSeV/dF (ts-rSeV/dF-mIFNbeta-DCs) effectively reduced tumor size, and its combination with gamma-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-mIFNbeta-DCs with gamma-irradiation is a hopeful strategy for the treatment of intractable neuroblastomas, warranting further investigation in the clinical setting.
Tatsuta
K
K
Department of Pediatric Surgery, Kyushu University, Higashi-ku, Fukuoka, Japan.
Tanaka
S
S
Tajiri
T
T
Shibata
S
S
Komaru
A
A
Ueda
Y
Y
Inoue
M
M
Hasegawa
M
M
Suita
S
S
Sueishi
K
K
Taguchi
T
T
Yonemitsu
Y
Y
D000818:Animals; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D004195:Disease Models, Animal; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008805:Mice, Inbred A; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D029082:Sendai virus / Q000235:genetics
D016899:Interferon-beta