Immunogene therapy using immunomodulating HVJ-E vector augments anti-tumor effects in murine malignant glioma.
The hemagglutinating virus of Japan envelope (HVJ-E) vector derived from inactivated replication-defective Sendai virus enhances anti-tumor immunity through activation of effector T cells and natural killer (NK) cells and inhibition of regulatory T cells (Tregs). Interleukin (IL)-2 enhances T cell proliferation and activates T cells and NK cells. However, recent studies have revealed that the application of IL-2 also has immune suppressive effects through expansion of Tregs. Here, we investigated the efficacy of IL-2 gene therapy using immunomodulating HVJ-E vector in murine malignant glioma models. A single intratumoral injection of HVJ-E containing pVAX-mIL-2 significantly suppressed tumor growth of intracranial gliomas, resulting in prolonged survival. Furthermore, HVJ-E, following intracavitary administration, delivered genes into post-operative residual tumor cells. Consequently, prolonged survival resulted from a single intracavitary administration of HVJ-E containing pVAX-mIL-2 following tumor removal. IL-2 gene therapy delivered via the HVJ-E vector significantly inhibited the expansion of Tregs in tumors compared to IL-2 gene transfer using retroviral vector and resulted in marked infiltration of CD4(+) and CD8(+) T cells into tumors. Through inhibition of Treg-mediated immunosuppression, HVJ-E enhanced effector T cell-mediated anti-tumor immunity induced by IL-2. This combination of an immunomodulating vector and immunostimulating cytokine gene shows promise as an attractive, novel immunogene therapy for malignant glioma.
Matsuda
Masahide
M
Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nimura
Keisuke
K
Shimbo
Takashi
T
Hamasaki
Toshimitsu
T
Yamamoto
Tetsuya
T
Matsumura
Akira
A
Kaneda
Yasufumi
Y
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D007155:Immunologic Factors; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D050130:Oncolytic Virotherapy; D029082:Sendai virus / Q000276:immunology*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D007155:Immunologic Factors; D007376:Interleukin-2