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Recombinant Sendai Virus Vector Induces Complete Remission of Established Brain Tumors through Efficient Interleukin-2 Gene Transfer in Vaccinated Rats

Authors' Affiliations: Departments of ¹ Neurological Surgery and ² Academic Surgery, Graduate School of Medicine, Chiba University; ³ Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan; and ⁴ DNAVEC Research, Inc., Tsukuba, Ibaraki, Japan

Requests for reprints: Yasuo Iwadate, Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, 260-8670 Chiba, Japan. Phone: 81-43-226-2158; Fax: 81-43-226-2159; E-mail: iwadatey{at}faculty.chiba-u.jp.

Purpose: Sendai virus (SeV), a murine parainfluenza virus type I, replicates independent of cellular genome and directs high-level gene expressions when used as a viral vector. We constructed a nontransmissible recombinant SeV vector by deleting the matrix (M) and fusion (F) genes from its genome (SeV/MF) to enhance its safety. We also estimated the therapeutic efficacy of the novel vector system against a rat glioblastoma model.

Experimental Design: We administered the recombinant SeV vector carrying the lacZ gene or the human interleukin-2 (hIL-2) gene into established 9L brain tumors in vivo simultaneous with peripheral vaccination using irradiated 9L cells. Sequential monitoring with magnetic resonance imaging was used to evaluate the therapeutic efficacy.

Results: We found extensive transduction of the lacZ gene into the brain tumors and confirmed sufficient amounts of interleukin 2 (IL-2) production by hIL2-SeV/MF both in vitro and in vivo. The magnetic resonance imaging study showed that the intracerebral injection of hIL2-SeV/MF brought about significant reduction of the tumor growth, including complete elimination of the established brain tumors. The ⁵¹Cr release assay showed that significant amounts of 9L-specific cytotoxic T cells were induced by the peripheral vaccination. Immunohistochemical analysis revealed that CD4⁺ T cells and CD8⁺ T cells were abundantly infiltrated in the target tumors.

Conclusion: The present results show that the recombinant nontransmissible SeV vector provides efficient in vivo gene transfer that induces significant regression of the established brain tumors and suggest that it will be a safe and useful viral vector for the clinical practice of glioma gene therapy.

Key Words: glioma • cytokine • interleukin-2 • gene therapy • vaccine