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Eradication of Rat Malignant Gliomas by Retroviral-mediated, in Vivo Delivery of the Interleukin 4 Gene¹

Laboratory of Neuro-Oncology and Gene Therapy [S. B., B. P., N. C., G. F.], and Departments of Neuroradiology [M. G. B.], Neuropathology [B. P.], and Neurosurgery [F. D.], Istituto Nazionale Neurologico Besta, 20133 Milano, Italy; Policlinico S. Matteo, Department of Neurosurgery 27100 Pavia, Italy [L. M.]; and Istituto Nazionale dei Tumori, Department of Experimental Oncology D, Milano, Italy [M. P. C.]

Overexpression of interleukin 4 (IL-4) can impair the tumorigenicity of glioma cells, but direct evidence of its antitumor efficacy after in vivo gene transfer into malignant gliomas has not been provided. To test this, we first injected into the brain of Sprague Dawley rats a 1:1 mixture of C6 rat glioblastoma cells and 2.L4SN²⁰ or E86.L4SN⁵⁰ retroviral producer cells (RPCs), secreting 20 and 50 ng of IL-4/5 x 10⁵ cells/48 h, respectively. Twenty-seven and 56% of rats receiving injections with these low- or medium-level IL-4 RPCs, respectively, survived tumor injection, whereas control rats died in about 1 month. E86.L4SN⁵⁰ RPCs coinjected with 9L gliosarcoma cells into syngeneic Fischer 344 rats yielded similar results. A novel IL-4 RPC clone expressing higher levels of IL-4, E86.L4SN²⁰⁰, coinjected with 9L cells increased to 75% the fraction of long-term survivors and induced tumor regression in 50% of rats when injected into established 9L gliosarcomas. Cured rats developed an immunological memory because they rejected a challenge of wild-type 9L cells into the contralateral hemisphere. Magnetic resonance imaging was used to monitor 9L and C6 gliomas and gave direct evidence for tumor rejection in treated rats. Immunohistology showed inflammatory infiltrates in IL-4-treated tumors in which CD8+ T lymphocytes were more abundant, although CD4+ T lymphocytes, B lymphocytes, and macrophages were also present. Overall, these findings suggest that IL-4 gene transfer is a new, promising approach for treating malignant gliomas.

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