Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene

Overexpression of interleukin 4 (IL-4) can impair the tumorigenicity of gli oma cells, but direct evidence of its antitumor efficacy after Ct vivo gene transfer into malignant gliomas has not been provided. To test this, we fi rst injected into the brain of Sprague Dawley rats a 1:1 mixture of C6 rat glioblastoma cells and Psi 2.L4SN(20) or E86.L4SN(50) retroviral producer c ells (RPCs), secreting 20 and 50 ng of IL-4/5 x 10(5) cells/48 h, respectiv ely. Twenty-seven and 56% of rats receiving injections with these low- or m edium-level IL-4 RPCs, respectively, survived tumor injection, whereas cont rol rats died in about 1 month. E86.L4SN(50) RPCs coinjected with 9L gliosa rcoma cells into syngeneic Fischer 344 rats yielded similar results. A nove l IL-4 RPC clone expressing higher levels of IL-4, E86.L4SN(200), coinjecte d with 9L cells increased to 75% the fraction of long-term survivors and in duced tumor regression in 50% of rats when injected into established 9L gli osarcomas. Cured rats developed an immunological memory because they reject ed a challenge of wild-type 9L cells into the contralateral hemisphere. Mag netic resonance imaging was used to monitor 9L and C6 gliomas and gave dire ct evidence for tumor rejection in treated rats. Immunohistology showed inf lammatory infiltrates in IL-4-treated tumors in which CD8+ T lymphocytes we re more abundant, although CD4+ T lymphocytes, B lymphocytes, and macrophag es were also present. Overall, these findings suggest that IL-4 gene transf er is a new, promising approach for treating malignant gliomas.