IFN-beta gene therapy induces systemic antitumor immunity against malignant glioma

We previously demonstrated that intratumoral administration of liposomes co ntaining the murine interferon beta (IFN-beta) gene [lip(pSV2muIFN-beta)] r esulted in stronger growth-inhibitory effect on GL261 (H-2(b)) mouse glioma inoculated in brains of syngeneic C57BL/6 mice than conventional exogenous IFN-beta administration, and histologic evaluation revealed the massive in filtration of T lymphocytes (CD8 > CD4) within the residual tumor. The pres ent study was aimed at determining whether such tumor-infiltrating lymphocy tes (TIL) have any tumor-specific cytotoxic effects. Intratumoral administr ation of lip(pSV2muIFN-beta) resulted in prolonged survival time and a 50% tumor-free incidence in the mice treated. The surviving animals were subseq uently re-challenged with either subcutaneous or intracranial injection of GL261 cells, and no tumors were found to develop over a 50-day period. In v ivo depletion of CD8, but not CD4 cells decreased the efficacy of lip(pSV2m uIFN-beta). Specific cytotoxic T lymphocytes (CTL) against GL261 cells were generated from both TIL and spleen cells of the mice treated. The results of flow cytometric analysis and antibody blocking test revealed that the bu lk CTL lines thus prepared were T cell receptor (TCR) alpha beta, CD8 T lym phocytes with H-2(b) restriction. These findings suggest that, in addition to direct growth-inhibitory effect s by the IFN-beta gene on the tumor cells, activation of systemic cellular immunity may participate in antitumor effects in vivo, despite the fact tha t central nervous system is generally regarded as an immunologically privil eged site.