RG-2 GLIOMA GROWTH ATTENUATION AND SEVERE BRAIN EDEMA CAUSED BY LOCALPRODUCTION OF INTERLEUKIN-2 AND INTERFERON-GAMMA

Two aspects of cytokine therapy of intracerebral tumors are considered in this study: modulation of tumor growth in vivo and central nervous system toxicity. Coimplantation of RG-2 glioma cells and retroviral v ector producer cell lines was performed to provide a local source of i nterleukin-2 (IL-2) or IFN-gamma within the tumor and coinitiate an an titumor immune response. We demonstrated that local intratumoral produ ction of IL-2 and IFN-gamma generates a cell-mediated antitumor respon se in vivo. This response was manifest as a diffuse infiltration of mo nocytes/macrophages, CD4(+) and CD8(+) T cells, and activation of micr oglial OX42(+) cells in intracerebral RG2 tumors. The cell-mediated an titumor immune response resulted in the early suppression of intracran ial and subcutaneous tumor growth, but the effect was not sustained an d there were no tumor regressions. The absence of increased survival o f animals with intracranial tumors is explained in part by the severe central nervous system toxicity caused by local production of IL-2 and IFN-gamma. Central nervous system toxicity included blood-brain barri er disruption, vasogenic brain edema, and dislocation of the brain mid line structures, as observed by dynamic magnetic resonance imaging and direct measurements of tissue water content. The clinical application of IL-2 and IFN-gamma gene transfer therapy for intracerebral tumors must consider the potential for severe vasogenic brain edema associate d with intracerebral production of these cytokines.