TREATMENT OF INTRACRANIAL GLIOMAS IN IMMUNOCOMPETENT MICE USING HERPES-SIMPLEX VIRUSES THAT EXPRESS MURINE INTERLEUKINS

This report describes a test of the hypothesis that the oncolytic effe ct of genetically engineered, replication competent herpes simplex vir uses (HSV) depends both on cell destruction by the virus and an immune response to the tumor cells induced in an immunocompetent animal syst em. The oncolytic vector was a HSV recombinant virus in which both cop ies of the gamma(1)34,5 gene were replaced with the murine genes encod ing the cytokine interleukin-4 (IL-4) or interleukin-10 (IL-10). The h ypothesis predicted that if an immune response plays a role in surviva l following intratumoral treatment of tumor-bearing animals with HSV, expression of IL-4 should prolong survival whereas expression of IL-10 should reduce it. The results are that (1) these cytokines can be exp ressed by HSV in productively infected cells both in vitro and in vivo ; (2) HSV-expressing IL-4 or IL-10 genes were able to infect and destr oy glioma cells in vitro; (3) intracerebral inoculation of HSV express ing either IL-4 or IL-10 into syngeneic murine glioma GL-261 cells imp lanted in the brains of immunocompetent C57BL/6 mice produced dramatic ally opposite physiologic responses. The IL-4 HSV significantly prolon ged survival of tumor bearers, whereas tumor-bearing mice that receive d the IL-10 HSV had a median survival that was identical to that of sa line treated controls; (4) immunohistochemical analyses of mouse brain s at 3 and 7 days after virus inoculation showed marked accumulation o f inflammatory cells composed primarily of macrophages/microglia, with various proportions of CD8(+) and CD4(+) T cells, but few B lymphocyt es. We conclude that the cytokines expressed from genes encoded in the viral genome influence HSV therapy of tumors and this is probably due to the host immune response. Thus, cytokine expression may be an impo rtant adjunct to tumor therapy utilizing genetically engineered HSV.