DEVELOPMENT OF ANTITUMOR IMMUNITY FOLLOWING THYMIDINE KINASE-MEDIATEDKILLING OF EXPERIMENTAL BRAIN-TUMORS

Using the 9L experimental brain tumor model, we studied long-term tumo r regression and immunologic consequences of tumor killing in a model of in vivo gene transfer of the herpes simplex virus 1 thymidine kinas e (HSV-TK) gene and ganciclovir (GCV) treatments. Fibroblasts modified to produce retroviral vectors carrying the HSV-TK gene were implanted into established 9L brain tumors in Fischer 344 rats to carry out gen e transfer. Animals were then treated with parenteral GCV. Significant tumor regression was seen following GCV treatments in short-term expe riments (17 days) as quantified by measurements of tumor volume. In lo ng-term studies, 7 of 32 (22%) treated animals survived 90 days. Histo logic examination of the brains of the successfully treated animals de monstrated residual tumor cells and inflammatory cells consisting pred ominantly of macrophages/microglia and T cells in the hemisphere with the residual tumor cyst. Rats surviving 90 days rejected repeat tumor injections into the contralateral brain and flank, whereas identical t umor injections in naive animals resulted in both brain and flank tumo rs. The presence of significant anti-tumor immunity following HSV-TK a nd GCV treatments suggests that the immune system plays a critical rol e in the sustained tumor regressions associated with these treatments. These findings show that while HSV-TK and GCV treatments can result i n long-term tumor regressions in this model, the success of these trea tments could be improved by better understanding the role played by th e host's immune systems.