AN HSVTK-MEDIATED LOCAL AND DISTANT ANTITUMOR BYSTANDER EFFECT IN TUMORS OF HEAD AND NECK ORIGIN IN ATHYMIC MICE

The ''bystander effect,'' produced by ganciclovir-mediated killing of cells transduced with a herpes simplex virus thymidine kinase (HSVtk) gene, defines the cooperative killing of non-HSVtk-transduced cells. I n vitro, a major contributor to this phenomenon is metabolic cooperati on involving transfer of cytotoxic small molecules between cells via g ap junctions. In this study, the bystander effect was assessed in vivo using cells of oral squamous cell carcinoma origin. Mixtures of HSVtk (+) and HSVtk(-) tumor cells were implanted subcutaneously in the left flank of nude mice, and naive HSVtk(-) cells were implanted subcutane ously in the right Flank. When tumors attained a size of 0.5 to 1 cm, the animals were treated with ganciclovir on a daily basis. The rumors comprised of mixed cells in the left flank resolved, consistent with a predicted bystander effect. The naive tumors in the right flank eith er resolved or became cytostatic showing little further growth compare d to controls. Similar results were obtained when naive tumors were gr own in both flanks and the tumor in the left flank received intratumor al injection of HSVtk retroviral producer cells or PA317 (HSVtk(+)) pa ckaging cells, but not parental NIH 3T3 cells. Concomitant treatment w ith dexamethasone impaired the antitumor effect on the contralateral s ide. When these experiments were performed in SCID-Beige mice, there w as a reduced antitumor effect on the ipsilateral flank and no antitumo r response in the contralateral flank. Together with histology of regr essing tumors, which showed an infiltration of lymphoid cells, these r esults are suggestive of an immune-related antitumor response that cou ld account for the distant bystander effect.