Chemotherapy and immunotherapy of tumours induced by gene-modified HPV16-transformed cells

HPV16 E6/E7 transformed mouse kidney cells designated MK16/1/IIIABC (MK16) were modified by the insertion of a suicide gene, viz. the thymidine-kinase gene of herpes simplex virus (HSV TK). Tumour induction by these cells, designated N2A, was suppressed by ganciclovir (GCV). The growth of already established tumours was partially inhibited by GCV. This effect was markedly potentiated by a single dose of cyclophosphamide (Cy). Ganciclovir- or GCV+ Cy-cured mice were not protected against challenge with MK16 cells. N2A tumour growth was suppressed by simultaneous administration of MK16-derived, non-oncogenic B9 and 181 cells, which express either mouse GM-CSF or mouse IL2, respectively, in addition to HSV TK. The animals treated were protected against challenge with MK16 cells. Animals with already established N2A tumours were treated with GCV and/or repeated doses of B9 or 181 cells. Ganciclovir treatment alone and immunotherapy alone resulted in partial suppression of tumour growth but not in tumour cure. On the other hand, combined chemo- and immunotherapy resulted in tumour rejection by nearly all animals. Similar results were obtained if the immunotherapy with homologous gene-modified cells was substituted by treatment with anti-CD4 antibody. The animals cured of tumours with GCV combined with cell-based vaccine therapy but not those cured by GCV and anti-CD4 antibody treatment were found resistant to challenge with MK16 cells. The present results suggest that combined specific and non-specific chemo- and immunotherapy of tumours induced by appropriately gene-modified cells might provide a special advantage in the treatment of established tumours.