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Chemotherapy and immunotherapy of tumours induced by gene-modified HPV16-transformed cells
Eva Sobotková1, Martina Dusková, Michal Smahel
1Department of Experimental Virology, Institute of Hematology and Blood Transfusion, 128 20 Prague 2, Czech Republic.
Abstract:
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.
Insights
This study shows that combining ganciclovir (GCV) chemotherapy with immunotherapy using gene-modified cells or anti-CD4 antibody can effectively treat established tumors. Combined therapy led to tumor rejection in most animals, suggesting a promising approach for cancer treatment.
Area of Science:
- Oncology
- Immunotherapy
- Gene Therapy
Background:
- Mouse kidney cells (MK16) transformed with HPV16 E6/E7 were engineered with a herpes simplex virus thymidine kinase (HSV TK) suicide gene, creating N2A cells.
- Ganciclovir (GCV) treatment suppressed tumor induction by N2A cells and partially inhibited established tumors.
- Cyclophosphamide (Cy) potentiated the anti-tumor effects of GCV.
Purpose of the Study:
- To investigate the efficacy of combined chemo- and immunotherapy for established tumors induced by gene-modified cells.
- To evaluate the protective effects against tumor re-challenge after treatment.
Main Methods:
- Mice bearing established N2A tumors were treated with ganciclovir (GCV) and/or cyclophosphamide (Cy).
- Immunotherapy was administered using syngeneic, non-oncogenic cells (B9, 181) engineered to express mouse GM-CSF or IL2, respectively, along with HSV TK, or with anti-CD4 antibody.
- Tumor growth, rejection, and resistance to subsequent tumor challenge were assessed.
Main Results:
- Combined chemo- and immunotherapy (GCV + B9/181 cells or GCV + anti-CD4 antibody) resulted in tumor rejection in nearly all animals.
- GCV or immunotherapy alone achieved partial tumor growth suppression but not complete tumor cure.
- Mice cured with GCV and cell-based immunotherapy were resistant to MK16 cell challenge, unlike those treated with GCV and anti-CD4 antibody.
Conclusions:
- Combined specific and non-specific chemo- and immunotherapy using gene-modified cells offers a significant advantage in treating established tumors.
- This multimodal approach demonstrates potent anti-tumor activity and potential for inducing protective immunity.
- The findings suggest a promising strategy for developing novel cancer therapies.
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