Systemic Activation of the Immune System during Ganciclovir Treatment Following Intratumoral Herpes Simplex Virus Type 1 Thymidine Kinase Gene Transfer in an Adolescent Ependymoma Patient

Abstract

During ganciclovir treatment of an adolescent ependymoma patient two weeks after intracranial implantation of HSVtk retroviral vector producer cells, increasing numbers of peripheral T- and B-cells were found as well as enhanced T-cell activation and elevated serum levels of interleukin 12 and soluble Fas ligand. These findings suggest the systemic activation of the immune system during ganciclovir treatment in our patient. The induction of an immune response by HSVtk/ganciclovir supports the concept of an anti-tumor vaccination effect by prodrug activating gene therapy systems and may open new promising perspectives for enhancing therapeutic efficiency by combined prodrug activating and immunological gene therapy strategies.

Key words

Brain Tumor Gene Therapy - T-Cell Activation - B-Cell Activation - IL-12 - sFasL

References

• 1 Erkeller-Yuksel F M, Deneys V, Yuksel B, Hannet I, Hulstaert F, Hamilton C. et al . Age-related changes in human blood lymphocytes subpopulations.  J Pediatr. 1992;  120 216-222
• 2 Freeman S M, Ramesh R, Marrogi A J. Immune system in suicide-gene therapy.  Lancet. 1997;  349 2-3
• 3 Gagandeep S, Brew R, Green B, Christmas S E, Klatzmann D, Poston G J. et al . Prodrug-activated gene therapy: involvement of an immunological component in the “bystander effect”.  Cancer Gene Ther. 1996;  3 83-88
• 4 Hishii M, Nitta T, Ishida H, Ebato M, Kurosu A, Yagita H. et al . Human glioma-derived interleukin 10 inhibits anti-tumor immune response in vitro.  Neurosurgery. 1995;  37 1160-1166
• 5 Husain N, Chiocca E A, Rainov N G, Louis D N, Zervas N T. Co-expression of Fas and Fas ligand in malignant glial tumors and cell lines.  Acta Neuropathol (Berl.). 1998;  95 287-290
• 6 Korholz D, Banning U, Bonig H, Grewe M, Schneider M, Mauz-Korholz C. et al . The role of interleukin-10 (IL-10) in IL-15-mediated T-cell responses.  Blood. 1997;  90 4513-4521
• 7 Mahaley M S. Brooks WH, Roszman TL. Immunobiology of primary intracranial tumors. I. Studies of the cellular and humoral general immune competence of brain tumor patients.  J Neurosurg. 1977;  46 467-476
• 8 Molnar-Kimber K L, Kang E H, Gelfand K, Abbas A E, Sterman D, Albelda S M. et al .Humoral anti-tumor immune response induced in mesothelioma patients by intrapleural administration of recombinant adenoviral-based gene therapy. Program of the Second Annual Meeting of the American Society of Gene Therapy, June 9 - 13, Washington, DC, USA, Abstract 12. 1999
• 9 Packer R J, Raffel C, Villablanca J G, Tonn J C, Burdach S E, Burger K. et al . Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration.  J Neurosurg. 2000;  92 249-254
• 10 Rainov N G, Kramm C M, Banning U, Riemann D, Holzhausen H J, Heidecke V. et al . Immune response induced by retrovirus-mediated HSV-tk/GCV pharmacogene therapy in patients with glioblastoma multiforme.  Gene Ther. 2000;  7 1853-1858