Tumor cells expressing the herpes simplex virus—thymidine kinase gene in the treatment of Walker 256 meningeal neoplasia in rats

Abstract

✓ A promising strategy in the treatment of neoplastic meningitis involves the use of herpes simplex virus—thymidine kinase (HSV-tk)—modified cells. In these experiments the authors used cells expressing HSV-tk to treat meningeal carcinomatosis in the rat Walker 256 model. Intrathecal injection of 2 × 105 Walker cells resulted in a median survival time of 15 days. Up to 80% of animals implanted with HSV-tk—modified Walker cells (Walker-tk+) and treated with ganciclovir showed long-term survival (120 days or more), whereas the remaining animals died from tumor growth between 37 and 44 days after implantation. Tumor cells from an animal in which the treatment failed were culturedin vitro and were shown to be still sensitive to ganciclovir. However, continuous ganciclovir administration for 6 weeks rather than 2 weeks did not improve survival. Histopathological studies confirmed leptomeningeal infiltration in the untreated Walker or Walker-tk+ animals. Walker-tk+ cells were mixed with Walker cells in 1:1, 10:1, or 50:1 ratios, respectively, and implanted intrathecally; the animals were treated with ganciclovir. All groups of treated animals had long-term survivors, with 40% of the rats in the 10:1 and 50:1 groups demonstrating long-term survival and absence of microscopic tumors in the brain or spinal cord. Similarly, murine fibroblast HSV-tk virus—producer cells improved survival. Walker-tk+ cells were better than fibroblast-producer cells in improving the survival of animals with Walker tumors at low (1:1) but not at high (10:1) effector-to-target cell ratios. Repeated intrathecal administration of Walker-tk+ cells resulted in inhibition of established Walker tumors. The authors conclude that Walker-tk+ cells are at least as effective as murine virus—producer cells and could be used in the treatment of meningeal neoplasia.