Malignant brain tumors, especially gliomas, universally resist treatment. Despite surgery, radiation and chemotherapy, prognosis of patients afflicted with these tumors is grim. The goal of the project is to improve local cellular immunotherapy as an adjunctive treatment for brain tumors. The research of the first project period translated into a Phase I clinical trial, testing intracavitary allogeneic cytotoxic T lymphocytes (CTL) and interleukin-2 for recurrent primary brian tumors; the allogeneic CTL are synthesized ex vivo to the patient's major histocompatibility complex (MHC) antigens. For the proposed project period, we will continue testing aspects of this therapy which should assist in optimization of the treatment currently being tested. Specifically, the aims of this project are to: 1) Upregulate MHC proteins on tumor cells to improve visibility of the tumor to the intracranially (ic) administered allogeneic CTL. We will investigate the effects of: a) exogenously supplied proinflammatory agents including alpha- and gamma- interferon (alpha- IFN, gama-IFN), or sequential administration of interleukin- 1 (IL-1) AND gamma-IFN, on the upregulation of MHC antigens. b) Transfecting tumor cells with viral constructs encoding murine gamma-IFN alone or together with thymidine kinase from Herpes simplex virus (HSVtk). The combination vector will prove useful both for regulating the tissue levels of gamma-IFN with ganciclovir (GCV) and may further improve tumor lysis through the """"""""bystander effect."""""""" 2) Test, in vitro and in animals, whether IL-2 secretion from transduced tumor cells will maintain proliferative and lytic activity of intracranially administered allogeneic CTL, using retroviral vectors encoding either IL-2 alone or both IL-2 and HSVtk. As before, the dual vector construction allows for regulation for tissue levels of the cytokine as well as the possibility of """"""""bystander effect."""""""" 3) Determine if the glucocorticoid, dexamethasone, affects the cytolytic activity of allogeneic CTL in vitro and in vivo. High doses of this steroid are commonly used to control edema in brain tumor patients; it is important to ascertain whether they inhibit CTL activity. Accordingly, we will also test the effect of dexamethasone on immuno- and gene therapeutic regimens shown effective by the experiments described in the aims listed above.
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