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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028905-09
Application #
2891787
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Tom P
Project Start
1990-08-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Gomez, German G; Read, Susana B; Gerschenson, Lazaro E et al. (2004) Interactions of the allogeneic effector leukemic T cell line, TALL-104, with human malignant brain tumors. Neuro Oncol 6:83-95
Read, Susana B; Kulprathipanja, Nisha V; Gomez, German G et al. (2003) Human alloreactive CTL interactions with gliomas and with those having upregulated HLA expression from exogenous IFN-gamma or IFN-gamma gene modification. J Interferon Cytokine Res 23:379-93
Nicholas, T W; Read, S B; Burrows, F J et al. (2003) Suicide gene therapy with Herpes simplex virus thymidine kinase and ganciclovir is enhanced with connexins to improve gap junctions and bystander effects. Histol Histopathol 18:495-507
Paul, David B; Read, Susana B; Kulprathipanja, Nisha V et al. (2003) Gamma interferon transduced 9L gliosarcoma. Cytokine gene therapy and its relevance to cellular therapy with alloreactive cytotoxic T lymphocytes. J Neurooncol 64:89-99
Burrows, Francis J; Gore, Martin; Smiley, W Russell et al. (2002) Purified herpes simplex virus thymidine kinase retroviral particles: III. Characterization of bystander killing mechanisms in transfected tumor cells. Cancer Gene Ther 9:87-95
Schiltz, Patric M; Gomez, German G; Read, Susana B et al. (2002) Effects of IFN-gamma and interleukin-1beta on major histocompatibility complex antigen and intercellular adhesion molecule-1 expression by 9L gliosarcoma: relevance to its cytolysis by alloreactive cytotoxic T lymphocytes. J Interferon Cytokine Res 22:1209-16
Gomez, G G; Hutchison, R B; Kruse, C A (2001) Chemo-immunotherapy and chemo-adoptive immunotherapy of cancer. Cancer Treat Rev 27:375-402
Virasch, N; Kruse, C A (2001) Strategies using the immune system for therapy of brain tumors. Hematol Oncol Clin North Am 15:1053-71
Kruse, C A; Visonneau, S; Kleinschmidt-DeMasters, B K et al. (2000) The human leukemic T-cell line, TALL-104, is cytotoxic to human malignant brain tumors and traffics through brain tissue: implications for local adoptive immunotherapy. Cancer Res 60:5731-9
Kruse, C A; Lamb, C; Hogan, S et al. (2000) Purified herpes simplex thymidine kinase retroviral particles. II. Influence of clinical parameters and bystander killing mechanisms. Cancer Gene Ther 7:118-27

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