Despite the availability of radiation and chemotherapy. the prognosis of patients with malignant brain tumors remains poor. The Derrver Brain Tumor Research Group (DBTRG) is currently utilizing Interleukin-Z (IL-2) and adoptive transfer of nonspecifically stimulated lymphocytes, implanted intratumorally. for treatment of high grade gliomas (BB-IND-2412). The focus of this proposal is to look at the role of tumor-sensitized cytotoxic T lymphocytes(CTL) in adoptive transfer. We will generate allogeneic (genetically dissimilar) CTL to 9L Fischer rat gliosarcoma tumor. Negative selection procedures will allow the isolation of CTL specifically lytic for tumor. The first three years of this study will provide: 1) reproducible and efficient methodology for isolating and expanding rat allogeneic CTL to glioma cells. 2) demonstration of the in vivo efficacy of the allogeneic CTL when they are placed intracranially in the rat bearing 9L tumor by a) extended survival or cure of rats bearing 9L tumor and by b) tumor volumetric measurements made histologically. 3) histological evidence that tumor is damaged and normal brain is relatively unaffected. 4) correlation of in vitro cytotoxicity and/or surface phenotype to in vivo efficacy. and 5) appropriate doses and therapy regimen to cure or optimally treat rats of their brain tumor. We will then develop allogeneic human CTL against autologous (self) brain tumor. To eliminate allergic encephalitis, CTL reactive to major histocompatibility differences will be negatively selected from CrL specifically lytic for tumor. Although allogeneic CTL may be impractical for treatment of systemic neoplasm. because the effectors can be administered intracranially. an immunologically privileged area, we expect to demonstrate a practical value for this approach. Final assessment of the role of allogeneic CTL in adjunctive therapy for brain tumor patients will come in testing these cells clinically.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Modified Research Career Development Award (K04)
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Neurology A Study Section (NEUA)
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University of Colorado Denver
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Kruse, C A; Roper, M D; Kleinschmidt-DeMasters, B K et al. (1997) Purified herpes simplex thymidine kinase Retrovector particles. I. In vitro characterization, in situ transduction efficiency, and histopathological analyses of gene therapy-treated brain tumors. Cancer Gene Ther 4:118-28
Kleinschmidt-DeMasters, B K; Conway, D R; Franklin, W A et al. (1995) Neural cell adhesion molecule expression in human pituitary adenomas. J Neurooncol 25:205-13
Kruse, C A; Schiltz, P M; Bellgrau, D et al. (1994) Intracranial administrations of single or multiple source allogeneic cytotoxic T lymphocytes: chronic therapy for primary brain tumors. J Neurooncol 19:161-8
Kruse, C A; Molleston, M C; Parks, E P et al. (1994) A rat glioma model, CNS-1, with invasive characteristics similar to those of human gliomas: a comparison to 9L gliosarcoma. J Neurooncol 22:191-200
Kruse, C A; Kong, Q; Schiltz, P M et al. (1994) Migration of activated lymphocytes when adoptively transferred into cannulated rat brain. J Neuroimmunol 55:11-21
Kruse, C A; Mitchell, D H; Kleinschmidt-DeMasters, B K et al. (1993) Systemic chemotherapy combined with local adoptive immunotherapy cures rats bearing 9L gliosarcoma. J Neurooncol 15:97-112
Kruse, C A; Mitchell, D H; Kleinschmidt-DeMasters, B K et al. (1992) Characterization of a continuous human glioma cell line DBTRG-05MG: growth kinetics, karyotype, receptor expression, and tumor suppressor gene analyses. In Vitro Cell Dev Biol 28A:609-14
Redd, J M; Lagarde, A C; Kruse, C A et al. (1992) Allogeneic tumor-specific cytotoxic T lymphocytes. Cancer Immunol Immunother 34:349-54
Mitchell, D H; Withrow, S J; Johnston, M R et al. (1991) Cytotoxicity against autologous, allogeneic, and xenogeneic tumor targets by human recombinant interleukin-2-activated lymphocytes from healthy dogs and dogs with lung tumors. Am J Vet Res 52:1132-6
Kruse, C A; Lillehei, K O; Mitchell, D H et al. (1990) Analysis of interleukin 2 and various effector cell populations in adoptive immunotherapy of 9L rat gliosarcoma: allogeneic cytotoxic T lymphocytes prevent tumor take. Proc Natl Acad Sci U S A 87:9577-81