Despite the availability of radiation and chemotherapy, the prognosis of patients with malignant brain tumor,,; remains poor. The Denver Brain Tumor Research Group (DBTRG) is currently utilizing Interleukin-2 (IL-2) and adoptive transfer of nonspecifically stimulated lymphocytes, implanted intratumorally, for treatment of high grade gliomas (BB-IFM-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 and not reactive to major histocompatibility, differences. The first three years of this study will provide: 1) reproducible and efficient methodology for isolating and expanding rat allogeneic CTL to glioma c(alls, 2) demonstration of the in vivo efficacy of the allogeneic CFL when they are placed intracranially in the rat bearing 9L tumor by a) extended survival or cure (:)f 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 proceed on to the development of allogeneic human CTL against autologous (self) brain tumor. What is novel about this approach is that all past studies with animals and humans have used autologous effectors sensitized against allogeneic tumor. We plan to use allogeneic effectors, sensitized against autologous tumor. Negative selection applied to the generation of human allogeneic CTL will eliminate the possibility of allergic encephalitis. 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. Overall, these studies should provide an appropriate evaluation of the role of specifically sensitized lymphocytes in the immunotherapy of brain tumor patients. Final assessment of the role of allogeneic CTL in adjunctive therapy for brain tumor patients will come in testing these cells clinically.
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