Restoring or augmenting immunity by the adoptive transfer of in vitro cultured antigen-specific T-cells has proven therapeutically effective for viral infections and tumors in animal models, and should be applicable to treatment of viral and malignant disease in man in situations in which human T-cells specific for virally encoded or tumor-derived antigens can be isolated. Preclinical studies in our laboratory have shown the presence of cytomegalovirus (CMV)-specific cytotoxic T-cells (Tc) in bone marrow transplant (BMT) recipients correlates with resistance to CMV infection, and studies in murine models have demonstrated that adoptive transfer of class I MHC-restricted CMV-specific Tn can prevent and/or treat severe CMV infection in immunocompromised hosts. We have developed the technology to generate and expand human CMV-specific CD8+ Tc and CD4+ T helper (Th) clones in vitro from seropositive marrow donors, and have initiated clinical studies to evaluate the safety of administering these clones to BMT recipients. Our studies to develop adoptive immunotherapy have been initiated with a viral disease since this permits the generation of T-cell clones with defined antigen specificity, thereby facilitating definition of the principles of effective adoptive transfer of immunity. Studies are proposed to expand these studies to include therapy of HIV in the post BMT setting, and our long range goal is to broaden the application of this approach to the therapy of human tumors. The illustration that tumor- derived immunoglobulin idiotype (Id) in B cell lymphomas can serve as a unique tumor antigen and elicit Id-specific T-cell responses has identified a situation in which we can now propose to explore immunotherapy with T- cell clones for the prevention of posttransplant relapse of a malignancy.
The specific aims of this project are 1) to evaluate specific immunological reconstitution in BMT recipients by adoptive immunotherapy with CMV- specific T-cell clones as prophylaxis or therapy for CMV infection, 2) to develop adoptive immunotherapy with CD8+ HIV-specific T-cell clones for HIV seropositive BMT recipients, including the use of retroviral-mediated gene transfer to introduce into these clones a selectable marker gene and a """"""""suicide"""""""" gene (herpes virus thymidine kinase) to increase the safety therapy in this setting, and 3) to develop posttransplant tumor-specific immunotherapy with CD4+ T-cell clones recognizing tumor-derived Id for patients receiving allogeneic BMT for B cell lymphomas.
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