CLONAL CVL/GVH REACTIONS AND ADOPTIVE IMMUNOTHERAPY

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Leukemia relapse after bone marrow transplantation is a significant clinical problem. Recent clinical and experimental studies have suggested that the problem may become worse with the use of T-cell depletion techniques to avoid graft-vs-host (GVH) disease. Thus, there is a need for therapeutic strategies which would provide an antileukemic or graft-vs-leukemia (GVL) reaction within the context of T-depleted bone marrow transplantation. The objective of this research proposal is to investigate the use of cloned cytotoxic T-lymphocytes (CTL) to provide a controlled GVL effect after allogeneic bone marrow transplantation. We propose to use a murine model (T-cell leukemia/lymphoma in AKR mice) to test the hypothesis that an effective GVL reaction can be produced in vivo by the adoptive transfer of allogeneic CTl clones which recognize genetically appropriate ("normal") cell surface antigens expressed on leukemia cells. Preferential GVL as opposed to GVH reactivity can be imparted to the reaction by selection and manipulation of clones which react to antigens with limited tissue distribution (but present on tumor cells) or by using clones with limited life-span in vivo. This approach obviates the requirement for tumor-specific antigens and an immune response by the tumor-bearing host to those antigens. Preliminary studies support the scientific validity of our hypothesis and demonstrate the feasibility of the approach. In the proposed research we will (a) isolate CTL clones with specificity for histocompatibility antigens encoded outside the major histocompatibility complex (minor antigens) and within the MHC (H-2K and H-2D), as well as differentiation antigens encoded in the T1a/Qa region, (b) characterize the CTL clones in vitro for antigen specificity, antigen-driven proliferation, IL-2 production and cell surface phenotype, (c) use in vivo assays to evaluate the conditions under which CTL clones can be given to immunosuppressed hosts without causing lethal GVH disease or any other unacceptable immunologic or pathologic antihost effects, (d) examine the life-span and tissue distribution of CTl clones in vivo, and (e) assess the GVl effect of cloned CTL in experimental models using allogeneic bone marrow transplantation and cytoreductive chemoradiotherapy to treat AKR mice with first-passage or in situ spontaneous leukemia/lymphoma. The proposed studies are a systematic approach to optimizing the GVL effect while minimizing the GVH effect of cloned CTL. In addition, they will enable us to gain significant new insights into the pathogenesis of clonal GVH reactions.