EBV-associated non-Hodgkin's lymphoma constitutes a frequent and usually lethal hematological complication of acquired immunodeficiency disease (AIDS). Current treatments of EBV+ lymphomas in AIDS patients can induce only brief remissions, and are often complicated by lethal opportunistic infections. EBV+ lymphomas of donor origin emerging in marrow transplant recipients present as high grade, often monoclonal, diffuse large cell lymphomas of B-cell phenotype which share the clinical aggressiveness, EBV antigen expression, and molecular characteristics of the EBV+ lymphomas commonly detected in severely compromised AIDS patients. Recently, the applicants have demonstrated that infusions of small doses of peripheral blood lymphocytes from a patient's HLA-compatible EBV-seropositive marrow donor can induce rapid, complete and durable regressions of these otherwise refractory lymphomas. In this proposal, they seek to identify and quantify the different effector cell populations in the blood of seropositive individuals which are capable of eradicating EBV+ lymphoma cells and EBV-transformed normal B-cells in vitro. The applicants will concurrently compare these results with assessments of effectors in HLA-matched transplant recipients and in AIDS patients at different times in the course of their disease. Secondly, they will analyze and compare isolated, human donor-derived, EBV-reactive T-cell effector populations for their capacity to prevent tumorigenesis or to induce regressions of lymphomas emerging following xenogeneic transplantation of primary EBV+ B-cell lymphomas. A similar test will be performed in SCID mice using B-cell lines EBV-transformed in vitro. Thirdly, they will develop and characterize novel retroviral transfection-based approaches for rapid propagation, selection and regulation of cytotoxic or cytoinhibitory EBV-specific T-cells for use in the adoptive immunotherapy of EBV-lymphoproliferative disorders and will perform a pre-clinical evaluation of them in SCID mice xenografted with EBV+ lymphoma cells or with in vitro EBV-transformed B-lymphoblastoid cell lines. The results of these experiments should provide a strong experimental basis, in xenografted SCID mice, for promising, safe strategies for selective generation of effectors demonstrated to be capable of limiting the growth of human EBV+ lymphomas. In the future, this approach may be extended to clinical trials in AIDS patients.
Showing the most recent 10 out of 12 publications
