The overall goal of this proposal is to develop strategies to eliminate lymphomas through the infusion of lymphocytes transduced with retroviral vectors containing the interleukin-I (IL-1) or interleukin-2 (IL-2) gene. The basic premise of these studies is that a defective immunosurveillance system leads to the occurrence of lymphomas. lnfusional therapy with exogenous IL-1 or IL-2 alone may be an inadequate means of producing an anti-lymphoma effect due to a failure of achieving sufficient local concentrations of lymphokines at the site of the tumor. Transduced lymphocytes with known cytolytic function against murine or human lymphoma cells represent a means of bypassing the need to infuse large quantities of potentially cytotoxic lymphokines. Therefore, we propose to utilize retroviral vectors which are capable of transducing human or mouse T-lymphocytes and producing IL-1 or IL-2 in vitro and in vivo. We will focus on identification of which T-cell subpopulations are capable of being transduced by these retroviral vectors. In addition, we will investigate the use of the herpesvirus thymidine kinase gene as a suicide marker to be used in instances in which the transduced lymphocytes become autonomously proliferating. Once we have obtained transduced lymphocyte populations, we will infuse human lymphocytes into severe combined immunodeficiency (SCID) mice or murine cells into normal mice. We will examine the persistence of these cell populations as well as the continued expression of these transduced lymphocytes and their tumorigenic potential. We will drive these lymphocytes in vivo with exogenous IL-1 and/or IL-2 as a means of promoting their persistence. Finally, we will examine the ability of these transduced lymphocyte populations to mediate an anti-lymphoma effect. Using SCID mice and human lymphoma cell lines or fresh lymphoma tissue, we will assess the potential benefit of transduced lymphocyte populations as in vivo cellular immunotherapy. A parallel study using murine lymphomas in normal or immunosuppressed mice will allow us to examine the effect of cellular immunotherapy in a setting in which the full species specific lymphohemopoietic system is intact. These data will be used in conjunction with the preclinical and clinical studies of immunotherapy for lymphoma to cumulatively design the most effective and safe adjunctive therapy for the elimination of lymphoma in the context of autologous bone marrow transplantation.
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