Cellular transfusion therapies in the past have been limited to erythrocytes, platelets, stem cells from a variety of sources, and rarely neutrophils. We propose to develop the relevant preclinical data base for the use of T lymphocytes as a safe and effective transfusion therapy for the eradication of residual leukemia. Graft-versus host disease (GVHD) and its accompanying Graft-versus-leukemia (GVL) effect contribute to the efficacy of allogeneic bone marrow transplantation (alloBMT) in treating hematologic malignancies. In patients who have relapsed after alloBMT for chronic myelogenous leukemia (CML), both the withdrawal of immunosuppression and more recently that infusion of infusion of pheresed lymphocyts have led to complete cytogenetic remissions, but with significant morbidity from GVHD. This raises the possibility of an exciting new method for treatment of leukemias, and perhaps for other cancers. A key advance in maximizing the therapeutic potential of such therapy would be a way to in vivo modulate t he GVHD which is the equivalent of a dose limiting toxicity. We propose to accomplish this by the introduction into lymphocytes of the Herpes Simplex Virus thymidine kinase (HSV1-tk)gene, which by virtue of its ability to activate selectively the nucleoside analogue ganciclovir, will render them susceptible to ganciclovir deletion. To test this hypothesis, we will study the impact of HSV1-tk expressing lymphocytes and ganciclovir treatment on GVHD and GVL in well established murine models. In addition, we will develop techniques of efficient gene transfer and expression into both human and murine lymphocytes.
The specific aims of this project are to: 1) Demonstrate that the GVHD induced by murine HSV-1tk expressing lymphocytes can be controlled with ganciclovir; 2) Establish relevant mouse models to test the efficacy of GVL induced by these transgenic lymphocytes, while maintaining adequate control of GVHD with ganciclovir; 3) Utilize HSV1-tk gene transfer into mouse lymphocytes, to compare efficacy between transgenic versus retrovirally transduced lymphocytes; 4) Develop techniques for HSV1-tk gene transfer and stable expression in human lymphocytes. The results of these studies will form the basis for well founded clinical studies using HSV1-tk transduced lymphocytes for the elimination of residual leukemia. In so doing, we believe that they will form the foundation for many future studies utilizing T cell transfusion therapies in the near future.
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