Use of donor T-lymphocytes expressing herpes-simplex thymidine kinase in allogeneic bone marrow transplantation: A phase I-II study

Allogeneic bone marrow transplantation (BMT) is associated with a severe complication; graft-versus-host disease (GvHD). While effectively preventing GvHD, ex-vivo T lymphocyte marrow depletion unfortunately increases graft rejection and reduces the graft-versus-leukemia (GvL) effect. The ex-vivo transfer of the herpes simplex thymidine kinase (HS-tk) suicide gene into T cells before their infusion with hematopoietic stem cells should allow for selective in vivo depletion of these T cells with ganciclovir (GCV) if subsequent GvHD was to occur. Thus, one could preserve the beneficial effects of the T cells on engraftment and tumor control in patients not experiencing severe GvHD. We have demonstrated that retroviral-mediated transfer of HS-tk and Neomycin resistance genes in T-lymphocytes followed by G418 selection results in T-cells specifically inhibited by GCV with no bystander effect. Escalating amounts of HS-tk expressing T-cells will be infused in conjunction with a T-cell depleted marrow grafts to allogeneic HLA identical leukemic recipients. Toxicity, survival, alloreactivity and GCV-sensitivity of the gene-modified cells will be monitored. Patients with leukemia undergoing an HLA-matched allogeneic BMT associated with a high risk of GvHD will be enrolled in the protocol.