GENE-TRANSFER APPLIED TO THE MODULATION OF ALLOREACTIVITY

Allogeneic hematopoietic stem cell transplantation is associated with a severe complication induced by the T-cells present in the graft: gra ft-vs-host disease (GVHD). While effectively preventing GVHD, ex vivo T-lymphocyte depletion of the graft unfortunately increases graft reje ction and reduces the graft-vs-leukemia (GVL) effect. The ex vivo tran sfer of the herpes simplex thymidine kinase (HS-tk) suicide gene into T-cells before their infusion with the hematopoietic stem cells should allow for selective in vivo depletion of these T-cells with ganciclov ir (GCV) if subsequent GVHD was to occur. In patients not experiencing GVHD, and therefore at a higher risk of relapse, one could preserve t he beneficial effects of the donor T-cells on tumor control. Lastly, t he early presence of donor T-cells in all patients should contribute t o successful engraftment. We have demonstrated that retroviral-mediate d transfer of HS-tk and Neomycine resistance genes in T-lymphocytes, f ollowed by G418 selection, results in T-cells specifically inhibited b y GCV with no bystander effect. In a phase I study, escalating amounts of HS-tk expressing T-cells will be infused in conjunction with a T-c ell depleted marrow graft to allogeneic HLA identical recipients. Toxi city, survival, alloreactivity and GCV-sensitivity of the gene-modifie d cells will be monitored. If successful, such an approach could signi ficantly contribute to expanding the use of alloreactivity as a treatm ent modality.