Bone marrow transplantation is the treatment of choice for high risk leukemia, aplastic anemia and other immunodeficiency disorders. It is also being used for therapy of other radiation sensitive tumors such as neuroblastoma and for inherited enzyme deficiency disorders. One complication of graft-versus-host disease(GVHD) caused by mature T cells in the donor marrow recognizing histocompatibility differences between donor and host. Studies in animals and humans have shown that removal of mature T cells from the donor marrow while preserving the pluripotent stem cells prevent GVHD. Autologous grafts avoid this complication but have the problem of tumor cells circumventing therapy by remaining in the marrow graft. Monoclonal antibodies linked to toxic proteins can specifically kill cells based on cell surface antigen differences. We have developed a panel of T cell selective toxins which kill up to 5 logs of T cells at concentrations non-toxic to human stem cells. We have begun to investigate immunotoxins for depletion of tumor cells from autologous bone marrow grafts. lnitial studies show that CRM 107 immunotoxins selectively kill human glioblastoma, medulloblastoma, breast carcinoma, lung carcinoma and leukemia cells at nanomolar concentrations or less. Ongoing experiments will determine the sensitivity of human multipotent stem cells to immunotoxins.
