Rainer F. Storb

Transplantation biology; basic and translational research into the biology of allogeneic blood and marrow hematopoietic cell transplantation (HCT)

Our laboratory pursues basic and translational research into the biology of allogeneic blood and marrow cell transplantation (HCT) both in a preclinical model and in human patients with malignant and nonmalignant hematologic diseases. Following are some of our goals:

Developing radically different approaches for HCT that have minimal toxicity, do not ablate the marrow, and thus are safe enough to administer in the ambulatory care setting. We have replaced the conventionally used intense conditioning regimens by optimal postgrafting immunosuppression which was aimed at controlling both serious graft-vs-host disease and host-versus-graft reactions. Studies in a preclinical model showed that conditioning with a nonmyeloablative dose of only 2 Gy total body irradiation followed by a short postgrafting course of the antimetabolite mycophenolate mofetil and the calcineurin inhibitor cyclosporine allowed stable engraftment of allogeneic hematopoietic cells. A further reduction in the TBI dose was accomplished by blocking T cell costimulatory signals while triggering the T cell receptor with donor antigen, resulting in antigen-specific hyporesponsiveness. The nonmyeloablative HCT approach outlined here was translated to the clinic and mixed hematopoietic chimerism was used as a platform for adoptive immunotherapy of malignant and nonmalignant diseases in more than 700 human patients who were not eligible for conventional HCT (such as elderly or medically infirm patients). With this kind of transplant, the eradication of underlying disease is accomplished through graft-versus tumor effects rather than high-dose cytotoxic therapy. Trials using both HLA-matched related and unrelated grafts and graft-vs-tumor effects have shown unanticipated success in both B-cell and myeloid malignancies. The elimination of the last vestiges of pre-transplant radiation through induction of host vs. donor immunological non-responsiveness continues to be a major research goal, which will be particularly important for pediatric patients and those with nonmalignant diseases, e.g. sickle cell disease.

Defining polymorphic minor histocompatibility antigens on solid tumors, e.g. breast, prostate, and colon cancer, and designing strategies to direct alloreactivites to specific tumor targets
This effort, done in collaboration with colleagues from both the Benaroya Research Institute and the University of Washington’s Genome Center, involves whole genome scanning for therapeutic minor histocompatibility antigens involved in allogeneic graft vs. tumor effects.

Investigating graft-host tolerance by establishing mixed hematopoietic chimerism as a prelude for acceptance of solid organ transplants. Kidney, lung, small bowel, and pancreatic islets have been used to test the stringency of tolerance.

Examining the transdifferentiation potential of adult primitive hematopoietic or mesenchymal stem cells which may be used to regenerate epithelial and muscle cells. A pre-clinical model of Duchenne muscular dystrophy is being pursued to test the plasticity of such cells.

Extending the use of nonmarrow-ablative allogeneic hematopoietic cell transplants and cell therapy to include patients with metastic solid tumors and autoimmune diseases.