The goal of this Program is to broaden the application and further the success of allogeneic hematopoietic cell transplantation (HCT) for treatment of patients with cancer. The work will focus on HCT approaches in which the burden of tumor eradication has been shifted from high-dose conditioning regimens to the donors' immune cells. Minimally toxic, nonmyeloablative, yet, immunosuppressive conditioning has replaced the myeloablative and toxic doses of chemotherapeutic agents customarily administered with or without high-dose total body irradiation. After HCT, control of residual host-vs.-graft and graft-vs.-host reactions is achieved by relatively brief courses of synergistic postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. The immunosuppressive regimen originated from studies in dogs and has been successfully used to treat patients with advanced hematological malignancies. Significantly, the low degree of regimen-related toxicity has enabled us to use allogeneic HCT in elderly patients and those with medical infirmities. Given that median patient ages at diagnoses for most candidate diseases range from 65-70 years, this has greatly expanded the number of patients benefiting from allogeneic HCT, and during the first 3 1/2 years of the grant, 439 patients have been transplanted. Four Research Projects and three Cores are proposed. Project 1 will focus on developing new non-toxic transplant approaches, with the aim of eliminating the last vestiges of cytotoxic therapy. Project 2 will use the canine model of stable mixed chimerism to develop clinically relevant approaches of effective adoptive immunotherapy with donor lymphocytes. The clinical Projects 3 and 4 will extend the current trials by developing disease-specific protocols for patients with leukemia's, multiple myelomas, Hodgkin's disease, non-Hodgkin lymphoma, and renal cell cancer. This way, we intend to obtain a better understanding of effectiveness and limitations of graft-vs.-tumor reactions in the various candidate diseases. Appropriate conditioning regimens will be defined, as will be the duration of postgrafting immunosuppression. Studies will be conducted with a consortium of collaborators, including 10 institutions outside of Seattle. All four projects will be supported by Cores with regard to protocol design, data monitoring and statistics, chimerism analyses and canine histocompatibility typing, and will provide administrative support.
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