The aims of our experimental marrow stem cell transplantation (SCT) program are firstly to improve the outcome after allogeneic SCT by optimizing the stem cell and lymphocyte doses of the transplant, and secondly to exploit the antitumor effect of donor immune cells to treat hematological and non-hematological malignant diseases by adoptive immunotherapy. Analysis of 50 patients receiving blood stem cell transplants indicate that our strategy of T cell depletion and delayed lymphocyte add-back confers a low risk of severe graft-versus-host disease (GVHD) and transplant-related mortality. Results also confirm the beneficial effect of high stem cell doses on disease-free survival found in earlier trials. A subsequent clinical trial compared GVHD incidence in patients receiving low-dose cyclosporine as immunosuppression with no cyclosporine. Despite a low T cell dose of 5 x 10^4 CD3 cells/kg in this study the removal of cyclosporine resulted in a significant incidence of grade II-IV GVHD. The current study evaluates the use of a lower T cell transplant dose to prevent GVHD without cyclosporine. T cell depleted transplants without post-transplant immunosuppression form the platform to safely reconstitute immunity after transplant using a technique (SD) to selectively deplete SCT of alloreacting lymphocytes which cause GVHD. A study to evaluate SD T cells in a non-myeloablative transplant setting has begun. Three patients have been enrolled and all have achieved engraftment with none or mild skin GVHD. We have treated over 100 patients using non-myeloablative (low intensity) SCT. The transplant procedure is well-tolerated, but that GVHD is the major cause of death in patients over 50 years. However, the complete and stable resolution of metastases in four patients with renal cell carcinoma and the absence of any detectable minimal residual disease in four patients with chronic myeloid leukemia is proof of principle that the transplant approach can exert a graft-versus-tumor effect. Our laboratory research has four objectives: 1) the detection and expansion of graft versus-leukemia/tumor lymphocytes to study interactions between alloreacting T cells and malignant cells; 2) the discovery of new leukemia antigens capable of initiating a graft-versus-leukemia (GVL) reaction and also antigens which cause graft-versus host disease (GVHD) 3) Development of techniques to select and expand leukemia-reacting T cells for adoptive immunotherapy of patients with malignant diseases; 4) development of assays to detect antigen-specific T cells for the direct monitoring in vivo of specific T cell responses to leukemia, tumor and viral antigens.5) Studying T cell responses to cytomegalovirus (CMV) to develop a vaccine strategy to prevent CMV reactivation after transplant. To further study interactions between T cells and normal or abnormal bone marrow cells, we are evaluating the use of immunosuppressive therapy to improve hematological function in myelodysplastic syndrome (MDS) - a disease believed to involve immune-mediated marrow suppression. Patients with MDS are treated with antithymocyte globulin (ATG) and cyclosporine as immunosuppression and monitored for recovery of bone-marrow function. A response-rate of 30% occurs. Prognostic factors favoring response include HLA DR2, younger age and a diagnosis of refractory anemia with pancytopenia.
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