The primary goals of the Clinical Transplantation Therapy Program is to develop and conduct novel clinical trials in allogeneic and autologous stem cell transplantation. These trials are being performed in a programatic fashion with other members of the Department of Experimental Transplantation and Immunology, as well with collaborators within the National Cancer Institute and NIH. Particular interests of the program include the therapeutic use of T cells to enhance engraftment in the setting of non-myelablative preparative regimens and to abrogate graft-versus-host disease and T-cell reconstitution. The program focuses primarily on B-cell malignancies and metastatic breast cancer. Our initial goal was to devise non-myeloablative regimens that allow engraftment across HLA barriers. Our first clinical allogeneic stem cell transplantation (alloSCT) protocol, CC #99-C-0143 (Th2 cells in AlloSCT), was based on preclinical work in murine models demonstrating that immune depleting chemotherapy at non-myeloablative doses resulted in significant host T cell depletion. This level of host T cell depletion was sufficient to permit the engraftment of fully-MHC mismatched allografts. Initial data on eleven patients indicate that these regimens in combination are highly effective in reducing host CD4+ and CD8+ T cell numbers with minimal toxicity. There was rapid and complete engraftment of HLA-matched T cell replete allografts. Thus, with our immunoablative approach we have been able to consistently achieve rapid, complete donor engraftment of HLA-matched related allogeneic stem cells without myeloablative therapy. Based on these data, we are currently investigating this immune depleting approach in the setting of T cell depleted HLA-matched allografts. Our next step will be to investigate this approach with T cell depleted HLA-mismatched allografts. In addition the program is looking specifically at the use of tumor vaccines in the allogeneic and autologous transplant settings in collaboration with the laboratory of Dr. Larry Kwak. Initial data in preclinical models from the DETI laboratories of Dr. Ron Gress and Dr. Daniel Fowler suggest that a graft-versus-tumor (GVT) effect exists in breast cancer; however, it is unknown whether a GVT effect can be induced in breast cancer patients. Using donor lymphocyte infusions (DLI) as an approach to study GVT, we designed a clinical protocol, CC # 00-C-0119 (AlloSCT in Metastatic Breast Cancer) to study GVT in breast cancer patients. This protocol, which incorporates our immune depleting chemotherapy approach to alloSCT, was designed specifically to permit the potential observation of a GVT effect independent of the anti-tumor effects of the transplant conditioning regimen. This protocol is open and accruing patients.
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