The ability of allogeneic lymphocytes to target and eradicate leukemia cells has been established as a true biological entity over the past ten (10) years. Whether such effects can be generated against non-hematological """"""""solid"""""""" malignancies remains unexplored. We initiated a clinical trail using a non-myleoablative approach of allogeneic stem cell transplantation in patients with treatment refractory metastatic renal cell carcinoma (RCC). Definitive evidence for an allogeneic graft-versus-RCC effect has been demonstrated with complete regression of large metastasis observed in some patients. We have subsequently initiated studies investigating immune reconstitution in those demonstrating an anti-RCC effect in attempts to identify both the effector cell populations mediating these regressions as well as their target antigens. This year we were able to confirm the expression of minor histocompatibility antigens on the surface of kidney cancer cells. We demonstrated that cytotoxic T-cell clones with specificity for minor antigens are capable of killing RCC cells. We also were able to expand T-cell clones in two responding patients that recognized either tumor cells specifically or broadly expressed antigens present on both patient hematopoietic cells and RCC cells. These observations provide the first insight into the immune mechanisms mediating the regression of metastatic cancer following non-myeloablative allogeneic transplantation. We are also pursing methods to develop ?tumor targeted' T-cell clones from healthy allogeneic donors (in vitro) for adoptive infusion posttransplant. Methods to expand these T-cell populations involve the use of allogeneic dendritic cells as stimulators (generated from donor monocytes) transfected with adenovirus encoding cancer associated genes (i.e., HTERT, PRAME, G250), or electrically or chemically fused to the patients tumor cells. Using the adenoviral transduction system we have been able to get high levels of tumor antigen expression in dendritic cells. The ability of these dendritic cells to expand tumor specific T-cell populations from healthy donors is a central focus of investigation and potentially could lead to future ?targeted' allogeneic immunotherapy regimens. These studies are being conducted in collaboration with the Urology Oncology Branch and the Surgical Oncology Branch of the National Cancer Institute.
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