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). Definition evidence for an allogeneic graft-versus-tumor (GVT) effect has been demonstrated with complete regression of large observed seen in some patients. We have subsequently initiated studies investigating immune reconstitution in those demonstrating a GVT effect in attempts to identify both the effector cell populations mediating these regressions as well as their target antigens. We first analyzed the beta chain of the T-cell receptor by PCR analysis of CDR3 length polymorphisms as well as by monoclonal antibody studies of V-beta family usage. We have identified T-cell subsets (cytotoxic, CD3+, activated), that appear to be mediators of this anti-tumor effect. In one case, we have identified a tumor specific T-cell population which appears to be recognize as an antigen restricted to kidney cancer cells. Through limiting dilution experiments, we are attempting to clone this and other T-cell population in responding patients to use them for the identification of RCC specific tumor antigens. Further, work has been and continues to be done for the development of allogeneic tumor specific T-cells through the transduction of donor dendritic cells with adenovirus encoding tumor antigens. Preliminary data reveals that this approach can result in a dendritic cell population, which is capable of stimulating tumor specific allogeneic T-cells. With the recent ability to grow tumor cell lines in the majority of our RCC patients, we have now initiated studies investigating the optimal approach to generate tumor/dendritic cell fusions to serve as stimulators for an allogeneic tumor specific T-cell population. We have now developed a GFP labeled RCC line from one of our kidney cancer patients to optimize this approach. 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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