The ability of allogeneic lymphocytes to target and eradicate leukemia cells has been established as a true biological entity over the past ten (20) 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. Recently we demonstrated a similar effect to have occured in a patient with colon carcinoma and prostate cancer. 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. Our laboratory has confirmed 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 in patients having a GVT effect post transplant. 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. Using c-DNA expression cloning, we are currently in the process of identifying the target antigen of an RCC specific T-Cell clone isolated and expanded from on resonding patient. If it turns out this antigen is expressed on a significant % of RCC cell, it could potentially serve as a target for a future kidney cancer vaccine. Recently we have developed a murine model of allogeneic SCT in hosts bearing metastatic RCC, in which reproducible GVT effects occur extending animal survival compared to recipients of autologous transplants. Post transplant tumor vaccination studies are being conducted in this model, as well as investigations into the impact of inhibiting angiogeneisis in the first few months of transplantation using PDGF, VEGF, and EGF-R tyrosine kinase inhibitors. Our group has recently shown that KIR incompatible NK cells are cytotoxic to solid tumor cells in vitro. Recently, we have developed a method to expand by > 4 logs NK cells from healthy donors for adoptive infusion in future NK-Cell based adoptive immunotherapy trials. We are also exploring methods to sensitize solid tumors to NK cell attack by altering the phenotype of tumor cells through targeted gene induction. Acute GVHD remains a major toxicity of allogeneic stem cell transplantation. Unfortunately, the diagnosis of GVHD is currently based on histopathic changes observed in biopsy specimens obtained from of involved organs. A turnover time of 48 hours for tissue confirmation of GVHD is typical. We are currently evaluating investigational methods to rapidly and specifically diagnose acute GVHD. The technique involves serum protein pattern recognition using SELDI. The assay requies a sample of serum and has a turn-over time of 2-3 minutes. In our first cohort of 20 patients with acute GVHD and 60 post-transplant GVHD negative controls, the assay had 100% sensitivity and specificity for the diagnosis of GVHD. A confirmation cohort is currently being pursued. Our group continues to explore the use of allogeneic SCT in patients with nonmalignant diseases such as PNH or ATGF-Refractory severe aplastic anemia. We have also recently shown that PNH can be cured following nonmyeloabaltive stem cell transplanation. In vitro studies conducted in our laboratory have shown PNH cells are equally sensitive to allogeneic immune attack as normal GPI-positive immune cells. At present, 27 patients with SAA/PNH have been transplanted with a day 200 TRM of 0%.
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