AIIogeneic hematopoietic stem cell transplantation (HCT) is a valuable therapy for refractory acute leukemias, leukemias with a high risk for relapse, and chronic myelogenous leukemia. Natural killer (NK) cells may influence early and late post-transplant complications. The overall objective of this study is to gain insight into the influence of specific NK killer cell Ig-like receptors (KIRs) on HCT outcome. The central theme is that a significant proportion of HLA identical transplants will involve donors with an inhibitory KIR genotype for which the recipient is missing the corresponding KIR ligand. According to this missing ligand hypothesis, patients lacking HLA ligand for donor KIR will engender an alloreactive NK effect, which may manifest itself in anti-leukemic activity. In addition, this effect will be seen not only in the unrelated HLA-identical transplant population, but also in the HLA-identical sibling transplants. It is predicted that certain leukemia and lymphoma patients who lack the KIR ligand for one or more of their inhibitory KIRs will have better overall survival, progression-free survival, and lower risk for relapse following chemotherapy and/or autologous stem cell transplantation due to NK cell mediated anti-tumor effects. These hypotheses will be tested in three specific aims.
Specific Aim 1 will test the influence of donor KIR genotype in combination with recipient HLA class I genotype on overall survival and post-transplant complications in patients receiving HLA-identical HCT for CML, AML, and ALL.
Specific aim 2 will evaluate NK reconstitution post-allogeneic and autologous transplantation, correlating KIR expression with post-transplant outcome and identifying NK clones with KIR-driven anti-tumor activity. Finally, specific aim 3 will determine if survival in patients with acute leukemia, diffuse large cell lymphoma, and Hodgkin's Disease is influenced by certain combinations of inhibitory KIR genes and their corresponding HLA class I ligands. Completion of these studies could have important implications for therapeutic strategies in allogeneic and autologous HCT by identifying patients with high and low risk for post transplantation relapse or disease progression.
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