6. Targeting Alloreactivity for Leukemia Eradication The eradication of leukemia after allogeneic hematopoietic stem cell transplantation (HCT) is in part mediated by T cells and represents a remarkable demonstration of the curative potential of immune-based therapy for human malignancy. There is substantial evidence that the immunologically mediated graft versus leukemia (GVL) effect results from recognition of leukemic cells by donor T cells specific for recipient minor histoco.mpatibility antigens. Unfortunately, T cell responses to minor histocompatibility antigens can also cause GVHD, and it has been difficult to segregate the GVL effect from GVHD. The discovery of minor histocompatibility antigens that are selectively expressed on leukemic cells and not on epithelium is providing new opportunities to augment the GVL effect of allogeneic HCT. However, implementing targeted immunotherapy in patients who receive unmodified allogeneic stem cell transplants and require the administration of immunosuppressive drugs post transplant has proven challenging. The discovery that naTve T cells in the stem cell inoculum are responsible for GVHD has provided the opportunity for manipulation of allogeneic hematopoietic cell grafts to remove this subset of cells and potentially reduce GVHD. The objectives of this project are to discover minor histocompatibility antigens that are targets for a selective GVL effect and to evaluate engineering the stem cell graft to remove naTve donor T cells that cause GVHD to provide a platform that enables selective targeting of allogeneic determinants on leukemic cells to promote an enduring GVL response.
The specific aims are: 1) To identify genes that encode novel human minor histocompatibility antigens presented by leukemic cells and recognized by CD8+T-cells. 2) To determine whether transplantation of stem cell grafts depleted of halve T cells reduces graft versus host disease in HLA identical sibling stem cell transplant recipients with acute leukemia. 3) To determine if vaccination of allogeneic HCT donors with minor histocompatibility antigens is safe and elicits a specific T-cell response. Relevance of this research to public health: Allogeneic hematopoietic cell transplantation (HCT) canbe curative for many malignancies that are otherwise incurable and is used to treat thousands of patients each year. Graft versus host disease and relapse of the malignancy are the two most frequent complications that contribute to patient suffering and death after allogeneic HCT. The studies in this proposal are aimed at discovering the cellular and molecular mechanisms by which HCT eliminates tumors and developing safer and more effective transplant regimens.
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