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Allogeneic stem cell transplant with grafts depleted of naive T cells for leukemi

Marie Bleakley

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National Institutes of Health (NIH)
The candidate's career goal is to become a principal investigator of a translational immunology laboratory that will develop new approaches to improve the disease-free survival of patients with leukemia that receive allogeneic hematopoietic stem cell transplantation (HCT). Specifically, the candidate aspires to develop immunotherapies to augment the graft versus leukemia (GVL) effect and thereby reduce the rates of relapse following HCT, and strategies to reduce the life-threatening immunological complications of HCT including graft versus host disease (GVHD). In the immediate term, the candidate aims to gain experience in translating her research to the clinic as the Principal Investigator of the clinical trial entitled "A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells from Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD (FHCRC Protocol 2222)", to develop further skills in antigen identification, and to become independent in designing, conducting, interpreting and funding her research. The research activities planned include the conduct and evaluation of the clinical trial of naive T cell depletion and associated immune reconstitution studies, and antigen discovery studies to generate a library of human minor histocompatibility (H) antigens. The candidate will obtain training in clinical trials, advanced flow cytometry, statistical analysis of immune monitoring, genetic linkage analysis and genome-wide association studies. The research and training activities will be primarily conducted at the Fred Hutchinson Cancer Research Center which is a superb environment for translational and clinical research, particularly in the field of HCT. The candidate will be mentored by Dr. Stanley Riddell, an experienced and successful mentor who has a distinguished career in the fields of translational immunology, immunotherapy and HCT. The applicant participated in all phases of development of the clinical trial, which is a novel, first-in-human study that will provide insights into the immunobiology of GVHD and the recovery of protective T cell immunity in recipients of stem cell grafts that contain a limited number of memory T cells. This approach may result in a new modality for allogeneic HCT with less GVHD and better immune reconstitution. The studies proposed in Aim 3 will employ new strategies for minor H antigen discovery and assist in laying the foundation for future immunotherapeutic approaches to the problem of relapse of leukemia after HCT. The specific aims are: 1. To determine whether transplantation of stem cell grafts depleted of TN is safe and reduces GVHD in HLA identical related donor stem cell transplant recipients. 2. To evaluate reconstitution of pathogen-specific TM and TN cells in recipients of HLA matched related stem cell grafts depleted of TN. 3. To develop a library of novel minor H antigens that are expressed selectively on hematopoietic cells including acute leukemia and presented in association with prevalent HLA alleles.

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