Allogeneic hematopoietic cell transplantation (Allo-HCT) is a well established curative approach for a variety of malignant and nonmalignant hematologic disorders. Recurrence of primary disease, graft-versus-host disease (GVHD), infection, and regimen related toxicity remain the primary causes of transplant failure. The tempo and quality of hematopoietic engraftment and immunologic reconstitution significantly influence morbidity and mortality following Allo-HCT. Adult recipients of an Allo-HCT experience deficiencies in their B and T cell reconstitution, which can persist for more than a year, and are associated with an increased risk of infections, relapse of malignancy, and the development of secondary malignancies. The purpose of Core C is to define hematopoietic cell grafts and adoptively transferred T-cell populations and their function prior to and following transplantation. The core will characterize allografts and monitor the effects of stem cell source, donor type, use of T cell depletion, immunomodulatory agents and/ or adoptive immunotherapy, as well as development of GVHD on the kinetics and quality of immune reconstitution, donor chimerism, and relapsed disease following Allo-HCT.
The Specific Aims of Core C are: 1) To characterize allografts by flow cytometry, clonogenic assays, and functional assays to predict graft outcome (Project 6); 2) To monitor the recovery of circulating T, B, and NK populations after allo-HCT. This will include assessment of subsets of CD4 and CD8 T cells, B cells, TREC expression, T cell responses to mitogens, alloantigens, recall and neoantigens, high-resolution quantification of human TCR diversity using deep sequencing, monitoring of biomarkers and cytokine levels and development of specific antibody responses following revaccination post HCT. These data will gauge the effects of ?/?+ T- lymphocyte depletion of the allograft, studies of the impact of the gut microbiome on HCT outcomes (including viral infections, the impact of antibacterial drug selection on microbiome integrity and fecal microbiota transplants (FMT), interactions between NK and T cells in HCT, as well as adoptive immunotherapy with CD19 CAR T cells (All Projects). 3) To monitor lineage-specific chimerism following allo-HCT. This will provide in vivo correlates of interventional studies including ?/?+ T-lymphocyte depletion of the allograft and adoptive cell therapy, and their effects on engraftment (Project 6), reconstitution of NK cells and interactions with T cells (Project 3), and donor-derived antigen-specific T cells and their effects on residual normal and malignant host hematopoietic elements (Projects 4, 5 and 6). 4) To characterize adoptively transferred T cells prior to and post infusion using multiparameter flow cytometry, functional assays, as well as high-resolution quantification of human TCR diversity to specifically track infused cells (Projects 4, 5 and 6). 5) To centralize specimen procurement, prioritization, and distribution for research, in coordination with the Clinical Cytotherapy/ Transplant Laboratory, inpatient units, and outpatient clinics, and to provide a centralized storage repository (All Projects).
Core C ? Narrative The purpose of Core C is to define hematopoietic cell grafts and adoptively transferred T-cell populations and their function prior to and following transplantation. The core will characterize allografts and monitor the effects of stem cell source, donor type, use of T cell depletion, immunomodulatory agents and/ or adoptive immunotherapy, as well as development of GVHD on the kinetics and quality of immune reconstitution, donor chimerism, and minimal residual disease following Allo-HCT. Core C will also centralize specimen procurement and provide a centralized storage repository. Over the last 25 years (the last 5 years under Dr. Perales? direction), this core facility has been responsible for performing phenotype, function, detection of minimal residual disease, and lineage specific chimerism in patients undergoing Allo-HCT in clinical trials at MSKCC.
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