ZIC BC 010934 (ZIC) | |||
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Title | Immune reconstitution following autologous and allogeneic stem cell transplant | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Hakim, Frances | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $679,729 | Project Dates | 10/01/2007 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Bone Marrow Transplantation (100.0%) Cancer (100.0%) Interferon (30.0%) |
Hodgkins disease (20.0%) Leukemia (10.0%) Multiple Myeloma (20.0%) Non Hodgkins Lymphoma (50.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Resources and Infrastructure Related to Cancer Control, Survivorship, and Outcomes Research |
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Abstract | |||
The Preclinical Development and Clinical Monitoring Facility (PDCMF) projects have developed from transplantation protocols implemented by the clinical staff of ETIB. Using peripheral blood and marrow, and tumor and CGVHD tissue biopsies, we have evaluated lymphocyte subsets, cytokine content, T cell receptor repertoire diversity and thymopoietic activity. All data are incorporated into protocol-specific spreadsheets, linking samples to protocol arms and transplant time points, and are accessible by branch clinicians over secure NIH networks. In several ongoing ETIB clinical trials of autologous and allogeneic stem cell transplantation therapies (04-C-0055, 07-C-0195, 11-C-0016, 11-C-0136; PIs Daniel Fowler, Steven Pavletic, Claude Sportes, Ronald Gress and Kirsten Williams) we have assessed lymphodepletion during conditioning and immune reconstitution after transplant. We currently are using multiparameter flow cytometry to characterize lymphocyte repopulation, plasma ELISA to monitor cytokines and molecular assays of gene expression and T cell receptor repertoire diversity. We correlate the laboratory findings with clinical outcomes of relapse, infection, and chronic graft versus host disease (CGVHD). These parallel studies involve analysis of ongoing trials that cover the breadth of current transplant practices: non-myeloablative reduced intensity allogeneic transplantation for lymphoma using sibling and unrelated donors, autologous transplantation for myeloma, and myeloablative transplant for acute leukemias. We also support ongoing studies of lineage-specific immune reconstitution in patients transplanted for monogenic immune deficiencies involving GATA2 or DOCK8 (09-C-0096, 10-C-0174, PI: Dennis Hickstein) by utilizing the ETIB Flow Cytometry Facility (William Telford) to sort lymphocytes for subset-specific donor chimerism analysis. These immune monitoring studies have contributed to a report on the efficacy of EPOCH-F, a novel non-myeloablative induction regimen, in allogeneic stem cell transplantation in patients with multiple myeloma and lymphoid malignancies (Salit et al, 2012; Salit et al, 2013), as well as reports on allogeneic transplant supported by adoptive transfer of T2-RAPA cells (Fowler et al, Blood 2013). Chronic graft vs host disease (CGVHD), the principle cause of non-relapse morbidity and mortality after allogeneic transplantation, is a major focus for research in the PDCMF core. We have supported the efforts of the multidisciplinary clinical team in an ongoing natural history protocol studying patients who have developed CGVHD (P.I. Steven Pavletic: 04-C-0281) by storing patient blood, biofluids and tissue for research. We have contributed to the research study by analyzing mechanisms of CGVHD pathogenesis. Furthermore, we have supported four therapeutic trials for CGVHD patient populations: (1) We are assessing leukotriene receptor (LTR) expression in leukocytes and in bronchial lavage cells to define the role of LTR in progressive fibrosis of lung airways in patients developing bronchiolitis obliterans, a severe complication of CGVHD (08-C-0097: P. I. Ronald Gress and Kirsten Williams:). (2) We have assessed the effect of Imatinib, a TGFbeta signaling inhibitor, on Th17 and Treg populations, as part of a collaborative trial testing Imatinib therapy on sclerotic cutantaneous CGVHD (Dermatology and Pediatric Branch, protocol 08-C-0148, P.I. Edward Cowen and Kristin Baird). (3) We are analyzing changes in inflammatory gene expression in a trial of Pomalidomide (12-C-0197; P.I. Steven Pavletic) to assess efficacy against fibrosis in CGVHD patients. (4) Finally we support tissue immunohistochemistry analyses and salivary cytokine tests in a trial of a mouthwash containing a potent steroid, Clobetasol, as a topical therapy for severe oral CGVHD (12-C-0068; P.I. Steven Pavletic/Jacqueline Mays). As part of our studies of the pathogenesis of CGVHD, we have characterized regulatory T cells in CGVHD through co" |