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 | $506,168 | Project Dates | 01/01/2007 - 00/00/0000 |
Fiscal Year | 2015 | 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 Researc |
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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. Peripheral blood, marrow aspirates, and tumor and CGVHD tissue biopsies from ongoing ETIB protocols are processed and preserved by the core facility. We have evaluated lymphocyte subsets, cytokine content, T cell receptor repertoire diversity, and gene expression to support research studies of clinical protocols. 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. These on-going studies involve analysis of ETIB trials that include non-myeloablative reduced intensity allogeneic HSCT for lymphoma using sibling and matched-unrelated donors, autologous transplantation for myeloma and for systemic autoimmunity, and myeloablative transplant for acute leukemias (04-C-0095, 04-C-0055, 07-C-0195, 08-C-0088, 11-C-0016, 11-C-0136; PIs Daniel Fowler, Steven Pavletic, Ronald Gress, Kirsten Williams and Christopher Kanakry (all ETIB)). In the past year, these immune monitoring studies have contributed to reports on allogeneic HSCT in lymphoma and renal carcinoma involving novel lymphodepletion regimens and utilization of adoptive transfer of T-RAPA cells (Fowler et al, Clin Cancer Res, 2015). We also have supported ongoing studies of lineage-specific immune reconstitution in patients transplanted for monogenic immune deficiencies (such as GATA2 or DOCK8) (09-C-0096, 10-C-0174, PI: Dennis Hickstein (ETIB)) by working with the ETIB Flow Cytometry Facility (William Telford) to assess subset-specific donor chimerism, and to monitor repopulation of deficient lineages after allogeneic transplant (Grossman et al, Biol Blood Marrow Transpl, 2014). This past year we have been completing immune reconstitution analysis of a matched unrelated donor allogeneic transplant trial comparing two distinct regimens of GVHD prophylaxis, one dependent on antibody-mediated depletion of donor lymphocytes following transplant, the second dependent on immune suppressive agents. We determined that lympho-depleting treatment resulted in severe and protracted reduction in T cell numbers for the first year compared to that in patients with immune suppression alone. Naive T cell populations, in particular, were severely reduced. Consistent with loss of naive cells, we determined that the overall T cell receptor repertoire diversity in the lympho-depleted arm was significantly reduced. The lymphocyte repopulation differences between the two arms correlated with significant differences in early viral infections, relapse and chronic GVHD. We also have participated in collaborative studies with Arya Biragyn (NIA) that demonstrated that activated B cells in aged adults and in post-autologous transplant patients support increased differentiation of cytotoxic CD8 effector cells, contributing to persistent immune activation in aging and after transplant (Lee-Chang et al, Blood, 2014). 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 CGVHD clinical team in an ongoing natural history protocol of CGVHD (P.I. Steven Pavletic: 04-C-0281) by characterizing immunologic changes of CGVHD. Furthermore, we have supported four therapeutic trials for CGVHD patient populations: (1) We have assessed expression of leukotriene receptors (LTR) in leukocytes and CRTH2 receptors on T cells and in blood and bronchial lavage fluids to define the role of Th2 lineage T cells and leukotriences 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 si |