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 | $441,077 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | 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 | |||
SUMMARY: The Preclinical Development and Clinical Monitoring Facility (PDCMF) projects have developed from transplantation protocols developed within ETIB. Peripheral blood, marrow aspirates, and tumor and CGVHD tissue biopsies from all ongoing ETIB protocols are processed and preserved by the PDCMF. 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. The work of this core is supported by close collaborative relationships with the Cell Processing Service of DTM, for support of microarray analysis and development of clinical products; the ETIB Flow Cytometry Facility, for support of sorting of clinical products for research endpoints; and the laboratory of Ronald Gress, for technical support in RNA and DNA isolation and quantitative assays. PDCMF supports studies of lymphocyte reconstitution following ETIB transplant trials that include: (1) non-myeloablative reduced intensity allogeneic transplant for lymphoma using sibling and matched-unrelated donors, (2) autologous transplantation for myeloma and for systemic autoimmunity, and (3) 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 support 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) and primary immune deficiencies (16-C-0003, PI: Jennifer Kanakry (ETIB)) by monitoring repopulation of deficient lineages after allogeneic transplant (Grossman et al, Biol Blood Marrow Transpl, 2014) and by working with the ETIB Flow Cytometry Facility (William Telford) to assess subset-specific donor chimerism. This past year we have analyzed immune reconstitution in a matched unrelated donor allogeneic transplant trial (07-C-0195: PI Steven Pavletic) comparing two distinct regimens of GVHD prophylaxis, one utilizing antibody-mediated depletion of donor lymphocytes following transplant, the second using immune suppressive agents. We determined that the lympho-depleting treatment resulted in severe and protracted reduction in T cell numbers for the first year, as compared to that in patients with immune suppression alone. Naive T cell populations, in particular, were severely reduced in the lymphodepleted arm, resulting in significant deficits in naive cell frequency and numbers at 6 and 12 months after transplant, that were only rectified by 24 months. Consistent with this deficit, we determined that the overall T cell receptor repertoire diversity in the lympho-depleted arm was significantly reduced throughout the first year. The lymphocyte repopulation differences between the two arms correlated with significant increases in early viral infections and relapse in the lymphocyte-depleted arm, and with significant increases in chronic GVHD (CGVHD) in the immune suppressive arm. We also identified a 10 fold difference between these two transplant arms in the median ratio of Treg cells/microliter to either naive CD4 or naive CD8 cells/microliter at 6 months, a time point prior to onset of CGVHD in most patients; these findings are consistent with evidence of a key role for naive T cells in initiation of CGVHD, and with the importance of the level of Treg cells in controlling CGVHD. CGVHD is the principle cause of non-relapse morbidity |