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 | $420,830 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | 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; the ETIB Flow Cytometry Facility, for support of sorting of clinical products; the ETIB T Cell Facility 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, 15-C-0067; PIs Daniel Fowler, Steven Pavletic, Ronald Gress, Kirsten Williams and Christopher Kanakry (all ETIB)). 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, 13-C-0132; PI: Dennis Hickstein) and primary immune deficiencies (16-C-0003, PI: Jennifer Kanakry (all ETIB)) by monitoring repopulation of deficient lineages after allogeneic transplant and by working with the ETIB Flow Cytometry Facility (William Telford) to assess subset-specific donor chimerism. Finally, in collaborations, we have analyzed allogeneic transplants of sickle cell disease (03-H-0170; PIs John Tisdale and Matthew Hsieh) and have examined immune reconstitution after radiation/chemotherapy treatment of glioblastoma (Johns Hopkins J1389; PIs Jian Campian and Stuart Grossman); the latter study is currently in press (Campian, J Neurol Oncol). We have focused on immune reconstitution in a matched unrelated donor allogeneic transplant trial (07-C-0195: PI Steven Pavletic) comparing two regimens of GVHD prophylaxis, one utilizing antibody-mediated depletion of host/donor lymphocytes at transplant, the second using immune suppressive agents. We determined that the lympho-depleting treatment resulted in severe and protracted reduction in T cell numbers, as compared to that in patients with immune suppression alone. 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. Most of the patients developing CGVHD had an expanded population of CD8+ T memory stem cells (Tscm) (CD45RA+CCR7dimCD95+). In both anti-tumor studies and in autoimmunity, this subpopulation is known to be associated with persistent expansion of CD8 effectors. In contrast, we identified a 10 fold increase (favoring the lymphodepletion arm) in the median ratio of Treg cells to either naive CD4 or naive CD8 cells at 6 months, a time prior to onset of CGVHD. In collaborative studies of sickle cell disease transplants (03-C-0170), treated under a regimen that prevented both acute and chronic GVHD, we had similarly determined that Treg expanded at 1 - 3 months post transplant. These findings are consistent with evidence of a key role for the level of Treg cells in controlling CGVHD and the possibility that Tscm may contribute to CGVHD. These studies of relative levels of Tsc |