The Preclinical Development and Clinical Monitoring Facility (PDCMF) projects have developed from transplantation protocols developed within ETIB. The PDCMF processes and preserves peripheral blood, marrow aspirates, and tumor and CGVHD tissue biopsies from all ongoing ETIB protocols. In close collaborative relationships with the Cell Processing Service of DTM, the ETIB Flow Cytometry Facility, the ETIB T Cell Facility, and the laboratory of Ronald Gress, 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 routine tasks describe the Facility's role in support of NHLBI collaborations 03-H-0170 (PI: John Tisdale) and 14-H-0077 (PI: Matthew Hsieh) and of ETIB protocols currently in the stages of long-term follow-up, including 11-C-0136 (PI: Chris Kanakry), 17-C-0027 (PI: Steven Pavletic), and 07-C-0195 (PI: Steven Pavletic). The Facility provides additional services unique to other studies. Those transplant-related protocols can be categorized as: 1) myeloablative transplant for acute leukemias; 2) transplantation for monogenic immune deficiencies; 3) GVHD therapies and natural history. The protocol 15-C-0067 (PI: Steven Pavletic) adopts the transplant and GVHD prophylaxis regimen of the TMS arm of 07-C-0195 and introduces recombinant keratinocyte growth factor to promote thymopoiesis and to prevent GVHD. As described in our 2017 Annual Report and 2016 publication in The Journal of Immunology, we have characterized T cell subpopulations and cytokine profiles in peripheral blood during the late time points, post-transplant, in 07-C-0195. We are utilizing these same strategies in studies of the early time points in 07-C-0195 and in 15-C-0067, as the latter protocol may progress to a Phase II study. Several protocols employing allogeneic transplants as a curative therapy for primary immunodeficiencies are conducted by ETIB. This Facility monitors the repopulation of deficient cell lineages, especially by preparing samples at post-transplant intervals for the ETIB Flow Cytometry Facility (William Telford) to then be assessed for subset-specific donor chimerism by the Hematology Service of the Department of Laboratory Medicine. 13-C-0132 (PI: Dennis Hickstein) and 10-C-0174 (PI: Nirali Shah) enroll patients with specific monogenic immune deficiencies (GATA2 and DOCK8, respectively), while 16-C-0003 (PI: Jennifer Kanakry) enrolls an array of patients with various defined mutations. We have characterized cells within a trio of 16-C-0003 patients sharing a genetic defect to supplement the clinical results in a manuscript in preparation and are compiling similar data for an entire cohort. CGVHD is the principal non-relapse cause of morbidity and mortality after allogeneic transplantation and has been a major focus for research in the PDCMF. Productive collaborations have resulted in contributions to a study of aberrant B cell signaling (Poe, et al Blood 2017) and a review of CGVHD biomarkers (Wolff, et al BMT 2018). For active ETIB protocols, we have supported the efforts of the multidisciplinary CGVHD clinical team in the ongoing natural history protocol 04-C-0281 (P.I. Steven Pavletic). We have also performed pharmacodynamics assays, including neutrophil activation in the presence of AZD9668 (16-C-0060, PI: Steven Pavletic) and cytokine stimulation in the presence of baracitinib (16-C-0094, PI: Steven Pavletic). In all of these trials, we have applied our standardized methods to characterize lymphocyte subsets, cytokine profiles, and gene expression patterns, thereby permitting cross-protocol comparisons.
Showing the most recent 10 out of 31 publications
