Immune reconstitution following autologous and allogeneic stem cell transplant

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

SUMMARY: 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 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, 18-C-0125, and 19-C-0085 (PI: Jennifer Kanakry) enrolls an array of patients with various defined mutations. We have characterized lymphocyte subsets within a trio of 16-C-0003 patients as part of a publication describing clinical outcomes and have compiled similar data for a manuscript encompassing 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. 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). Our pharmacodynamics assays, specifically neutrophil activation in the presence of MPH966 (formerly AZD9668), in support of 16-C-0060 (PI: Steven Pavletic) supplements the pharmacokinetic assays performed by Dr. Pavletic's various collaborators. Similarly, an emerging collaboration with a lab within the Pediatric Oncology Branch may expand our findings from our pharmacodynamics assay, measuring the phosphorylation of various STAT upon cytokine stimulation in the presence of baracitinib (16-C-0094, PI: Steven Pavletic). In all of these GVHD therapeutic trials, we have applied our standardized methods to characterize lymphocyte subsets, cytokine profiles, and gene expression patterns, thereby permitting cross-protocol comparisons.