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Advances in Ex Vivo T Cell Depletion - Where Do We Stand?

ABSTRACT: Graft-versus-host (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). As donor T cells are recognized as key drivers of GVHD, some approaches to prevent GVHD have focused on T cell depletion of the allograft. In this review we summarize methods and outcomes of ex vivo T cell depleted (TCD) HCT with a focus on CD34+ selection. This platform is efficacious in preventing acute and chronic GVHD across a wide range of hematologic malignancies, and with the exception of chronic myeloid leukemia, is not associated with adverse relapse or survival outcomes compared to conventional GVHD prophylaxis platforms. In retrospective comparisons recipients of CD34+ selected HCT have higher rates of GVHD-free relapse-free survival (GRFS) than conventional HCT counterparts. Although CD34+ selected allografts require myeloablative and antithymocyte-globulin based conditioning to support engraftment, abrogation of calcineurin inhibitors and methotrexate in this approach reduces its toxicity such that it can be considered in select older and more comorbid patients who could benefit from ablative HCT. A trial comparing GVHD prophylaxis regimens (BMT CTN 1301, NCT02345850) has completed accrual and will be the first to compare CD34+ selected HCT with conventional HCT in a randomized prospective setting. Its findings have potential to establish CD34+ selected HCT as a new standard-of-care platform for GVHD prevention.

SUBMITTER: Bryant AR

PROVIDER: S-EPMC6521977 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Advances in <i>Ex Vivo</i> T Cell Depletion - Where Do We Stand?

Bryant Adam R AR Perales Miguel-Angel MA

Advances in cell and gene therapy 20181204 1

Graft-versus-host (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). As donor T cells are recognized as key drivers of GVHD, some approaches to prevent GVHD have focused on T cell depletion of the allograft. In this review we summarize methods and outcomes of <i>ex vivo</i> T cell depleted (TCD) HCT with a focus on CD34+ selection. This platform is efficacious in preventing acute and chronic GVHD across a wide range of hematologic m ...[more]

PMID: 31106295

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Project description:BackgroundPoor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells.MethodsWe studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood.ResultsCoculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×10(7) total nucleated cells per kilogram of body weight and 1.81×10(6) CD34+ cells per kilogram--doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P=0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001).ConclusionsTransplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00498316.).

Project description:Successfully replacing damaged cartilage with tissue-engineered constructs requires integration with the host tissue and could benefit from leveraging the native tissue's intrinsic healing capacity; however, efforts are limited by a poor understanding of how cartilage repairs minor defects. Here, we investigated the conditions that foster natural cartilage tissue repair to identify strategies that might be exploited to enhance the integration of engineered/ grafted cartilage with host tissue. We damaged porcine articular cartilage explants and using a combination of pulsed SILAC-based proteomics, ultrastructural imaging, and catabolic enzyme blocking strategies reveal that integration of damaged cartilage surfaces is not driven by neo-matrix synthesis, but rather local depletion of proteoglycans. ADAMTS4 expression and activity are upregulated in injured cartilage explants, but integration could be reduced by inhibiting metalloproteinase activity with TIMP3. These observations suggest that catabolic enzyme-mediated proteoglycan depletion likely allows existing collagen fibrils to undergo cross-linking, fibrillogenesis, or entanglement, driving integration. Catabolic enzymes are often considered pathophysiological markers of osteoarthritis. Our findings suggest that damage-induced upregulation of metalloproteinase activity may be a part of a healing response that tips towards tissue destruction under pathological conditions and in osteoarthritis, but could also be harnessed in tissue engineering strategies to mediate repair. Statement of significance: Cartilage tissue engineering strategies require graft integration with the surrounding tissue; however, how the native tissue repairs minor injuries is poorly understood. We applied pulsed SILACbased proteomics, ultrastructural imaging, and catabolic enzyme blocking strategies to a porcine cartilage explant model and found that integration of damaged cartilage surfaces is driven by catabolic enzyme-mediated local depletion of proteoglycans. Although catabolic enzymes have been implicated in cartilage destruction in osteoarthritis, our findings suggest that damage-induced upregulation of metalloproteinase activity may be a part of a healing response that tips towards tissue destruction under pathological conditions. They also suggest that this natural cartilage tissue repair process could be harnessed in tissue engineering strategies to enhance the integration of engineered cartilage with host tissue.

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Advances in Ex Vivo T Cell Depletion - Where Do We Stand?

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Advances in <i>Ex Vivo</i> T Cell Depletion - Where Do We Stand?

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