Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation

Solomon, Scott R.; Mielke, Stephan; Savani, Bipin N.; Montero, Aldemar; Wisch, Laura; Childs, Richard W.; Hensel, Nancy F.; Schindler, John; Gheţie, Victor; Leitman, Susan F.; Mai, Thao; Carter, Charles S.; Kurlander, Roger; Read, Elizabeth J.; Vitetta, Ellen S.; Barrett, A. John

doi:10.1182/blood-2005-01-0393

Cited by 137 publications

(97 citation statements)

References 32 publications

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“…Clinical studies employing anti-CD25 conjugated immunotoxin to eliminate CD25-expressing alloactivated T cells in ex vivo mMLR have been conducted previously in both haploidentical and matched sibling transplants. 32,33 The studies in haploidentical transplants found that infusion of SD donor lymphocytes significantly aided immune reconstitution, 32 but persisting GVHD was observed in matched sibling transplants. 33 Further studies revealed that donor CD4 + CD25 + FOXP3 + Tregs significantly contributed to protection against acute GVHD in these transplants.…”

Section: Discussionmentioning

confidence: 99%

“…32,33 The studies in haploidentical transplants found that infusion of SD donor lymphocytes significantly aided immune reconstitution, 32 but persisting GVHD was observed in matched sibling transplants. 33 Further studies revealed that donor CD4 + CD25 + FOXP3 + Tregs significantly contributed to protection against acute GVHD in these transplants. 6 Our experiments show that SD with adenosine spares these critical Tregs, highlighting the potential for GVHD protection by this approach.…”

Section: Discussionmentioning

confidence: 99%

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Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia

et al. 2016

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Selective depletion (SD) of alloreactive T cells from allogeneic hematopoeitic stem cell transplants to prevent graft-versus-host disease (GVHD) without compromising immune reconstitution and antitumor responses remains a challenge. Here, we demonstrate a novel SD strategy whereby alloreacting T cells are efficiently deleted ex vivo with adenosine. SD was achieved in human leukocyte antigen (HLA) mismatched cocultures by multiple exposures to 2 mmol/l adenosine over 7 days. Adenosine depleted greater than to 90% of alloproliferating T cells in mismatched, haploidentical, and matched sibling pairs while conserving response to third-party antigens. Alloreactive CD4 and CD8 T cells were targeted for depletion while NK and B cells were preserved. Our novel approach also preserved nonalloreactive naive, central, and effector memory T-cell subsets, Tregs, and notably preserved T-cell responses against DNA viruses that contribute to transplant related mortality after allogeneic hematopoeitic stem cell transplants. Additionally, T cells recognizing leukemia-associated antigens were efficiently generated in vitro from the cell product post-SD. This study is the first to demonstrate that adenosine depletion of alloactivated T cells maintains a complete immune cell profile and recall viral responses. Expansion of tumor antigen-specific subsets postdepletion opens the possibility of generating T-cell products capable of graft-versus-tumor responses without causing GVHD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia

et al. 2016

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“…7,28 Allodepletion with this IT ex vivo has yielded encouraging results in several clinical trials. 9,10,12 However, since other methods for depleting CD25 þ cells might be equally effective or superior to the IT, and since two other agents are readily available, our study was designed to compare our IT to these agents. To this end, PBMCs activated in a one-way MLR were subjected to allodepletion by the anti-CD25 IT, anti-CD25 MACS, Ontak or IT plus MACS.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 Several studies have been carried out using this particular IT to deplete alloreactive cells prior to transplantation and results have been encouraging. [8][9][10][11][12] Ontak has been used for the treatment of patients with relapsed or refractory cutaneous T cell lymphoma (CTCL), 13 but its effectiveness in allodepleting T cells has not been investigated. The use of MACS to deplete CD4 þ or CD8 þ T cells from transplants has shown promise in several clinical trials in highrisk patients 14,15 and anti-CD25 MACS have effectively depleted alloreactive cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

A comparison of an anti-CD25 immunotoxin, Ontak and anti-CD25 microbeads for their ability to deplete alloreactive T cells in vitro

Vaclavkova

Cao

et al. 2006

Bone Marrow Transplant

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Ex vivo depletion of alloreactive CD25 þ T cells from a stem cell transplant (SCT) can reduce the incidence of graft-versus-host disease (GVHD) while preserving antimicrobial and perhaps antileukemia activity. However, the most effective methods for allodepleting T cells prior to transplant have not been determined. In this study, we have compared three agents that deplete CD25 þ activated, alloreactive T cells. These included Ontak (Denileukin Diftitox), an IL-2 fusion toxin, anti-CD25 microbeads (MACS), an anti-CD25 immunotoxin (IT) and a combination of the IT and MACS. Peripheral blood mononuclear cells (PBMCs) activated in a primary mixed lymphocyte reaction (MLR) were allodepleted using optimal amounts of each agent, and the cells were then analyzed by flow cytometry. The treated cells were examined both for remaining alloreactivity and for the preservation of third party reactivity by testing them in a secondary MLR. Our data demonstrate that both the anti-CD25 IT and the anti-CD25 MACS were equally effective in depleting CD4 þ CD25 þ cells and in sparing T cells that were reactive with third party cells. The anti-CD25 IT was, however, superior in depleting alloreactive CD8 þ CD25 þ cells. In contrast, Ontak did not eliminate alloreactive cells and the Ontak-treated cells retained significant reactivity against the original stimulator cells.

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“…This promising approach has been validated in animal models in a number of centers, and three clinical trials using a CD25 immunotoxin to selectively deplete alloreactivity (two in haploidentical peripheral-blood stem-cell transplantations in pediatric patients, and one in adults with hematological malignancies in HLA-identical sibling transplants) indicate that the concept is feasible, reducing GVHD while promoting rapid immune reconstitution. [11][12][13] We used a photodepletion (PD) technique which works by preferential killing of alloactivated cells which retain the photosensitive dye TH9402. To restrict the allostimulation and conserve GVL reactions, expanded T lymphocytes from the patients were co-cultured with the responder cells.…”

Section: Manipulation Of T Lymphocytesmentioning

confidence: 99%

Prophylaxis of acute GVHD: manipulate the graft or the environment?

Barrett

Blanc

2008

Best Practice & Research Clinical Haematology

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Graft-versus-host disease (GVHD) is the immune response of donor T lymphocytes responding to the recipient's alloantigens. The cellular and cytokine mechanisms driving GVHD are now well defined and have led to several prophylactic approaches. Selective allodepletion techniques promise to prevent GVHD without causing immune deficiency provoked by global T-cell depletion. Targeted dosing other (non-T-cells) cells in the graft -such as CD34 + progenitors, regulatory T cells, natural killer cells and mesenchymal stromal cells -can also lead to transplants designed to retain immune capability without causing GVHD. Immunosuppressive drugs such as methotrexate, cyclosporine and anti-lymphocyte antibodies are the mainstay in the prevention of GVHD and can be used in conjunction with engineered grafts to eliminate GVHD. In future it is anticipated that further refinements in targeting the elimination or suppression of GVHD reacting T cells should be selective enough to preserve the important graft-versus-leukemia effect which contributes to the cure of malignant diseases by allogeneic stem-cell transplantation. Keywords selective T-cell depletion; regulatory T cells; natural killer cells; mesenchymal stromal cells; calcineurin inhibitors; graft-versus-leukemiaWhile the classic rules of the conditions necessary for GVHD development proposed by Billingham remain as valid today as they did when he proposed them, we have since greatly refined our understanding of the positive and negative factors influencing the development of GVHD. 1 Figure 1 summarizes factors regulating the development of acute GVHD. This schema identifies key events leading to GVHD which are susceptible to therapeutic intervention to prevent GVHD. GVHD development can be interrupted at two distinct stages: (1) selection of the cells to be engrafted, and (2) modulation of the post-transplant milieu.

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Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation

Abstract: We have selectively depleted host-reactive donor T cells from peripheral blood stem cell (PBSC) transplant allografts ex vivo using an anti-CD25 immunotoxin.

Cited by 137 publications

References 32 publications

Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia

Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia

A comparison of an anti-CD25 immunotoxin, Ontak and anti-CD25 microbeads for their ability to deplete alloreactive T cells in vitro

Prophylaxis of acute GVHD: manipulate the graft or the environment?

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