Preemptive administration of human αβ T cell receptor-targeting monoclonal antibody GZ-αβTCR potently abrogates aggressive graft-versus-host disease in vivo

Blank, Gregor; Welker, Christian; Sipos, Bence; Sonntag, Katja; Müller, Friederike; Eckert, Franziska; Seitz, Christian; Nadalin, Silvio; LaCorcia, Gina; Königsrainer, Alfred; Snell, Daniel C.; Handgretinger, Rupert; Schilbach, Karin

doi:10.1007/s00277-015-2471-3

Cited by 6 publications

(6 citation statements)

References 48 publications

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“…It was also demonstrated that the clonogenic potential of CD34 + HSC after depletion remained unaffected [10]. New developments are now in sight following the reports that a novel humanized anti-αβ TCR antibody, endowed with an improved capacity to target CD4 + T cells for GVHD prevention both in vitro and in vivo in a mouse-human model of HSCT [39,40], may become available for clinical use.…”

Section: Discussionmentioning

confidence: 99%

Selective Depletion of αβ T Cells and B Cells for Human Leukocyte Antigen–Haploidentical Hematopoietic Stem Cell Transplantation. A Three-Year Follow-Up of Procedure Efficiency

Pira

Malaspina

Girolami

et al. 2016

Biology of Blood and Marrow Transplantation

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HLA-haploidentical family donors represent a valuable option for children requiring allogeneic hematopoietic stem cell transplantation (HSCT). Because graft-versus-host diseases (GVHD) is a major complication of HLA-haploidentical HSCT because of alloreactive T cells in the graft, different methods have been used for ex vivo T cell depletion. Removal of donor αβ T cells, the subset responsible for GVHD, and of B cells, responsible for post-transplantation lymphoproliferative disorders, have been recently developed for HLA-haploidentical HSCT. This manipulation preserves, in addition to CD34 progenitors, natural killer, γδ T, and monocytes/dendritic cells, contributing to anti-leukemia activity and protection against infections. We analyzed depletion efficiency and cell yield in 200 procedures performed in the last 3 years at our center. Donors underwent CD34 hematopoietic stem cell (HSC) peripheral blood mobilization with granulocyte colony-stimulating factor (G-CSF). Poor CD34 cell mobilizers (48 of 189, 25%) received plerixafor in addition to G-CSF. Aphereses containing a median of 52.5 × 10 nucleated cells and 494 × 10 CD34 HSC were manipulated using the CliniMACS device. In comparison to the initial product, αβ T cell depletion produced a median 4.1-log reduction (range, 3.1 to 5.5) and B cell depletion led to a median 3.4-log reduction (range, 2.0 to 4.7). Graft products contained a median of 18.5 × 10 CD34 HSC/kg recipient body weight, with median values of residual αβ T cells and B cells of 29 × 10/kg and 33 × 10/kg, respectively. Depletion efficiency monitored at 6-month intervals demonstrated steady performance, while improved recovery of CD34 cells was observed after the first year (P = .0005). These data indicate that αβ T cell and B cell depletion of HSC grafts from HLA-haploidentical donors was efficient and reproducible.

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Section: Discussionmentioning

confidence: 99%

Selective Depletion of αβ T Cells and B Cells for Human Leukocyte Antigen–Haploidentical Hematopoietic Stem Cell Transplantation. A Three-Year Follow-Up of Procedure Efficiency

Pira

Malaspina

Girolami

et al. 2016

Biology of Blood and Marrow Transplantation

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“…Selective depletion of T cells that cause GVHD from allogeneic stem cell grafts and preservation of T cells specific for pathogens may improve the outcomes of HSCT. 26,27 After HSCT, donor T cells are activated first by host APCs through direct cell contact. Chen and colleagues reported that IMMU-114, a humanized anti-human leukocyte antigen-DR (HLA-DR) moAb, selectively inhibited the proliferation of HLA-DR + T cells and reduced CD25 alloreactive T cells in allogeneic mixed leukocyte reactions (MLRs) by depleting human PBMCs of all APCs, including B cells, monocytes, myeloid DC type-1 (mDC1), mDC2, and plasmacytoid DCs (pDCs), which could efficiently suppress GVHD.…”

Section: Discussionmentioning

confidence: 99%

“…Both GVL and GVHD reactivity are largely systemic responses that are primarily mediated by donor T cells. , Donor T cells play a crucial role in GVHD-associated pathologic damage. Selective depletion of T cells that cause GVHD from allogeneic stem cell grafts and preservation of T cells specific for pathogens may improve the outcomes of HSCT. , After HSCT, donor T cells are activated first by host APCs through direct cell contact. Chen and colleagues reported that IMMU-114, a humanized anti-human leukocyte antigen-DR (HLA-DR) moAb, selectively inhibited the proliferation of HLA-DR + T cells and reduced CD25 alloreactive T cells in allogeneic mixed leukocyte reactions (MLRs) by depleting human PBMCs of all APCs, including B cells, monocytes, myeloid DC type-1 (mDC1), mDC2, and plasmacytoid DCs (pDCs), which could efficiently suppress GVHD. , Therefore, we hypothesized that temporarily encapsulating T cells within nanoscale biomaterials could attenuate GVHD by reducing the direct contact between donor T cells and host APCs.…”

Section: Discussionmentioning

confidence: 99%

Conformal Nanoencapsulation of Allogeneic T Cells Mitigates Graft-versus-Host Disease and Retains Graft-versus-Leukemia Activity

Zhao¹,

Zhang

Han³

et al. 2016

ACS Nano

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Allogeneic transplantation of hematopoietic stem cells (HSC) in combination with T cells has a curative potential for hematopoietic malignancies through graft-versus-leukemia (GVL) effects, but is often compromised by the notorious side effect of graft-versus-host disease (GVHD) resulting from alloreactivity of the donor T cells. Here, we tested if temporary immunoisolation achieved by conformally encapsulating the donor T cells within a biocompatible and biodegradable porous film (~450 nm in thickness) of chitosan and alginate could attenuate GVHD without compromising GVL. The nanoencapsulation was found not to affect the phenotype of T cells in vitro in terms of size, viability, proliferation, cytokine secretion, and cytotoxicity against tumor cells. Moreover, the porous nature of the nanoscale film allowed the encapsulated T cells to communicate with their environment, as evidenced by their intact capability of binding to antibodies. Lethally irradiated mice transplanted with bone marrow cells (BMCs) and the conformally encapsulated allogeneic T cells exhibited significantly improved survival and reduced GVHD together with minimal liver damage and enhanced engraftment of donor BMCs, compared to the transplantation of BMCs and non-encapsulated allogeneic T cells. Moreover, the conformal nanoencapsulation did not compromise the GVL effect of the donor T cells. These data show that conformal nanoencapsulation of T cells within biocompatible and biodegradable nanoscale porous materials is a potentially safe and effective approach to improve allogeneic HSC transplantation for treating hematological malignancies and possibly other diseases.

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“…The αβTCR is highly important in the pathogenesis of GVHD because it is the primary signal for activating T cells. The humanized MoAb of GZ-αβTCR attenuates the function T cells, suppresses clinical signs of GVHD and increases the survival of patients (111). It is most desirable that allo-HCT may cause high GVL effect and negligible GVHD.…”

Section: Recent Advancements In Allo-hctmentioning

confidence: 99%

The Role of Co-stimulatory/Co-inhibitory Signals in Graft-vs.-Host Disease

2018

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Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapeutic approach for various hematologic and immunologic ailments. Despite the beneficial impact of allo-HCT, its adverse effects cause severe health concerns. After transplantation, recognition of host cells as foreign entities by donor T cells induces graft-vs.-host disease (GVHD). Activation, proliferation and trafficking of donor T cells to target organs and tissues are critical steps in the pathogenesis of GVHD. T cell activation is a synergistic process of T cell receptor (TCR) recognition of major histocompatibility complex (MHC)-anchored antigen and co-stimulatory/co-inhibitory signaling in the presence of cytokines. Most of the currently used therapeutic regimens for GVHD are based on inhibiting the allogeneic T cell response or T-cell depletion (TCD). However, the immunosuppressive drugs and TCD hamper the therapeutic potential of allo-HCT, resulting in attenuated graft-vs.-leukemia (GVL) effect as well as increased vulnerability to infection. In view of the drawback of overbroad immunosuppression, co-stimulatory, and co-inhibitory molecules are plausible targets for selective modulation of T cell activation and function that can improve the effectiveness of allo-HCT. Therefore, this review collates existing knowledge of T cell co-stimulation and co-inhibition with current research that may have the potential to provide novel approaches to cure GVHD without sacrificing the beneficial effects of allo-HCT.

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Preemptive administration of human αβ T cell receptor-targeting monoclonal antibody GZ-αβTCR potently abrogates aggressive graft-versus-host disease in vivo

Cited by 6 publications

References 48 publications

Selective Depletion of αβ T Cells and B Cells for Human Leukocyte Antigen–Haploidentical Hematopoietic Stem Cell Transplantation. A Three-Year Follow-Up of Procedure Efficiency

Selective Depletion of αβ T Cells and B Cells for Human Leukocyte Antigen–Haploidentical Hematopoietic Stem Cell Transplantation. A Three-Year Follow-Up of Procedure Efficiency

Conformal Nanoencapsulation of Allogeneic T Cells Mitigates Graft-versus-Host Disease and Retains Graft-versus-Leukemia Activity

The Role of Co-stimulatory/Co-inhibitory Signals in Graft-vs.-Host Disease

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