Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Al-Homsi, Ahmad Samer; Feng, Yi; Duffner, Ulrich; Malki, Monzr M. Al; Goodyke, Austin; Cole, Kelli; Muilenburg, Marlee; Abdel-Mageed, Aly

doi:10.1016/j.exphem.2016.05.005

Cited by 23 publications

(22 citation statements)

References 45 publications

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“…With regard to the use of cyclophosphamide and bortezomib, both have immune modulatory effects other than targeting B cells or plasma cells 27 . For example, cyclophosphamide can facilitate the chimerism induction in sensitized recipients by reducing memory T cells as shown in our previous study 28 .…”

Section: Discussionmentioning

confidence: 87%

Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice

Lin

Boon

Bockermann

et al. 2020

American Journal of Transplantation

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Mixed hematopoietic chimerism induction as a way to foster tolerance to donor organs in recipients who have been sensitized to donor antigens is challenging. Donor‐specific antibodies (DSA) are a dominant barrier toward successful donor bone marrow engraftment. Although desensitization methods are routinely used in recipients with allosensitization for allogeneic bone marrow transplantation, engraftment is frequently unsuccessful. To overcome the barrier of prior sensitization we tested enzymatic desensitization of donor‐specific IgG using imlifidase and endoglycosidase of Streptococcus pyogenes (EndoS), which both partially block the function of DSA in mice, as a novel approach to improve murine bone marrow engraftment in primed hosts. We found that EndoS was capable of inhibiting antibody‐mediated killing of donor cells in vivo. Furthermore, the effect of EndoS depended on the titer of DSA and the genetic background of the recipients. In combination with imlifidase, EndoS improved the survival of donor bone marrow cells. Together with cyclophosphamide, bortezomib, T cell depletion, and nonlethal irradiation, imlifidase in combination with EndoS allowed allogeneic bone marrow engraftment in sensitized recipients. We conclude that enzymatic inactivation of DSA, using the combination of imlifidase and EndoS, can be used for inducing donor hematopoietic chimerism in allosensitized recipient mice in combination with other desensitization strategies.

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Section: Discussionmentioning

confidence: 87%

Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice

Lin

Boon

Bockermann

et al. 2020

American Journal of Transplantation

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“…We believe that the addition of a proteasome inhibitor to PTC is attractive for several reasons. Proteasome inhibitors suppress DC maturation and function (reviewed in [8]). Consequently, as opposed to the conventional calcineurin inhibitor-based prophylactic regimens that affect T cells exclusively, the combination of PTC and a proteasome inhibitor targets GVHD development at 2 key stages: DC activation and T cell activation and proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Current GVHD prevention strategies that exclusively and broadly suppress or deplete T cells are only partially effective and abrogate the graft-versus-tumor effect [2,3]. Emerging alternative pharmacologic strategies to prevent GVHD employ post-transplantation cyclophosphamide (PTC) [4,5], costimulation blocking agents [6], chemo-cytokine antagonists [7], proteasome inhibitors (recently reviewed in [8]), and epigenetic modulators [9,10]. Some of these approaches have been claimed to maintain the graft-versus-tumor effect or incorporate cytotoxic activity to prevent disease relapse.…”

Section: Introductionmentioning

confidence: 99%

“…Proteasome inhibitors possess immune-modulatory effects that span a wide variety of cellular processes of dendritic cells (DC) that are crucial for the development of GVHD [8]. In animal models and early clinical studies, proteasome inhibitors ameliorate GVHD when administered early in the posttransplantation period [8]. Additionally, proteasome inhibitors have cytotoxic effects and are active against a variety of hematological malignancies.…”

Section: Introductionmentioning

confidence: 99%

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Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone

Al-Homsi

Goodyke

McLane

et al. 2017

Biology of Blood and Marrow Transplantation

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Lapses in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) warrant novel approaches. Such approaches include, among others, the use of post-transplantation cyclophosphamide (PTC) and proteasome inhibitors. Although PTC alone consistently produces low rates of chronic GVHD, the incidence of acute GVHD remains significant. Inversely, prolonged post-transplantation administration of proteasome inhibitors carries a risk of paradoxical aggravation of GVHD. We examined whether the combination of cyclophosphamide and ixazomib addresses the limitations of each of these agents when used alone to prevent GVHD in mice subjected to allogeneic HSCT across MHC barriers. We chose ixazomib, an orally bioavailable proteasome inhibitor, because of its favorable physiochemical characteristics. The combination of cyclophosphamide and ixazomib improved overall survival of mice in comparison to an untreated control group and to groups receiving either cyclophosphamide alone or ixazomib alone. Furthermore, cyclophosphamide prevented the surge of IL-1β, GVHD aggravation, and sudden death associated with prolonged administration of ixazomib after HSCT. Finally, we demonstrated that although ixazomib was administered before cyclophosphamide, it did not impair the preferential depletion of proliferating as opposed to resting donor T cells. Our data suggest that the combination of cyclophosphamide and ixazomib for the prevention of GVHD after allogeneic HSCT is promising and merits further investigation in clinical trials.

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“…Proteasome inhibitors have multiple immune modulatory effects that span different stages of GvHD development including dendritic and T-cell differentiation, proliferation and function. Proteasome inhibitors also foster the expansion of regulatory T-cells (39,40). Despite the fact that the results of a recent phase II trial examining the combination of bortezomib with CN and mTORI compared to a standard TAC and MTX combination were disappointing (41), we hypothesized based on pre-clinical data that proteasome inhibitors remain appealing agents when paired with PTCy.…”

Section: Ptcy As a Platform For Cn And Mtor Inhibitor-free Gvhd Prevementioning

confidence: 99%

Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation

Williams

Cirrone²,

Cole³

et al. 2020

Front. Immunol.

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Following allogeneic blood and marrow transplantation (BMT), graft-versus-host disease (GvHD) continues to represent a significant cause of treatment failure, despite the routine use of conventional, mainly calcineurin inhibitor-based prophylaxis. Recently, posttransplant cyclophosphamide (PTCy) has emerged as a safe and efficacious alternative. First, omitting the need for ex vivo T-cell depletion in the setting of haploidentical transplantation, growing evidence supports PTCy role in GvHD prevention in matchedrelated and matched-unrelated transplants. Through improved understanding of GvHD pathophysiology and advancements in drug development, PTCy emerges as a unique opportunity to design calcineurin inhibitor-free strategies by integrating agents that target different stages of GvHD development.

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Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Cited by 23 publications

References 45 publications

Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice

Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice

Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone

Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation

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