Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease

Nahas, Myrna; Soiffer, Robert J.; Kim, Haesook T.; Alyea, Edwin P.; Arnason, Jon; Joyce, Robin; Antin, Joseph H.; Ho, Vincent T.; Stroopinsky, Dina; Li, Shuli; Levine, James D.; McMasters, Malgorzata; Jain, Salvia; Hamdan, Ayad; Tzachanis, Dimitrios; Bryant, Mary Paty; Logan, Emma; Bazemore, Josie; Ja, Stewart; Joyce, Amy; Stephenson, Susan; Washington, Abigail; Cole, Leandra; Pyzer, Athalia R.; Leaf, Rebecca Karp; Avigan, David; Rosenblatt, Jacalyn

doi:10.1182/blood-2017-05-780239

Cited by 31 publications

(23 citation statements)

References 51 publications

(56 reference statements)

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“…The anti-CD52 mAb Alemtuzumab, which targets and deplete B cells, T cells, dendritic cells (DCs), and natural killer (NK) cells, is also promising for the treatment of cGvHD ( 107 ). In addition, a number of studies have reported the use of fusion proteins to treat cGvHD ( 108 , 123 ). The use of some of these mAbs, antibody-drug conjugates, and fusion proteins for the treatment of cGvHD are discussed below.…”

Section: Emerging Therapies For Chronic Graft-versus-host Diseasementioning

confidence: 99%

“…This compound is used for treating the autoimmune disease rheumatoid arthritis, and also seems promising for the treatment of Scl-cGvHD. When administered at 10 mg/kg, it has been reported to be well-tolerated and to offer 44% of PRs and reduction in prednisone usage to half of the responsive patients ( 123 ).…”

Section: Emerging Therapies For Chronic Graft-versus-host Diseasementioning

confidence: 99%

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New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

et al. 2020

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Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions.

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Section: Emerging Therapies For Chronic Graft-versus-host Diseasementioning

confidence: 99%

Section: Emerging Therapies For Chronic Graft-versus-host Diseasementioning

confidence: 99%

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

et al. 2020

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“…Decitabine has also been demonstrated to alter Treg maturation and activate the expression of endogenous retroviruses resulting in engagement of the dsRNA response/interferon-beta pathway thus, suggesting a non-cell autonomous mechanism of action is also at play in AML (101, 102, 106–108). Indeed, preclinical data indicates that hypomethylating agents potentiate the response to anti-CTLA-4 immunotherapy (101) and a dendritic cell/AML fusion vaccine (109) with ongoing clinical trials in AML currently exploring the combination of HMA and checkpoint inhibitors (NCT02890329) or dendritic cell/AML fusion vaccine.…”

Section: Immunomodulation and Anti-leukemia Therapymentioning

confidence: 99%

The Interplay Between the Genetic and Immune Landscapes of AML: Mechanisms and Implications for Risk Stratification and Therapy

2019

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AML holds a unique place in the history of immunotherapy by virtue of being among the first malignancies in which durable remissions were achieved with “adoptive immunotherapy,” now known as allogeneic stem cell transplantation. The successful deployment of unselected adoptive cell therapy established AML as a disease responsive to immunomodulation. Classification systems for AML have been refined and expanded over the years in an effort to capture the variability of this heterogeneous disease and risk-stratify patients. Current systems increasingly incorporate information about cytogenetic alterations and genetic mutations. The advent of next generation sequencing technology has enabled the comprehensive identification of recurrent genetic mutations, many with predictive power. Recurrent genetic mutations found in AML have been intensely studied from a cell intrinsic perspective leading to the genesis of multiple, recently approved targeted therapies including IDH1/2-mutant inhibitors and FLT3-ITD/-TKD inhibitors. However, there is a paucity of data on the effects of these targeted agents on the leukemia microenvironment, including the immune system. Recently, the phenomenal success of checkpoint inhibitors and CAR-T cells has re-ignited interest in understanding the mechanisms leading to immune dysregulation and suppression in leukemia, with the objective of harnessing the power of the immune system via novel immunotherapeutics. A paradigm has emerged that places crosstalk with the immune system at the crux of any effective therapy. Ongoing research will reveal how AML genetics inform the composition of the immune microenvironment paving the way for personalized immunotherapy.

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“…Results from a phase I trial evaluating the use of abatacept in patients with SR-cGVHD were presented at the 2016 ASH conference. 132 A total of 17 patients were enrolled and 16 were treated with a planned total of six doses of abatacept. In all, 7/16 (44%) evaluable patients had a PR based on the NIH consensus criteria.…”

Section: Immune Checkpoint Blockadementioning

confidence: 99%

New and emerging therapies for acute and chronic graftversushost disease

Hill

Alousi

Kebriaei

et al. 2017

Therapeutic Advances in Hematology

101

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Graft versus host disease (GVHD) remains a major cause of morbidity and mortality following allogeneic hematopoietic stem-cell transplantation (HSCT). Despite the use of prophylactic GVHD regimens, a significant proportion of transplant recipients will develop acute or chronic GVHD following HSCT. Corticosteroids are standard first-line therapy, but are only effective in roughly half of all cases with ~50% of patients going on to develop steroidrefractory disease, which increases the risk of nonrelapse mortality. While progress has been made with improvements in survival outcomes over time, corticosteroids are associated with significant toxicities, and many currently available salvage therapies are associated with increased immunosuppression, infectious complications, and potential loss of the graft versus leukemia (GVL) effect. Thus, there is an unmet need for development of newer treatment strategies for both acute and chronic GVHD to improve long-term post-transplant outcomes and quality of life for HSCT recipients. Here, we provide a concise review of major emerging therapies currently being studied in the treatment of acute and chronic GVHD.

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Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease

Cited by 31 publications

References 51 publications

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

The Interplay Between the Genetic and Immune Landscapes of AML: Mechanisms and Implications for Risk Stratification and Therapy

New and emerging therapies for acute and chronic graftversushost disease

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