Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-Beta-1 mAb in patients with T-cell large granular lymphocytic leukemia

Waldmann, Thomas A.; Conlon, Kevin C.; Stewart, Dawn; Worthy, Tat Yana A.; Janik, John E.; Fleisher, Thomas A.; Albert, Paul S.; Figg, William D.; Spencer, Shawn D.; Raffeld, Mark; Decker, Jean M.; Goldman, Carolyn K.; Bryant, Bonita R.; Petrus, Michael; Creekmore, Stephen P.; Morris, John C.

doi:10.1182/blood-2012-08-450585

Cited by 61 publications

(54 citation statements)

References 50 publications

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“…Administration of HuMikb1 to patients was safe but clinical responses were not observed. 114 A phase 1 study with an anti-CD2 mAb (siplizumab) was conducted in 2005 in patients with relapsed/refractory CD2 1 T-cell lymphoma/ leukemia, including T-LGL leukemia (#NCT00123942). To our knowledge, the results of this trial have not been published.…”

Section: Second-line Therapymentioning

confidence: 99%

LGL leukemia: from pathogenesis to treatment

Lamy

Moignet

Loughran

2017

Blood

244

391

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Large granular lymphocyte (LGL) leukemia has been recognized by the World Health Organization classifications amongst mature T-cell and natural killer (NK) cell neoplasms. There are 3 categories: chronic T-cell leukemia and NK-cell lymphocytosis, which are similarly indolent diseases characterized by cytopenias and autoimmune conditions as opposed to aggressive NK-cell LGL leukemia. Clonal LGL expansion arise from chronic antigenic stimulation, which promotes dysregulation of apoptosis, mainly due to constitutive activation of survival pathways including Jak/Stat, MapK, phosphatidylinositol 3-kinase–Akt, Ras–Raf-1, MEK1/extracellular signal-regulated kinase, sphingolipid, and nuclear factor-κB. Socs3 downregulation may also contribute to Stat3 activation. Interleukin 15 plays a key role in activation of leukemic LGL. Several somatic mutations including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3 have been demonstrated recently in LGL leukemia. Because these mutations are present in less than half of the patients, they cannot completely explain LGL leukemogenesis. A better mechanistic understanding of leukemic LGL survival will allow future consideration of a more targeted therapeutic approach than the current practice of immunosuppressive therapy.

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Section: Second-line Therapymentioning

confidence: 99%

LGL leukemia: from pathogenesis to treatment

Lamy

Moignet

Loughran

2017

Blood

244

391

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“…They both blocked RLI-mediated CTLL-2 cell proliferation efficiently with an IC 50 of 0.3 μg/ml (Supplemental Figure 2). Like all other anti-CD122 antibodies that effectively block IL-15 transpresentation and interaction of IL-2 with its intermediate affinity receptor (CD122/CD132), neither TM-β1 nor ChMBC7 could efficiently inhibit the interaction of IL-2 with its high-affinity receptor complex (CD25/CD122/CD132) (83). Likewise, neither TM-β1 nor ChMBC7 could block the IL-2-mediated proliferation of CTLL-2 (IC 50 > 20 μg/ml).…”

Section: Methodsmentioning

confidence: 99%

CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms

Yuan¹,

Dong²,

Tsurushita³

et al. 2018

JCI Insight

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“…76 A Phase I clinical trial of IL-15 blockade in T-cell LGL leukemia was conducted by Waldmann et al using the Hu-Mikβ1 mAb that blocks IL-15 transpresentation to cells expressing IL-2/IL-15Rβ and γc (Table 1). 76 However, Hu-Mikβ1 did not block IL-15 action on the cells that express the heterotrimeric receptor in a cis orientation. In this trial, Hu-Mikβ1 therapy was not effective in the treatment of patients with monoclonal T-LGL.…”

Section: Critical Analysis Of the Potential For Targeting Il-15 In Camentioning

confidence: 99%

IL-15 as a potential target in leukemia

Xiong¹,

Bensoussan²,

Decot³

2015

BLCTT

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Leukemia, one of the most aggressive hematopoietic malignancies, is characterized by excessive proliferation, survival, and impaired differentiation of hematopoietic stem cells. Interleukin 15, a proinflammatory cytokine, induces proliferation and promotes cell survival of human T and B lymphocytes, as well as natural killer cells. However, it may also play a detrimental role in the onset of leukemia. This review provided an overview of the aberrant expression of Interleukin 15 and its role in the development and progression of this hematological malignancy. Also, we critically explored the potential therapeutic opportunities involved in targeting the disruption of interleukin-15 signaling as well as in interleukin-15-mediated enhancement of antitumor immunity.

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Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-Beta-1 mAb in patients with T-cell large granular lymphocytic leukemia

Abstract: • Hu-Mik␤1 monoclonal antibody was evaluated in patients with LGL leukemia.• Hu-Mik␤1 blocks the transpresentation of IL-15.

Cited by 61 publications

References 50 publications

LGL leukemia: from pathogenesis to treatment

LGL leukemia: from pathogenesis to treatment

CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms

IL-15 as a potential target in leukemia

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