Targeting IL-15 in Large Granular Lymphocyte Leukemia
Targeting IL-15 in Large Granular Lymphocyte Leukemia
Evaluation of: Waldmann TA, Conlon KC, Stewart DM et al. Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-β-1 mAb in patients with T-cell large granular lymphocytic leukemia. Blood 121(3), 476–484 (2013).
IL-15 is a cytokine that stimulates the proliferation of NK and T cells. Previous studies have shown that IL-15 is critical to the induction of T-cell large granular lymphocyte (T-LGL) leukemia. A Phase I trial of a humanized antibody (Hu-Mikβ1) to the IL2/IL15Rβ receptor, expressed on T-LGL, is explored in this trial to evaluate the safety, pharmacokinetics, specificity and clinical efficacy of Hu-Mikβ1. The study demonstrated no toxicity and favorable saturation of IL2/IL15Rβ receptor, but no clinical efficacy in this Phase I study.
Large granular lymphocyte (LGL) leukemia is a class of rare lymphoproliferative disorders. The T-cell form (T-LGL) is CD3 and is classified by the WHO as a mature peripheral T-cell neoplasm. T-LGL generally runs an indolent clinical course and frequently presents with neutropenia, anemia and rheumatoid arthritis. A computational systems biology approach was previously used to identify IL-15 and PDGF as master regulators of leukemic LGL survival, demonstrating that dysregulation of these cytokines could explain all known molecular features of LGL leukemia. Furthermore, dysfunctional activation-induced cell death due to chronic viral infection or antigen stimulation is thought to be critical to disease pathogenesis. Multiple survival pathways are known to be dysregulated in LGL leukemia including JAK/STAT, sphingolipid, MAPK and PI3K/AKT signaling. More recently, STAT3 mutations have been shown to occur in approximately 40% of patients with T-LGL leukemia.
Treatment of LGL leukemia patients with immunosuppressive agents such as low-dose methotrexate, cyclophosphamide or cyclosporine has led to an overall response rate of approximately 50% in retrospective studies. Our recently conducted Eastern Cooperative Oncology Group trial was the first prospective clinical trial in LGL leukemia, demonstrating a 39% response rate to methotrexate as initial therapy. Treatment with an anti-CD52 antibody (alemtuzumab) showed a response rate in four out of eight patients with refractory LGL leukemia. Clearly, there is an urgent need for development of better therapeutics. Other potential targets include FasL, PDGFR, STAT3, NF-κB, the sphingolipid rheostat, MAPK and PI3K/AKT signaling. This study evaluates therapy targeting the IL-15 receptor.
IL-15 is a member of the IL-2 family that regulates T- and NK-cell activation and proliferation. IL-15 signals through a heterotrimeric receptor to activate downstream signals including JAK/STAT and MAPK signaling. Monocytes and dendritic cells express the IL-15-specific subunit (IL15Ra) and secrete IL-15 locally. IL15Ra presents IL-15 to the other two receptor subunits, IL-2/IL-15Rβ (specific to IL-2 and IL-15) and g-c common subunit (shared among multiple interleukins), which are expressed on NK and cytotoxic T cells. The presentation of IL-15 from one receptor subunit on one cell type to the two other receptor subunits is known as trans presentation of IL15. Interestingly, it has recently been identified that in some patients with T-LGL leukemia, IL-15Ra is expressed in the T-LGL cells, leading to all three subunits being expressed in cis. Dysregulated IL-15 has been reported in patients with autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis and Celiac's disease), as well as HTLV-1 infection.
Abstract and Introduction
Abstract
Evaluation of: Waldmann TA, Conlon KC, Stewart DM et al. Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-β-1 mAb in patients with T-cell large granular lymphocytic leukemia. Blood 121(3), 476–484 (2013).
IL-15 is a cytokine that stimulates the proliferation of NK and T cells. Previous studies have shown that IL-15 is critical to the induction of T-cell large granular lymphocyte (T-LGL) leukemia. A Phase I trial of a humanized antibody (Hu-Mikβ1) to the IL2/IL15Rβ receptor, expressed on T-LGL, is explored in this trial to evaluate the safety, pharmacokinetics, specificity and clinical efficacy of Hu-Mikβ1. The study demonstrated no toxicity and favorable saturation of IL2/IL15Rβ receptor, but no clinical efficacy in this Phase I study.
Introduction
Large granular lymphocyte (LGL) leukemia is a class of rare lymphoproliferative disorders. The T-cell form (T-LGL) is CD3 and is classified by the WHO as a mature peripheral T-cell neoplasm. T-LGL generally runs an indolent clinical course and frequently presents with neutropenia, anemia and rheumatoid arthritis. A computational systems biology approach was previously used to identify IL-15 and PDGF as master regulators of leukemic LGL survival, demonstrating that dysregulation of these cytokines could explain all known molecular features of LGL leukemia. Furthermore, dysfunctional activation-induced cell death due to chronic viral infection or antigen stimulation is thought to be critical to disease pathogenesis. Multiple survival pathways are known to be dysregulated in LGL leukemia including JAK/STAT, sphingolipid, MAPK and PI3K/AKT signaling. More recently, STAT3 mutations have been shown to occur in approximately 40% of patients with T-LGL leukemia.
Treatment of LGL leukemia patients with immunosuppressive agents such as low-dose methotrexate, cyclophosphamide or cyclosporine has led to an overall response rate of approximately 50% in retrospective studies. Our recently conducted Eastern Cooperative Oncology Group trial was the first prospective clinical trial in LGL leukemia, demonstrating a 39% response rate to methotrexate as initial therapy. Treatment with an anti-CD52 antibody (alemtuzumab) showed a response rate in four out of eight patients with refractory LGL leukemia. Clearly, there is an urgent need for development of better therapeutics. Other potential targets include FasL, PDGFR, STAT3, NF-κB, the sphingolipid rheostat, MAPK and PI3K/AKT signaling. This study evaluates therapy targeting the IL-15 receptor.
IL-15 is a member of the IL-2 family that regulates T- and NK-cell activation and proliferation. IL-15 signals through a heterotrimeric receptor to activate downstream signals including JAK/STAT and MAPK signaling. Monocytes and dendritic cells express the IL-15-specific subunit (IL15Ra) and secrete IL-15 locally. IL15Ra presents IL-15 to the other two receptor subunits, IL-2/IL-15Rβ (specific to IL-2 and IL-15) and g-c common subunit (shared among multiple interleukins), which are expressed on NK and cytotoxic T cells. The presentation of IL-15 from one receptor subunit on one cell type to the two other receptor subunits is known as trans presentation of IL15. Interestingly, it has recently been identified that in some patients with T-LGL leukemia, IL-15Ra is expressed in the T-LGL cells, leading to all three subunits being expressed in cis. Dysregulated IL-15 has been reported in patients with autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis and Celiac's disease), as well as HTLV-1 infection.
Source...