Table 1.
Therapies targeting cytokine signaling in Large Granular Lymphocytic Leukemia.
| Therapeutic agent | Mechanism/findings | Reference |
|---|---|---|
| Agents tested against LGLL in vivo | ||
| Hu-Mikβ1 | Anti-CD122 (shared IL-2 and IL-15 receptor β-chain) monoclonal antibody. Blocks trans presentation of IL-15 to T cells. In a phase I study in LGLL, the drug was safe but showed no clinical efficacy. | (80) |
| BNZ-1 | Multi-cytokine inhibitor that prevents IL-2, IL-9, and IL-15 from interacting with the gamma receptor subunit CD132. Wang et al. (81) demonstrated that treating T-LGLL cell lines and primary patient samples with BNZ-1 led to reduced tumor cell viability, decreased downstream signaling, and increased apoptosis. Additionally, Brammer et al. (83) showed apoptosis of LGLL cells in patients treated with BNZ-1 within 24 h of treatment. A phase I/II clinical trial (NCT03239392) showed a 90% decline in T and NK cells by day 15 of treatment (82). | (81–83) |
| 5-azacytidine | Hypomethylating agent: treatment of the LGLL cell line MOTN-1 cells with 5-azacytidine resulted in decreased IL-15 expression; implicating IL-15 promoter hypermethylation as a key driver of IL-15 induced LGLL. Decreasing IL-15 production by demethylating the promoter is being explored in a phase I clinical trial (NCT05141682) evaluating an oral 5-azacytidine formulation (CC-486) in patients with LGLL. | (71) |
| Agents tested against LGLL in vitro | ||
| Siltuximab and tocilizumab | Anti-IL-6 and anti-IL-6R, monoclonal antibodies currently approved for treatment of rheumatoid arthritis by inhibiting JAK pathway signaling. In vitro anti-IL-6 antibody treatment of LGLL patients’ PBMCs led to malignant cell apoptosis (12). | (12, 84) |
| Agents of interest in LGLL | ||
| Imatinib mesylate (STI-571) | A receptor tyrosine kinase inhibitor that can target PDGF receptors. | (85) |
| Secukinumab and ixekizumab | Anti-IL-17 monoclonal antibodies that prevent IL-17 receptor binding and downstream JAK/STAT and NFkB signaling. Currently, FDA-approved for ankylosing spondylitis and psoriatic arthritis treatment. | (86) |
| Risankizumab | Anti-IL-23 humanized monoclonal antibody binds the p19 subunit of IL-23 to block signaling. Currently, FDA-approved for plaque psoriasis treatment. | (87) |
LGLL, large granular lymphocytic leukemia; IL, interleukin; PBMCs, peripheral blood mononuclear cells; CML, chronic myelogenous leukemia; FDA, Food and Drug Administration.