Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients
- Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Godfrey, Dale , Ritchie, David , Berzins, Stuart
- Date: 2010
- Type: Text , Journal article
- Relation: Leukemia Vol. 24, no. 3 (2010), p. 592-600
- Full Text: false
- Reviewed:
- Description: Myelodysplastic syndrome (MDS) comprises a group of clonal bone marrow disorders characterized by ineffective hematopoiesis and increased predisposition to acute myeloid leukemia. The causes of MDS remain poorly defined, but several studies have reported the NKT cell compartment of patients with MDS is deficient in number and functionally defective. In support of a central role for NKT cells, a pilot clinical study reported that lenalidomide (an approved treatment for MDS) increased NKT cell numbers in patients with MDS, and several in vitro studies showed lenalidomide specifically promoted NKT cell proliferation and cytokine production. We tested this in a much larger study and confirm a moderate in vitro augmentation of some NKT cell functions by lenalidomide, but find no impact on the NKT cell compartment of patients treated with lenalidomide, despite a consistently positive clinical response. We further show that the frequency and cytokine production of NKT cells is normal in patients with MDS before treatment and remains stable throughout 10 months of lenalidomide therapy. Collectively, our data challenge the concept that NKT cell defects contribute to the development of MDS, and show that a clinical response to lenalidomide is not dependent on modulation of NKT cell frequency or function. © 2010 Macmillan Publishers Limited All rights reserved.
Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy
- Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, Kellie , Quach, Hang , Prince, Henry , Harrison, Simon , Godfrey, Dale , Ritchie, David , Berzins, Stuart
- Date: 2014
- Type: Text , Journal article
- Relation: Clinical and Experimental Immunology Vol. 175, no. 1 (2014), p. 49-58
- Full Text: false
- Reviewed:
- Description: The causes of multiple myeloma (MM) remain obscure and there are few known risk factors; however, natural killer T (NKT) cell abnormalities have been reported in patients with MM, and therapeutic targeting of NKT cells is promoted as a potential treatment. We characterized NKT cell defects in treated and untreated patients with MM and determined the impact of lenalidomide therapy on the NKT cell pool. Lenalidomide is an immunomodulatory drug with co-stimulatory effects on NKT cells in vitro and is an approved treatment for MM, although its mode of action in that context is not well defined. We find that patients with relapsed/progressive MM had a marked deficiency in NKT cell numbers. In contrast, newly diagnosed patients had relatively normal NKT cell frequency and function prior to treatment, although a specific NKT cell deficiency emerged after high-dose melphalan and autologous stem cell transplantation (ASCT) regimen. This also impacted NK cells and conventional T cells, but the recovery of NKT cells was considerably delayed, resulting in a prolonged, treatment-induced NKT cell deficit. Longitudinal analysis of individual patients revealed that lenalidomide therapy had no in-vivo impact on NKT cell numbers or cytokine production, either as induction therapy, or as maintenance therapy following ASCT, indicating that its clinical benefits in this setting are independent of NKT cell modulation.