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Title: Lenalidomide and the new-generation anti-CD20 antibodies in mantle cell lymphoma
Author: Eve, Heather E.
ISNI:       0000 0004 2736 6889
Awarding Body: Exeter and Plymouth Peninsula Medical School
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2012
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Lenalidomide is a second-generation immunomodulatory drug with clinical activity in mantle cell lymphoma (MCL). In vitro work shows that lenalidomide enhances NK-mediated cytotoxicity against MCL yet the significance of this in vivo remains unproven. Since NK cells are key effectors of antibody-dependent cellular cytotoxicity (ADCC), there is a clear rationale for combining lenalidomide with monoclonal antibodies. However, one concern regarding this is the potential for lenalidomide to downregulate target antigen expression on malignant B Iymphocytes. This thesis presents phase II clinical trial data (EudraCT 2007-005472- 13) confirming the safety, efficacy and immunomodulatory activity of lenalidomide in relapsed/refractory MCL. Using a novel regimen, the benefit of lenalidomide as a low-dose maintenance agent is highlighted. Peripheral T and NK cells increased in responding patients with the NK rise preceded by an initial dip suggesting tumour infiltration. Peripheral Tregs were higher in MCL patients than controls and expanded further following lenalidomide. Bioloqically relevant changes were observed in plasma IL-12p40, IL-7, IL-10, adiponectin and MMP9. A significant correlation between gender and response suggested that female patients were more sensitive to lenalidomide than males. Finally, retrospective analysis of a historical cohort confirmed that thalidomide remains a valid treatment option for MCL patients unsuitable for lenalidomide. The new-generation anti-CD20 antibodies ofatumumab and GA 101 show superiority to rituximab in several B-cell malignancies although data regarding their efficacy in MCL is scarce. Cell culture work using the MCL cell line Granta519 showed ofatumumab was superior to rituximab at inducing complement-dependent cytotoxicity whilst GA 101 was superior to both rituximab and ofatumumab at inducing direct cytotoxicity and ADCC. Combining lenalidomide with these antibodies failed to have any additive cytotoxic effect. Lenalidomide induced significant CD20 downregulation on Granta519 cells. The alternative pan-B cell markers CD19 and, to a lesser extent, CD22 were also downregulated. Thus, if lenalidomide is to be combined with monoclonal antibodies in a clinical setting, sequential administration may be more beneficial than simultaneous administration.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available