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Title: New approaches to the management of mantle cell lymphoma
Author: Furtado, Michelle V.
ISNI:       0000 0004 6057 9632
Awarding Body: University of Plymouth
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2016
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Mantle cell lymphoma is an incurable disease that generally exhibits a poor prognosis. It is now recognised that there is a wide spectrum of MCL disease behaviour with a minority of patients exhibiting indolent disease behaviour which ea rr be simply monitored whilst the majority of patients have multiple disease relapses requiring therapy. The optimal treatment of second relapse and beyond is not known and established therapies such as proteasome inhibition and immunomodulatory agents are beginning to be recognised as useful in the management of MCL. This thesis presents the results of a study demonstrating the potential efficacy of using serum free light chains (sFLCs) as a new biomarker of MCL disease behaviour as well as two clinical trials exploring new treatments for relapsed or refractory MCL. The first of these clinical trials demonstrates an improvement in overall survival of patients treated with the addition of the proteasome inhibitor bortezomib to standard CHOP chemotherapy compared to those treated with CHOP alone. The second trial, of the novel anti-CD20 antibody ofatumumab as monotherapy for MeL was halted early due a low overall response rate of 8.3% but highlighted potential administration changes and side effects to be aware of if this drug is to be utilised in NHL in th-e future. It is unclear whether the different MCL disease behaviours will all respond in the same way to treatments and this thesis also contains pre-clinical work comparing the relative activities of the new anti-CD20 antibodies, ofatumumab and GA 101 (obinutuzumab) to rituximab on cells representing a spectrum of MCL proliferation rates and CD20 expression. It also investigates the potential modulation of CD20 from the MCL cell surface by exposure to these antibodies and to the immunomodulatory drug lenalidomide which has demonstrated efficacy as MCL treatment. Ofatumumab is superior to rituximab at inducing complement dependent cytotoxicity for an MCL disease behaviours. GA 101 is superior to the other antibodies at inducing antibody-dependent cellular cytotoxicity and a marked direct cytotoxic effect. More indolent MCL disease behaviour appears to resist this effect, possibly due to an unusual ability to internalise and break down the GA101-CD20 complex. Significant modulation of cell surface CD20 is demonstrated exposure to the anti-CD20 antibodies or to lenalidomide. Binding of ofatumumab and rituximab to MCL cells induces internalisation of the CD20-antibody comp1exes with a significant loss of total CD20 from the cells, potentially explaining why rituximab is less effi-cacious in MCL as in other non-Hodqkins lymphoma subtypes .. Lenalidomide is demonstrated to downregulate cell surface CD20 and induce 'capping' of the CD20 protein at the poles of the cells in -30% of cells exposed to it. This may have implications for the future scheduling of drugs if immunomodulatory agents are to be combined with anti-CD20 antibodies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available