- Author
-
I. de Weerdt
- Title
- Unraveling immunity in chronic lymphocytic leukemia
- Subtitle
- Therapeutic implications
- Supervisors
-
A.P. Kater
T.D. de Gruijl - Co-supervisors
-
J.J. van der Vliet
- Award date
- 5 June 2020
- Number of pages
- 276
- ISBN
- 9789463759175
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Chronic lymphocytic leukemia (CLL) is the most prevalent hematological malignancy in western countries. In CLL, malignant B cells accumulate in blood, lymph nodes, spleen and bone marrow. The disease course of CLL is diverse, ranging from patients that will remain asymptomatic for over a decade to fatal progression within one to two years. Although the large majority of patients initially responds to chemotherapy, resistance is eventually inevitable. Interaction with immune cells is critical in CLL progression, and leads to activation of signaling pathways that stimulate proliferation and inhibit apoptosis of CLL cells.
This thesis aims to provide a better understanding of such immune interactions, hypothesizing that such knowledge will ultimately translate into improved therapeutic possibilities.
In recent years, therapies that interfere with pro-tumor signaling pathways have been developed, which include inhibitors of pivotal kinases and the inhibitor of anti-apoptotic protein Bcl-2 venetoclax. In the first part of this thesis, the mechanism of action, toxicity and combination regimens of these novel agents are discussed. Additionally, the unintended effects of novel agents on immune cells are investigated in vitro and in vivo.
Immunotherapy represents another promising therapeutic strategy in CLL, in which T cells from the patient are redirected to eradicate leukemic cells. In the second part of this thesis, the anti-leukemic properties and functionality of a subset of T cells termed Vγ9Vδ2-T cells are explored. Finally, the generation of a bispecific antibody is described, which efficiently enhance the elimination of CLL cells by Vγ9Vδ2-T cells. - Note
- Please note that the sections 'Dankwoord' and 'Curriculum Vitae' are not included in the thesis downloads.
- Persistent Identifier
- https://hdl.handle.net/11245.1/106aefd3-dfe7-4ec1-b679-1e759b575b2c
- Downloads
-
Thesis
Front matter
Chapter 1: Introduction
Chapter 2: The biological rationale and clinical efficacy of inhibition of signaling kinases in chronic lymphocytic leukemia
Chapter 3: Incidence and management of toxicity associated with ibrutinib and idelalisib: A practical approach
Chapter 4: Dissection of the effects of JAK and BTK inhibitors on the functionality of healthy and malignant lymphocytes
Chapter 5: Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment
Chapter 6: Combining novel agents in chronic lymphocytic leukemia: Greater than the sum of its parts?
Chapter 7: Innate lymphoid cells are expanded and functionally altered in chronic lymphocytic leukemia
Chapter 8: Improving CLL Vγ9Vδ2-T cell fitness for cellular therapy by ex vivo activation and ibrutinib
Chapter 9: A bispecific VHH deprives chronic lymphocytic leukemia of prosurvival CD40 signaling and promotes Vγ9Vδ2-T cell-mediated antitumor responses
Chapter 10: A bispecific single domain antibody boosts autologous Vγ9Vδ2-T cell responses towards CD1d in chronic lymphocytic leukemia
Chapter 11: Discussion
Summary; Nederlandse samenvatting; List of publications; PhD portfolio
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