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dc.contributor.author
Kiefer, Jonathan D.
dc.contributor.supervisor
Neri, Dario
dc.contributor.supervisor
Detmar, Michael
dc.date.accessioned
2020-07-03T10:09:37Z
dc.date.available
2020-06-12T13:31:48Z
dc.date.available
2020-06-15T07:10:08Z
dc.date.available
2020-07-03T10:09:37Z
dc.date.issued
2019
dc.identifier.uri
http://hdl.handle.net/20.500.11850/420129
dc.identifier.doi
10.3929/ethz-b-000420129
dc.description.abstract
Acute Myeloid Leukemia (AML) originates from hematopoietic stem and progenitor cells (HSPCs). A minority of AML patients can be cured by intensive induction chemotherapy and subsequent hematopoietic stem cell transplantation (HSCT). Unfortunately, this therapeutic intervention is no option for elderly and unfit patients, which comprise the majority of AML patients. We propose to replace intensive chemotherapeutic regimens with specific disease elimination by immunotherapy. As a target for immunotherapeutic intervention we chose the cell-of-origin antigen CD117. CD117 (c-Kit), which is a surface marker expressed on healthy HSPCs and the majority of malignant AML blast cells, plays a crucial role during hematopoiesis, as well as proliferation and differentiation of the early myleoid compartment. This thesis reports the generation and characterization of three specific therapeutic interventions targeting CD117+ AML blast cells and HSPCs. In one experimental chapter we describe the selection and characterization of novel monoclonal antibodies against murine CD117. These newly generated antibodies were shown to increase the number of early primitive myeloid precursor cells in vivo. In a second experimental chapter we report the generation and characterization of a bispecific antibody targeting human CD117 and CD3 on T cells. The bispecific antibody was able to specifically eliminate CD117-expressing AML blasts in vitro and prevented leukemia engraftment in vivo. A third experimental chapter describes the generation of Chimeric Antigen Receptor (CAR) T-cells targeting human CD117. The genetically engineered T cells were shown to efficiently eliminate CD117-expressing healthy and malignant hematopoietic cells. In a therapeutic setting, the CAR T-cells eradicated human AML in vivo in xenografted immunodeficient mice.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
ETH Zurich
en_US
dc.subject
Acute myeloid leukemia (AML)
en_US
dc.subject
Antibodies
en_US
dc.subject
Immunotherapy
en_US
dc.subject
Hematology
en_US
dc.title
Treating Acute Myeloid Leukemia with Novel Antibody-Based Therapies
en_US
dc.type
Doctoral Thesis
dc.date.published
2020-06-15
ethz.size
249 p.
en_US
ethz.code.ddc
DDC - DDC::6 - Technology, medicine and applied sciences::600 - Technology (applied sciences)
en_US
ethz.identifier.diss
26289
en_US
ethz.publication.place
Zurich
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03463 - Neri, Dario (ehemalig) / Neri, Dario (former)
en_US
ethz.date.deposited
2020-06-12T13:31:57Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Embargoed
en_US
ethz.date.embargoend
2023-06-15
ethz.rosetta.installDate
2020-06-15T07:10:28Z
ethz.rosetta.lastUpdated
2022-03-29T02:34:38Z
ethz.rosetta.versionExported
true
ethz.COinS
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