Treating Acute Myeloid Leukemia with Novel Antibody-Based Therapies
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Date
2019
Publication Type
Doctoral Thesis
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yes
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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.
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Examiner: Neri, Dario
Examiner : Detmar, Michael
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Publisher
ETH Zurich
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Subject
Acute myeloid leukemia (AML); Antibodies; Immunotherapy; Hematology
Organisational unit
03463 - Neri, Dario (ehemalig) / Neri, Dario (former)