New Therapeutic Approaches for Cell Growth Inhibition of Acute Myeloid & Lymphoblastic Leukemia

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Dokumentart: PhDThesis
Date: 2019-06-21
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Handgretinger, Rupert (Prof. Dr.)
Day of Oral Examination: 2019-01-28
DDC Classifikation: 500 - Natural sciences and mathematics
Keywords: Leukämie
Other Keywords:
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Leukemia is a severe blood cell malignancy which is characterized by a high number of abnormal immature white blood cells, so-called leukemic blasts. Starting from the bone marrow, the infiltration into several organs like spleen, liver and lymph nodes leads to severe bleeding problems due to disseminated intravascular coagulation and thrombocytopenia as well as to increased risk of infections due to a lack of mature blood cells. Despite enormous improvement in cancer cell therapy, especially in targeted therapy strategies over the last decades, the two subtypes acute myeloid (AML) and acute lymphoblastic leukemia (ALL) are still life-threatening diseases for children and adults. Therefore, new therapeutic approaches for AML and ALL are urgently needed. The goal of the study is to establish a pharmacological-based therapy for AML and a CAR T cell-based approach for ALL. Since successful therapeutic approaches for AML are still limited due to the high heterogeneity of AML subtypes, in the present study the combination of arsenic trioxide (ATO) and granulocyte-colony stimulating factor (G-CSF) was considered as a potential new pharmacological therapeutic approach for AML. The in vitro studies and the in vivo observations in a xenotransplantation mouse model shown in this study demonstrated that the combination of ATO and G-CSF has a synergistic anti-leukemic effect on AML cells potentially via a G-CSF-mediated upregulation of the main ATO transporter AQP9. Even G-CSF as a single agent displayed an anti-leukemic effectiveness in vivo rendering G-CSF to an important adjuvant in future AML therapy. Despite the massive progress in targeted ALL therapy by introduction of chimeric antigen receptor (CAR) T cell therapy, severe therapy-associated complications like cytokine release syndrome and ‘on target off tumor’ toxicities demand further optimization of CAR T cell therapy. For that, bispecific CAR T cells as well as universal adapter anti-biotin CAR T cells are promising tools and need to be validated for their efficacy and specificity in leukemia therapy. Both methods were tested in this study and demonstrated good effectiveness in killing B cell-ALLs in vitro and in vivo. Bispecific CAR T cells seem to be a good approach to prevent specific escape strategies of leukemic blasts during therapy like antigen loss, while the modularity of the adapter anti-biotin CAR T cells allows to target any antigen which is accessible to a biotinylated antibody. Therefore, adapter CAR T cells might be the future method of choice for targeting a wide range of tumors. In conclusion, two therapeutic approaches for two types of acute leukemia resulted in a therapeutic success. The high heterogeneity among acute leukemia requires a development of a wide spectrum of treatment possibilities.

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