T cell redirection therapeutics such as a bispecific antibodies and chimeric antigen receptor T cells (CAR T) have shown clinical relevance for hematological malignancies with the recent approvals of blinatumomab and tisagenlecleucel. Hematological malignancies, including acute myeloid leukemia (AML), originate in the bone marrow (BM). Dysfunctions in the AML BM are immune-suppressive and contribute to resistance, compared to healthy BM. Previous studies have shown that AML cells are protected against chemotherapeutic and immune-based therapies when they are co-cultured on BM stromal cells. To evaluate the protective effect of BM stromal cells, we utilized a bispecific antibody targeting both CD123 (AML cells) and CD3 (T cells) with AML cells grown in co-culture with BM stromal cells. We observed that the cytotoxic activity of our CD123xCD3 bispecific antibody was inhibited with multiple BM stromal cell types. Inhibition of the CD44 receptor with either a neutralizing antibody or a knock-out (KO) using clustered regularly interspaced short palindromic repeats (CRISPR) technology on both AML and stromal cells restored the activity of our CD123xCD3 bispecific antibody. Combination of anti-CD44 agents with T cell redirection agents may be a rational approach to improve their efficacy and provide deeper responses.
|Advisor:||Pape-Zambito, Dana, Gaudet, François|
|Commitee:||Peethambaran, Bela, Klase, Zachary, Kalota, Anna|
|School:||University of the Sciences in Philadelphia|
|Department:||Cell & Molecular Biology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 82/10(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Molecular biology, Biology|
|Keywords:||Acute Myeloid Leukemia, Bispecific antibody, Bone marrow stroma, T cells|
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