The Chronic Lymphocytic Leukemia (CLL) Microenvironment and Novel Targeted Therapies

Abstract

Activation of the B-cell receptor (BCR), and subsequent signalling via the Bruton's tyrosine kinase (BTK), phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK), plays a significant role in the pathogenesis of CLL. This thesis aimed to better understand the role of the CLL microenvironment and to investigate novel treatment strategies for targeting CLL cells in the lymph nodes or bone marrow. We demonstrated using the DotScan cluster of differentiation (CD) antibody microarray, that immunophenotypic changes induced on CLL cells by co-culture with fibroblasts expressing the CD40 ligand can be blocked by ibrutinib or idelalisib. These data provide insight on the mechanisms underlying the lymphocytosis observed in patients treated with these agents. We demonstrated that as a single agent the MEK1/2 inhibitor, binimetinib was effective against CLL cells under certain in vitro conditions and that the drug was effective and synergistic with the AKT inhibitor, MK2206, but not idelalisib. These data suggest that this combination of drugs may represent a novel therapeutic option for CLL effective against CLL cells in the tumour microenvironment. Next, we demonstrated efficacy of the dual PI3K/PIM inhibitor, IBL-202 and showed high synergy with the Bcl-2 inhibitor, venetoclax against CLL cells under conditions that mimic the tumour microenvironment and against a TP53 knock-out cell line we derived from the OSU-CLL cell line using the CRISPR-Cas9 system. This combination was synergistic in terms of apoptosis and inhibition of both the proliferative and migratory capacities of CLL cells. These data suggest that IBL-202 in combination with venetoclax may be an effective treatment option for high risk CLL disease. Collectively, the data presented highlight several pathways and novel drugs that may contribute to the development of therapeutic strategies for CLL patients.