Unraveling immunity in chronic lymphocytic leukemia Therapeutic implications

Chronic lymphocytic leukemia (CLL) is the most prevalent hematological malignancy in western countries. In CLL, malignant B cells accumulate in blood, lymph nodes, spleen and bone marrow. The disease course of CLL is diverse, ranging from patients that will remain asymptomatic for over a decade to fatal progression within one to two years. Although the large majority of patients initially responds to chemotherapy, resistance is eventually inevitable. Interaction with immune cells is critical in CLL progression, and leads to activation of signaling pathways that stimulate proliferation and inhibit apoptosis of CLL cells.
This thesis aims to provide a better understanding of such immune interactions, hypothesizing that such knowledge will ultimately translate into improved therapeutic possibilities.
In recent years, therapies that interfere with pro-tumor signaling pathways have been developed, which include inhibitors of pivotal kinases and the inhibitor of anti-apoptotic protein Bcl-2 venetoclax. In the first part of this thesis, the mechanism of action, toxicity and combination regimens of these novel agents are discussed. Additionally, the unintended effects of novel agents on immune cells are investigated in vitro and in vivo.
Immunotherapy represents another promising therapeutic strategy in CLL, in which T cells from the patient are redirected to eradicate leukemic cells. In the second part of this thesis, the anti-leukemic properties and functionality of a subset of T cells termed Vγ9Vδ2-T cells are explored. Finally, the generation of a bispecific antibody is described, which efficiently enhance the elimination of CLL cells by Vγ9Vδ2-T cells.