Reinvigorating T and NK cells in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a malignancy of CD19⁺CD5⁺ B cells that, despite the development of new targeted drugs is considered to be incurable. The only treatment that has shown curative potential in CLL patients is allogeneic stem cell transplantation (allo-SCT). Although most CLL patients are too frail for allo-SCT, this indicates the immune system harbors the potential to cure CLL patients. Novel immunotherapeutic strategies have been developed that aim to recruit immune cells to treat cancer patients. In CLL, most of these strategies show disappointing results, which is probably related to the immunosuppressive tumor micro-environment. This thesis investigates the functionality of two important effector cells for immunotherapy, T cells and natural killer (NK) cells, in both healthy individuals and CLL patients, in order to determine their potential use for immunotherapy in CLL. We show that NK cells of CLL patients are hypo-responsive, but can still be induced to initiate anti-tumor responses via ADCC mechanisms. By comparing virus-specific T cell populations, we were able to unravel the dysfunctional phenotype of T cells in CLL patients in detail, thereby defining what restrictions T cells may have when being used in immunotherapeutic strategies. Finally, we also studied the effects of small molecule inhibitors both in vitro and in vivo in order to analyze their effects on non-malignant lymphocytes. We find that many immunomodulatory effects of CLL on the immune system are reversible, which indicates that successful first-line treatment of CLL patients may open the door for immunotherapy as a consolidation treatment.