Discovery beyond the void: Energizing T cells in chronic lymphocytic leukemia

In the last decade, efficacy of treatment of chronic lymphocytic leukemia (CLL) has improved considerably. Highly effective targeted therapies such as ibrutinib and venetoclax have been developed and replaced chemoimmunotherapy as first-line treatment for CLL. However, these targeted therapies are not curative. CAR-T cell therapy for the treatment of hematological malignancies has curative potential, but CLL patients treated with CAR-T cells show poor responses. The current dogma is that exhaustion of T cells in CLL is to blame for CAR-T cell inefficacy. Since CAR-T cell therapy is a single dose therapy and has the potential to be curative, it is worthwhile to investigate and invent novel methods to increase its efficacy in CLL. Therefore this thesis focused on identifying the mechanism of T-cell exhaustion in CLL, whether this is reversible, and how we use this information to improve existing autologous based immunotherapies such as CAR-T cell therapy. In in this manuscript it is described that T cells in CLL patients are functionally and metabolically impaired. However, T cells in CLL are not terminally exhausted. In the final chapters of this thesis we present multiple methods to reverse T cell dysfunction in CLL, creating new possibilities to improve autologous based therapies in CLL.