Immunomodulation and immune reconstitution in chronic lymphocytic leukemia

Over the past decade, there have been significant advances in our understanding of the pathogenesis of chronic lymphocytic leukemia (CLL), which has been accompanied by an explosion in treatment options. Although the combination of fludarabine, cyclophosphamide, and rituximab is the current frontline treatment of choice for fit patients, targeted therapies such ibrutinib, idelalisib, and ABT-199 are showing great promise in clinical trials. However, none of these drugs seems curative, and allogeneic hematopoietic stem cell transplantation remains the only strategy that produces durable clinical remissions in otherwise poor-risk disease. Immune reconstitution remains an enticing prospect in CLL, as malignant B cells should be particularly susceptible to a T cell-mediated attack. It has recently been demonstrated that the T-cell defect in CLL can be effectively overcome by both lenalidomide treatment and by adoptive transfer of chimeric antigen receptor T cells. A variety of other immunotherapies are in development, including CLL vaccines, CD40 ligand therapies, and monoclonal antibody immune checkpoint blockade. This review explores the nature of the immune defect in CLL and summarizes the recent developments in the immunotherapeutic field.