Immunotherapy of Plasma Cell Dyscrasias
Our research has focused on understanding the genetic basis and pathogenesis of Waldenström's macroglobulinemia (WM) and on developing therapeutics for this B cell malignancy, which affects 6,000 to 10,000 patients a year in the United States. As part of our efforts, we recently characterized a familial form of WM, describing its incidence and clinical, laboratory, and cytogenetic characteristics. Importantly, we also demonstrated differing patterns of gene losses among WM patients, including the genes BLIMP1, PAX5, and members of the unfolded protein response (UPR), including XBP1 and IRE1a. Our studies have also provided important insight into the pathogenesis of WM by demonstrating a role for the excess mast cells found in the bone marrow of patients with WM. We recently demonstrated that mast cells serve as potent inducers of growth and enhancers of tumor cell survival through a host of mediators including CD40 ligand, a proliferation-inducing ligand (APRIL), B lymphocyte stimulator (B-LYS) protein, platelet-derived growth factor (PDGF alpha), and vascular endothelial growth factor (VEGF). At the same time, we showed that WM tumor cells induce expression of several of these ligands through soluble CD27. These discoveries have helped in the development of novel therapeutic strategies targeting mast cells and mast cell-tumor cell interactions in WM. In other studies, we have sought to advance the therapy for WM by conducting clinical trials utilizing monoclonal antibodies as single agents and in combination with nucleoside analogs, cytotoxic agents, and immunomodulating agents, as well as phosphodiesterase and proteasome inhibitors. As part of this work, our lab has defined the mechanisms of action and resistance for these agents, specifically the role of Fc gamma receptor polymorphisms in predicting clinical responses to the CD20-directed monoclonal antibody rituximab. This work has resulted in several novel agents for treating WM, and ongoing clinical trials are evaluating their efficacy and toxicity.