Laboratory of Molecular Immunology and Immunotherapy
Blood Research Institute, Blood Center of Wisconsin
Our laboratory studies the basic biology and clinical utilization of natural killer (NK) cells. NK cells are a unique white blood cell that accounts for approximately 5-10% of circulating lymphocytes. While T cells need specific antigens to activate function, many malignant cells find ways to evade T-cell mediated death through down-regulation of these antigens. NK cells are naturally designed to target and kill malignant or dysregulated cells through a complex system of recognizing these cells. The following are the major areas of our focus:
Basic Biology of NK Cell Immunotherapy
The main focus of our laboratory is to evaluate the elaborate signaling mechanisms that drive how NK cells work. Hundreds of signaling molecules take part in transducing membrane-proximal events into meaningful cellular functions. Through a multitude of murine knock-out models, we can specifically test the role of each protein in this context. By investigating these pathways, our group has expanded knowledge of NK cell basic immunobiology.
Clinical and Translational Work in NK Cell-Mediated Immunotherapy
NK cells hold significant promise in the formulations of novel cellular immunotherapies targeted to chemo-resistant/relapsing malignant hematopoietic and solid tumors. Recent scientific breakthroughs have helped to formulate successful Chimeric Antigen Receptor (CAR)-based cellular immunotherapy, which is now FDA-approved for the treatment of B-cell precursor ALL that is refractory or in second or later relapse. However, CAR-mediated therapy can also cause a significant side effect called, 'cytokine-release syndrome' (CRS), a potentially fatal condition in two-thirds of patients due to uncontrolled inflammation. Formulations of novel methods that regulate inflammation are of high clinical relevance and are central to prevent CRS and improve the safety of CAR therapy.
Our current work focuses on generating NK cell-based novel immunotherapies. Our clinical group headed by Dr. Monica Thakar currently offers an un-manipulated NK cell-based immunotherapy to cancer patients. She employs a cellular and adoptive immunotherapy strategy that incorporates hematopoietic cell transplantation (HCT) followed by the infusion of donor-derived NK cells into cancer patients. Clinical grade NK cells are manufactured under FDA-approved IND BB 13794 (Dr. Thakar) and infused into the patients. This therapy is being offered at the Children’s Hospital of Wisconsin and Froedtert Hospital. In addition, we are interested in defining the precise molecular mechanisms by which anti-tumor cytotoxicity and induction of inflammation are individually regulated in NK and T cells. This molecular blueprint is central to the success of the CAR-mediated clinical applications. Our group has identified a unique Fyn-ADAP-Carma1 signaling pathway that is exclusively responsible for the production of inflammatory cytokines, not anti-tumor cytotoxicity (61/866,348; 8/15/2013). We are currently working to engineer a ‘CRS-free-CAR’ therapy.