Professor and Chief
Nohl Division of Hematology and Center for the Study of Blood Diseases; Bloom Chair in Lymphoma Research; Associate Director for Translational Research USC/Norris Cancer Center
Keck School of Medicine
- Chimeric Antigen Receptor based Cellular Therapies
- Stem Cell Microtransplantation for treatment of blood cancers
- NF-kappaB signaling
- Viral oncogenesis
- Drug development
- Animal models of hematologic malignancies
Research OverviewChimeric antigen receptors (CAR) are artificial T cell receptors that are under investigation as a therapy for cancer, using a technique called adoptive cell transfer. Hematopoietic cells are removed from a patient and modified so that they express receptors that recognize proteins that are specific to the particular form of cancer. The cells, which can then recognize and kill the cancer cells, are reintroduced into the patient. One of the problems identified with the use of CAR modified cells is that these cells are short-lived when introduced back into the patient and have limited proliferative potential. The purpose of this project is to enhance the efficacy of CAR-modified cells and to develop CAR cells targeting different hematologic malignancies.
A second project in the laboratory relates to stem cell microtransplantation. Microtransplantation involves administration of lower (standard) doses of chemotherapy followed by infusion of stem cells from a donor. Unlike the conventional Bone Marrow Transplantation (BMT), the donor for microtransplantation does not need to be fully matched to the patient. As such, any suitable immediate family member (e.g. brother, sister, father, mother, son or a daughter) can serve as a donor, thereby considerably expanding the pool of eligible donors and potentially making this therapy available to most patients with Acute Leukemia. Furthermore, there is no risk of Graft vs Host Disease (GVHD), a potentially fatal complication of conventional BMT, in the case of microtransplantation. As a result, microtransplantation does not require the use of immunosuppressive drugs, thereby sparing the patients morbidity and mortality from infectious complications associated with long-term immunosuppression. The purpose of this project is to identify the mechanisms responsible for the enhanced Graft vs Leukemia effect without GVHD in microtransplantation using a mouse model of leukemia and lymphoma.
Finally, my laboratory is interested in understanding the molecular basis of human cancer and translating these insights into clinical practice. One of the major areas of my research interest is the role of a protein encoded by the human herpesvirus 8 (HHV8 or Kaposis sarcoma associated herpes virus) in the pathogenesis of primary effusion lymphomas and related lymphoproliferative disorders. We demonstrated that this protein, designated K13 vFLIP (viral FLICE Inhibitory Protein), can activate the classical and alternate NF-kappaB pathways by interacting with a multi-subunit kinase (IKK) complex. In subsequent studies, we demonstrated that K13 vFLIP can induce cellular survival, proliferation, transformation and induce lymphomas in a transgenic mouse. Our future plans include further characterization of the mechanism of NF-kB activation by K13, delineation of its biological effects, isolation of small molecule compounds that can block the activation of NF-kappaB pathway by K13 and testing them in pre-clinical models and, subsequently, in patients with HHV8-associated malignancies. My laboratory is also interested in translating the insights gained from their studies of HHV8-associated lymphomas to other hematological malignancies, such as multiple myeloma and non-Hodgkin lymphomas, in which NF-kappaB pathway has been implicated.