Dr. Pennell's laboratory is investigating novel strategies for immunotherapy, drawing on the immune system's inherent specificity as part of a personalized medicine approach for treating cancer. His team is using the tools of immunology, molecular biology, genetic engineering, and transgenic animals in two research areas that have potentially synergistic applications: the development of DNA-based cancer vaccines; and the development of T-cell chimeric antigen receptors engineered to recognize and bind specific tumor cell-surface antigens, activating T-cell cytotoxicity.Pennell's team developed DNA-based vaccines designed to increase antigen expression on tumor cells, which in turn enables CD8 T-cells to recognize and bind to these tumor cells, activating T-cell cytotoxicity. Initially they used plasmid DNA as a delivery vehicle. Because few cells tend to take up the new DNA plus the fact that expression of the DNA-encoded protein is transient, the therapeutic effects register at a very low level. Recently they turned to using smaller DNA minicircle constructs as delivery vehicles, with notable success. Minicircle DNA confers higher levels of sustained transgenic expression than plasmid DNA upon delivery in an infectious disease model in mice. Pennell and fellow University faculty are now adapting minicircle DNA delivery for cancer vaccine immunotherapy in a mouse model with the long-term goal of developing minicircle-based DNA vaccines to treat human cancer.Pennell's team is coupling its research on DNA vaccines with that in a related field called T-cell chimeric antigen receptors (CARs). Like DNA vaccines, CAR technology is also based on co-opting a patient's own immune system specificity. CARs are genetically engineered receptors introduced into white blood cells, specifically T cells. CARs override the native specificity of the T cell and cause the T cell to become activated when the CAR specifically binds an antigen. An antibody-derived fragment displayed on the outside of the T cell confers CAR specificity; the inside of the CAR receptor contains T cell-derived proteins required for activation. The antibody effects a higher affinity binding than the usual T-cell receptor–major histocompatibility complex (MHC) molecule binding. T cells modified to express antibody-based CARs circumvent MHC restriction and potently kill tumor cells bearing the antigen for which the CAR is specific.CAR-based therapy has shown dramatic success in adoptive immunotherapy trials of patients with acute lymphocytic leukemia (ALL) who are refractory to standard chemotherapy. Pennell's laboratory is developing CAR mouse models to address the side effects of CAR immunotherapy in ALL. The side effects include the depletion of healthy B-cells as well as tumor B-cells, making the patients B-cell aplastic, and the potential massive release of pro-inflammatory cytokines. Pennell and his University colleagues (notably Drs. Bruce Blazar and Mark Osborn in the Department of Pediatrics) are using clinically tested mouse T-cell CARs with human components that recognize the human antibody CD19, which they have engineered to be expressed in mice B-cell tumors. Their goal is to determine the right dose-based balance between achieving anti-tumor effects and avoiding potentially harmful side effects of CAR therapy.
