Our immunologists are interested in fundamental principles that regulate adaptive and innate immune responses as well as their implications for pathogenesis and treatment of cancer and autoimmune diseases.
Drs. Yang Liu and Pan Zheng have identified sialoside-based pattern recognition, which involves sialic acid-containing glycans and Siglecs family members, as a critical regulator that discriminates self from nonself in innate immunity. This new concept has important implications not only in treatment of inflammatory diseases, such as sepsis and other infections, as well as graft vs host diseases, but also in pathogenesis of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Multiple clinical trials are either ongoing or being planned to test this new concept in clinical setting.
The other main immunological focus of the team is on the role for mTOR in development and function of both adaptive and immune effector cells. They have established a critical role for mTOR regulation in survival and quiescence of hematopietic stem cells and T lymphocytes. Such quiescence and survival is critical for regulation of T cell function, as its defects leads to lymphopenia and development of autoimmune diseases. The molecular mechanism of mTOR function in hematopoiesis and aging is all being actively pursued.
Cancer immunology focuses on studying the interaction between the immune system and cancer cells. In particular, our investigators seek to take advantage of the fact that the immune system is capable of recognizing cancer specific antigens. Two avenues are being pursued, one seeking to optimize the patients’ own immune system to recognize and subsequently destroy cancer cells, the other seeks to provide a patient with a new immune system (from a donor) capable of destroying cancer cells. Dr. Liu and Zheng’s group are developing new types of cancer vaccine that targets mutated antigens identified in cancer patients. Molecular therapeutics that maintain and enhance anti-tumor T cell immunity are being actively tested in their laboratories.
An important area of our cancer immunology program is tumor-host interaction in tumor microenvironment. Stephan Ladisch, MD,’s laboratory also focuses on characterizing the effect of tumor gangliosides on the biology of human neuroblastoma, specifically the antitumor immune response. This research is based upon the hypothesis that specific gangliosides shed by tumors act as intercellular signaling molecules and protect tumor cells from host destruction. They have found significant shedding and potent immunosuppressive activity of human neuroblastoma tumor gangliosides. They also have shown inhibition of murine antitumor immune responses, identified antigen presenting cells as primary tumor ganglioside targets, and most recently have uncovered a link between tumor gangliosides and the accumulation of immune suppressor cells in the tumor microenvironment. In collaboration with Sasa Radoja, PhD, Dr. Ladisch’s lab uncovered a novel mechanism by which these molecules interfere with the cytotoxic function of lymphocytes that is important for tumor cell destruction.
Most recently, the group has discovered an important role of gangliosides in the tumor microenvironment in enhancing the accumulation and function of host myeloid-derived suppressor cells, a key cell in subverting anti-tumor immune responses.
Leukemia is among the most common childhood malignancies. Current therapy can result in complete remission (CR) in nearly 90 percent of pediatric acute myeloid leukemia (AML). Unfortunately, relapsed AML (rAML) occurs in almost 50% patients within two years of CR. Among them, more than 60 percent succumb to AML within two years of relapse. Novel approaches are therefore needed to address the unmet medical need of rAML. Recent studies suggest that leukemia stem cells (LSC) are highly resistant to conventional chemotherapy and thus likely responsible for relapse. Therefore, therapeutic elimination of LSC may offer new approach for the treatment of rAML. Drs. Liu, Zheng and Wang’s laboratories have recently reported that hypoxia-inducible factor (HIF) 1α is activated in and essential for maintenance of the AML stem cells. Importantly, at doses that have no reported toxicity, Echinomycin, an HIF inhibitor, is effective in eliminating AML stem cells in xenogeneic mouse models and provide effective therapy for mouse rAML caused by mutations frequently found in pediatric AML. Echinomycin has been used in multiple phase I and phase II clinical trials in adult patients with solid tumors, but has not been tested in hematological malignancies. Moreover, due to lack of analytic methods, these trials were performed without pharmacokinetic (PK) information. Nevertheless, these prior clinical trials demonstrated that Echinomycin is well-tolerated even at doses that are 30-50-fold higher than our projected therapeutic doses which are derived from effective doses xenogenic rAML models. Based on these exciting results, Drs. Liu, Reuven Schore,MD, Wang and Zheng have initiated a collaborative project involving investigators at Children’s National Medical Center and the National Cancer Institute to carry out phase I clinical trials for children with relapsed AML. Drs. Wang and Schore are also collaborating to test if the drug is effective for acute lymphocytic leukemia.
To address the issue of cancer genes that are not druggable at the moment, Dr. Han’s laboratory has developed a Drosophila model for human leukemia, in which introduction of mutations in human cancer patients can rapidly induce the development of leukemia. He has further optimized the system to allow high throughput screening for drugs and/or target genes that can be used to treat the leukemia that are not responsive to current therapeutics.
Investigators in this program: