The IL-7 pathway is critical for regulating the number of lymphocytes as has been shown in humans as well as in mice. We and our collaborators recently showed that the IL-7 receptor is mutated in pediatric lymphocytic leukemia, and the mutant receptors drive cell division. We developed a panel of monoclonal antibodies against mutant receptors, all of which also react with normal receptors. These mouse monoclonals have been chimerized with human IgG1 to optimize antibody-dependent cell-mediated cytotoxicity. These monoclonals are effective, as single agents, in treating human leukemia cells transplanted into mice. A clinical trial is being developed together with the Fannin Group and Baylor Medical Center in Houston Texas. Pediatric lymphocytic leukemia patients that relapsed following chemotherapy will be treated with our monoclonal antibodies. This clinical trial is expected to begin within two years. In addition to leukemias, the IL-7 pathway has also been implicated in other neoplasias including lung cancer, and we aim to explore treatment of these other cancers with our monoclonal antibodies. Using a different approach, we recently reported that drugs which block signaling from the IL-7 receptor combined with drugs that block the Ras pathway are effective in killing leukemia cells in vitro and in mice. These drug combinations will be evaluated for treating patients. The same monoclonal antibodies and drugs will also be evaluated in autoimmune diseases. It was previously found by others that a polymorphism in the coding region of IL-7 receptor predisposes to autoimmune diseases. We recently found that this polymorphism regulates the strength of signal by the receptor, offering promise for inhibiting these signals in autoimmunity. Therefore, antagonists of the IL-7 pathway may be effective in autoimmunity, and we are exploring this possibility. While blocking the IL-7 pathway has promise in autoimmunity and cancer, IL-7 itself has therapeutic potential in clinical settings that could benefit from its potent activities in stimulating the immune system. Together with collaborators, we recently reported results of a small clinical trial in sepsis patients, showing that IL-7 effectively rescues immune cells that are severely suppressed. A larger trial in sepsis patients is planned. There is a great need for improved treatment of these patients who suffer high mortality from secondary infections. In another project, together with collaborators at NCI, we developed a new method for delivering IL-7 that is incorporated in a slow-release hydrogel. We are evaluating this material for improving immunotherapy because it greatly improves transfer of immune cells.
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