The goal of this proposal is to develop a novel hybrid bifunctional cytokine (""""""""fusokine"""""""") to promote immune reconstitution and inhibit graft-versus-host disease (GVHD) in cancer patients undergoing hematopoietic stem cell transplantation. The fusokine, termed Ha7, consists of IL-7 linked to a peptide derived from the alpha chain of hepatocyte growth factor (HGF). To improve stability and extend in vivo half-life each cytokine is fused to the Fc of IgG molecules that were modified to promote the formation of heterodimers during mammalian cell expression. Based on the known properties of IL-7, Ha7 is predicted promote immune reconstitution by stimulating T and B cell lymphopoiesis as well as homeostatic maintenance of mature T cells. The HGF moiety will enhance hematopoiesis, as well as inhibit GVHD in the setting of allogeneic bone marrow transplantation in immunosuppressed cancer patients. Another benefit predicted from the combined treatment with both IL-7 and HGF is the preservation of thymic architecture and function in immunosuppressed cancer patients. In this proposal, stable cell lines secreting high levels of recombinant Ha7 will be produced and the fusokine will be purified for functional studies. Its activity will be studied in vitro for stimulation of T cell functions and HGF activity. Ha7 will be further tested in vivo to evaluate immune reconstitution in immunosuppressed mice given syngeneic bone marrow transplantations (BMT). Ha7 will also be tested in a model of allogeneic BMT in mice that also bear a syngeneic leukemia. In this model, therapeutic efficacy of Ha7 will be demonstrated if it suppresses GVHD while promoting the graft-versus-leukemia effect. This preclinical work will provide the foundation for future development of a novel therapy to restore the immune system and prevent GVHD in cancer patients undergoing stem cell transplantation.
The goal of this project is to develop a novel bifunctional hybrid cytokine for immune reconstitution of cancer patients undergoing stem cell transplantation.