Biology and Immunotherapy of iNKT Cells

Abstract Project 1 Allogeneic hematopoietic cell transplantation has proven to be a life-saving therapy for a broad range of hematological malignancies, genetic disorders and bone marrow failure states. However, the immunological consequences of graft vs host disease (GVHD) and in patients with malignancies, relapse continue to be major obstacles to the successful outcome of patients. In this Project we will study a rare population of lymphocytes termed invariant natural killer T (iNKT) cells that have a number of properties that make them highly attractive to address these issues. iNKT cells express a unique and invariant T cell receptor that recognizes a non-MHC like molecule CD1d that is expressed on many different hematological malignancies. We have demonstrated that allogeneic and third party iNKT cells have immunoregulatory properties and are capable of suppressing GVHD more potently then regulatory T cells. Further, we have demonstrated that introduction of a CAR into iNKT cells unleashes both direct and indirect mechanisms of cytolytic function. In this Project we will explore both the immunoregulatory and cytolytic function of iNKT cells with the goal of developing a fundamental mechanistic understanding of their function and translating these concepts into early phase clinical trials. This Project interacts with all of the other Projects and Cores of the Program and aims to develop fundamental new concepts and a clinical treatment candidate to address GVHD and disease relapse.