Antigen Specific Immunotherapy with Transduced HSC

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DESCRIPTION (provided by applicant): The goal of this project is to investigate the utility of bone marrow transplant (BMT) with gene modified BM to induce potent anti-tumor immunity. A major focus of cancer immunotherapy is to develop strategies to induce T cell responses through efficient presentation of tumor antigens by dendritic cells (DCs). Current vaccination strategies are limited in their ability to efficiently load DCs in vivo. Ex vivo generated DCs can be efficiently loaded, but after re-injection, few DCs traffic to secondary lymphoid organs, which are the critical sites for antigen presentation to T cells. To enhance the efficiency and durability of antigen presentation by DCs, we transduced hematopoietic stem cells (HSC) with a lentiviral vector encoding a model tumor antigen, then transplanted the modified cells. Our results showed high-level expression of a transgene by DCs in lymphoid organs. The combination of bone marrow-transplant using antigen expressing HSC and systemic agents that activate DCs along with mature donor lymphocyte infusions resulted in dramatic expansion and activation of antigen specific T cells. This tripartite therapy provided potent antigen specific immunotherapy of an aggressive established murine lymphoma. In this application, we are proposing to investigate the mechanism and kinetics of the immune response to the tumor, selective expression of the tumor Ag by regulatable vectors, and optimization of the treatment strategy. Specifically, we will: (1) examine the T cell immune responses in mice receiving Ag-transduced bone marrow stem/progenitor cells (HSCs), using HA as a model tumor Ag; (2) investigate combinations of molecules for in vivo activation of DCs and T cell priming subsequent to HSC transduction/transplantation, and develop DC specific and pharmacologically regulatable vectors to enhance immune responsiveness to antigen; (3) determine the efficacy of tumor Ag expression in the BM for myeloablative and nonmyeloablative allogeneic BMT; and (4) determine whether transplantation of Ag transduced BM will be effective against solid tumors.