Immunization of Stem Cell Transplant Donors to Enhance Graft-versus-Tumor Effect

点击翻译按钮获取中文摘要

DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. The central hypothesis of this proposal is that breaking tolerance to tumor antigens is more easily accomplished by immunizing healthy donors compared with cancer patients, who may be immunocompromised from the underlying disease or prior treatment. We propose testing a novel therapeutic strategy combining cancer vaccine therapy with reduced-intensity conditioning, allogeneic stem cell transplantation (SCT), with the goal of transferring tumor antigen-specific immunity from stem cell donors to patients with myeloma to reduce the risk of relapse. This strategy is based on our previous preclinical and clinical studies demonstrating proof of principle in patients with multiple myeloma. Specifically, under an approved FDA Investigational New Drug application, SCT donors were immunized with a safe, well-defined tumor vaccine, consisting of highly purified myeloma-derived idiotype protein. Direct transfer of myeloma idiotype-specific T-cell immunity from donor to recipient was observed after myeloablative bone marrow transplantation and was associated with favorable long-term survival. In this project, we will determine whether antigen-specific immunity, induced in the stem cell donor, can be passively transferred to the allogeneic SCT recipient (Specific aim 1) and determine the fine specificity, frequency, phenotype, and effector function of adoptively transferred, idiotype-specific T cells (Specific aim 2). The higher T-cell content in the peripheral blood stem cell grafts is likely to enhance the transfer of idiotype-specific T cells following donor immunization. Furthermore, non-myeloablative conditioning may reduce the transplant- related mortality, improving the overall success of this novel treatment. The long-term goal of this project is to transfer highly enriched populations of idiotype-specific T cells from donor to recipient (i.e., educated donor lymphocyte infusions), which may enhance the antitumor effect of the allograft without exacerbating graft-versus-host disease and thereby reduce the risk of relapse of myeloma. PERFORMANCE SITE(S) (organization, city, state) The University of Texas M. D. Anderson Cancer Center Houston, Texas KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Kwak, Larry W. LARRY_KWAK M. D. Anderson Principal Investigator Giralt, Sergio SGIRALT M. D. Anderson Co-Investigator Cha, Soung-Chul SOUNGCHA M. D. Anderson Research Instructor To be named M. D. Anderson Research Assistant II Palmer, J. Lynn JLPALMER M. D. Anderson Statistician OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells No Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://stemcells.nih.gov/registry/index.asp. Use continuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line Disclosure Permission Statement. Applicable to SBIR/STTR Only. See SBIR/STTR instructions. Yes No