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

说明：请参阅说明。说明应用程序的广泛、长期目标和具体目标，并提及与健康相关的 项目(即与该机构使命的相关性)。简明扼要地描述实现这些目标的研究设计和方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句简单明了的话描述这项研究与公共卫生的相关性。如果应用程序得到资助，则此 原样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空格 但前提是。 这一提议的中心假设是，打破对肿瘤抗原的耐受性更容易 与癌症患者相比，健康捐赠者通过免疫来实现，癌症患者可能是 免疫功能因潜在疾病或先前的治疗而受损。我们建议测试一种新的治疗方法 将癌症疫苗治疗与低强度条件处理、异基因干细胞相结合的策略 移植(SCT)，目标是将干细胞捐赠者的肿瘤抗原特异性免疫转移到 减少骨髓瘤患者复发的风险。这一战略是基于我们之前的临床前和 临床研究证明了多发性骨髓瘤患者的原则。具体地说，在 FDA批准的研究新药申请，SCT捐赠者接种了安全、明确的 肿瘤疫苗，由高度纯化的骨髓瘤独特型蛋白组成。骨髓瘤直接转移术 清髓骨髓后供受者的独特型T细胞免疫功能观察 移植，并与良好的长期生存有关。在这个项目中，我们将确定 在干细胞捐献者体内诱导的抗原特异性免疫能否被动地转移到 同种异体SCT受体(特异性目标1)，并确定良好的特异性、频率、表型和 过继转移的独特型特异性T细胞的效应功能(特定目标2)。更高的T细胞 外周血干细胞移植中的含量可能会促进独特型特异性T细胞的转移 在捐赠者免疫后。此外，非清髓性调节可能会减少移植- 相关死亡率，提高了这一新疗法的总体成功。这个项目的长期目标是 将高度丰富的独特型特异性T细胞从供者转移到接受者(即，受过教育的人 供者淋巴细胞输注)，这可以增强同种异体移植物的抗肿瘤效果，而不会加剧 移植物抗宿主病，从而降低骨髓瘤复发的风险。 演出现场(S)(组织、市、州) 德克萨斯大学安德森癌症中心 德克萨斯州休斯顿 关键人员。请参阅说明。根据需要使用续页，以如下所示的格式提供所需信息。 从首席调查员开始。按字母顺序列出所有其他关键人员，姓氏在前。 名称时代共享用户名项目上的组织角色 郭伟强，首席调查员 Sergio SGIRALT M.D.Anderson共同调查员吉拉特 Cha Soung-Chul Songgcha医学博士安德森研究讲师 将被任命为M.D.安德森研究助理II 帕尔默·J·林恩·JLPALMER M.D.安德森·统计学家 其他重要贡献者 命名项目中的组织角色 人类胚胎干细胞否是 如果建议的项目涉及人类胚胎干细胞，请从下面的列表中列出特定细胞系(S)的注册号： Http://stemcells.nih.gov/registry/index.asp.根据需要使用续页。 如果此时不能引用某一特定行，请附上一条声明，说明将使用注册处的一行。 细胞系 披露许可声明。仅适用于SBIR/STTR。请参阅SBIR/STTR说明。是，不是

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