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

干细胞移植供体的免疫增强移植物抗肿瘤效应

• 批准号: 7491055
• 负责人: LARRY W KWAK
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491055
• 关键词: Allogenic; Allografting; Antigens; Authorization documentation; Bone Marrow Transplantation; Cancer Patient; Cancer Vaccines; Cell Line; Cities; Clinical Research; Confidential Information; Disclosure; Disease; Donor Lymphocyte Infusion; Donor person; Frequencies; Funding; Goals; Graft-Versus-Tumor Induction; Health; Human Resources; Immunity; Immunization; Immunocompromised Host; Immunoglobulin Idiotypes; Instruction; Investigational New Drug Application; Language; Last Name; Malignant Neoplasms; Methods; Mission; Multiple Myeloma; Names; Numbers; Patients; Peripheral Blood Stem Cell; Phenotype; Population; Principal Investigator; Proteins; Public Health; Registries; Relapse; Research; Research Design; Research Personnel; Risk; Role; Specificity; Stem cell transplant; Stem cells; T-Lymphocyte; Techniques; Testing; Texas; Time; Transplantation; Tumor Antigens; United States Food and Drug Administration; University of Texas M D Anderson Cancer Center; Vaccination; base; conditioning; graft vs host disease; human embryonic stem cell; improved; instructor; mortality; novel; novel therapeutics; performance site; pre-clinical; success

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

描述：参见说明。说明申请的广泛、长期目标和具体目标，并提及 该项目（即，与原子能机构的使命相关）。简要描述研究设计和实现这些目标的方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句话，用通俗的语言描述这项研究与公共卫生的相关性。如果申请得到资助， 这样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空间 提供了 该建议的中心假设是，打破对肿瘤抗原的耐受性更容易 通过免疫健康捐赠者与癌症患者相比， 基础疾病或既往治疗导致的免疫功能低下。我们建议测试一种新的治疗方法 癌症疫苗治疗与低强度预处理、同种异体干细胞联合策略 干细胞移植（SCT），目的是将肿瘤抗原特异性免疫从干细胞供体转移到 骨髓瘤患者，以降低复发的风险。这一策略是基于我们之前的临床前和 在多发性骨髓瘤患者中证明原理的临床研究。具体而言，根据 在FDA批准的研究性新药申请中，SCT供体使用安全、定义明确的 肿瘤疫苗，由高度纯化的骨髓瘤衍生的独特型蛋白组成。骨髓瘤直接转移 清髓性骨髓移植后，观察到供者对受者的独特型特异性T细胞免疫 移植，并与良好的长期生存。在这个项目中，我们将确定 在干细胞供体中诱导的抗原特异性免疫是否可以被动地转移到 异基因SCT受体（具体目标1），并确定精细的特异性，频率，表型， 过继转移的独特型特异性T细胞的效应子功能（特异性目的2）。较高的T细胞 外周血干细胞移植物中的含量可能会增强特异型T细胞的转移 捐赠者免疫后。此外，非清髓性预处理可能会减少移植- 相关死亡率，提高了这种新型治疗的总体成功率。该项目的长期目标是 为了将高度富集的独特型特异性T细胞群从供体转移到受体（即，教育 供体淋巴细胞输注），这可能会增强同种异体移植物的抗肿瘤作用，而不会加剧 移植物抗宿主病，从而降低骨髓瘤复发的风险。 履约地点（组织、城市、州） 德克萨斯大学M. D.安德森癌症中心 德克萨斯州休斯顿 关键人员。参见说明。根据需要使用续页，以下列格式提供所需信息。 从首席研究员开始。按字母顺序列出所有其他关键人员，姓在前。 名称eRA Commons用户名组织在项目中的角色 作者：Larry W. LARRY_KWAK M. D.安德森主要研究者 塞尔吉奥·斯吉拉尔特·吉拉尔特D.安德森合作研究者 车成哲D.安德森研究讲师 被命名为M。D.安德森研究助理II 作者：J. Palmer，林恩JLPALMER M. D.安德森斯塔奇安 其他重要贡献者 名称组织在项目中的角色 人类胚胎干细胞的分类 如拟进行的项目涉及人类胚胎干细胞，请在以下列表中列出特定细胞系的注册号： http://stemcells.nih.gov/registry/index.asp.根据需要使用续页。 如果此时无法引用特定的行，请包括一个声明，说明将使用注册表中的一行。 细胞系 披露许可声明。仅适用于SBIR/STTR。参见SBIR/STTR说明。是否