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: 7272657
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7272657
• 关键词: Allogenic; Allografting; Antigens; Bone Marrow Transplantation; Cancer Patient; Cancer Vaccines; Clinical Research; Condition; Disease; Donor Lymphocyte Infusion; Donor person; Favorable Clinical Outcome; Frequencies; Future; Goals; Graft-Versus-Tumor Induction; Immune; Immunity; Immunization; Immunocompromised Host; Immunoglobulin Idiotypes; Investigational New Drug Application; Malignant Neoplasms; Measures; Multiple Myeloma; Patients; Peripheral Blood Stem Cell; Phenotype; Population; Proteins; Randomized Controlled Trials; Recurrent disease; Relapse; Risk; Specificity; Stem cell transplant; Stem cells; T-Lymphocyte; Testing; Time; Transplantation; Tumor Antigens; United States Food and Drug Administration; Vaccination; base; conditioning; graft vs host disease; improved; mortality; novel; novel therapeutics; pre-clinical; response; success; vaccination strategy

DESCRIPTION (provided by applicant): 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. The current studies will further optimize this novel vaccination strategy for future clinical studies. Myeloma Id- specific T-cell immunity over time will be measured, characterized, and correlated to anti-myeloma responses. The long-term goal of this project is to transfer highly enriched populations of specific T cells from donor to recipient (e.g., educated DLI). Following completion of this proposal, we anticipate the initiation of a subsequent randomized, controlled trial using DLI from immune versus non-immune donors in non- myeloablative PBSCT to definitively test the hypothesis that transfer of myeloma Id-specific T-cell immunity produces favorable clinical outcome. Multiple myeloma patients who have persistent or relapsing disease at least three months post HLA-matched related allo-transplant will be included in the future study.

描述（由申请方提供）：该提案的中心假设是，与癌症患者相比，通过免疫健康供体更容易打破对肿瘤抗原的耐受性，癌症患者可能因基础疾病或既往治疗而免疫功能低下。我们建议测试一种新的治疗策略，将癌症疫苗治疗与降低强度的预处理，异基因干细胞移植（SCT）相结合，目的是将肿瘤抗原特异性免疫力从干细胞供体转移到骨髓瘤患者，以降低复发风险。该策略基于我们先前的临床前和临床研究，证明了多发性骨髓瘤患者的原则证据。具体而言，根据FDA批准的研究性新药申请，SCT供体使用安全、明确定义的肿瘤疫苗进行免疫接种，该疫苗由高度纯化的骨髓瘤衍生独特型蛋白组成。清髓性骨髓移植后，骨髓瘤独特型特异性T细胞免疫从供体直接转移到受体，并与良好的长期生存相关。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转移到同种异体SCT受体（具体目标1），并确定过继转移的独特型特异性T细胞的精细特异性，频率，表型和效应功能（具体目标2）。外周血干细胞移植物中较高的T细胞含量可能增强供体免疫后独特型特异性T细胞的转移。此外，非清髓性预处理可降低移植相关死亡率，提高这种新型治疗的总体成功率。该项目的长期目标是将高度富集的独特型特异性T细胞群体从供体转移到受体（即，受过教育的供体淋巴细胞输注），这可以增强同种异体移植物的抗肿瘤作用而不加重移植物抗宿主病，从而降低骨髓瘤复发的风险。目前的研究将进一步优化这种新的疫苗接种策略，用于未来的临床研究。将测量、表征骨髓瘤Id特异性T细胞免疫随时间的变化，并将其与抗骨髓瘤应答相关联。该项目的长期目标是将高度富集的特异性T细胞群体从供体转移到受体（例如，教育DLI）。在完成该提案后，我们预计将启动一项后续随机对照试验，在非清髓性PBSCT中使用来自免疫与非免疫供体的DLI，以明确检验骨髓瘤Id特异性T细胞免疫转移产生有利临床结局的假设。在HLA匹配的相关同种异体移植后至少三个月患有持续性或复发性疾病的多发性骨髓瘤患者将被纳入未来的研究。