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

描述(申请人提供)：这项建议的中心假设是，与癌症患者相比，通过免疫健康捐赠者更容易打破对肿瘤抗原的耐受性，癌症患者可能会因潜在疾病或先前的治疗而免疫受损。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条件处理相结合，即异基因干细胞移植(SCT)，目的是将肿瘤抗原特异性免疫从干细胞捐赠者转移到骨髓瘤患者，以降低复发的风险。这一策略是基于我们之前的临床前和临床研究，证明了多发性骨髓瘤患者的原则证据。具体地说，根据FDA批准的研究新药申请，SCT捐赠者用一种安全、定义明确的肿瘤疫苗进行免疫，该疫苗由高度纯化的骨髓瘤独特型蛋白组成。在清髓性骨髓移植后，骨髓瘤独特型特异性T细胞免疫从供者直接转移到接受者，这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供体中诱导的抗原特异性免疫是否可以被动地转移到同种异体SCT受体(特异性目标1)，并确定过继转移的独特型特异性T细胞的良好特异性、频率、表型和效应功能(特异性目标2)。在供者免疫后，外周血干细胞移植物中较高的T细胞含量可能会促进独特型特异性T细胞的转移。此外，非清髓性预适应可降低移植相关死亡率，提高这一新疗法的总体成功率。该项目的长期目标是将高度浓缩的独特型特异性T细胞从供者转移到接受者(即，受过教育的供者淋巴细胞输注)，这可能会增强同种移植物的抗肿瘤效果，而不会加剧移植物抗宿主疾病，从而降低骨髓瘤复发的风险。目前的研究将为未来的临床研究进一步优化这一新的疫苗接种策略。随着时间的推移，骨髓瘤ID特异性T细胞免疫将被测量、表征并与抗骨髓瘤反应相关。该项目的长期目标是将高度浓缩的特定T细胞群体从捐赠者转移到接受者(例如，受过教育的DLI)。在这项建议完成后，我们预计将启动一项后续的随机对照试验，使用非清髓性PBSCT中免疫和非免疫捐赠者的DLI来明确测试骨髓瘤ID特异性T细胞免疫转移产生良好临床结果的假设。未来的研究将包括在人类白细胞抗原相合相关的同种异体移植后至少三个月有持续性或复发性疾病的多发性骨髓瘤患者。

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.