Optimizing myeloma-specific immunity after autologous stem cell transplantation

自体干细胞移植后优化骨髓瘤特异性免疫

• 批准号: 10603047
• 负责人: Geoffrey Roger HILL
• 金额: $ 220.81万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603047
• 关键词: Optimizing; myeloma; specific; immunity; after

Abstract Multiple myeloma is the second most common hematological malignancy and despite improved patient outcomes in the era of novel agents, it remains largely incurable. Clinical studies show that autologous stem cell transplantation (ASCT) remains an efficacious consolidation treatment for eligible patients and a subset of transplant recipients achieve long-term control of disease. Currently, the prolongation of plateau-phase induced by ASCT is attributed to the use of myeloablative chemotherapy and cytoreduction. However, ASCT generates inflammation and profound lymphodepletion, whilst disrupting the marrow microenvironment, all of which has the potential to induce anti-myeloma immunity. We have recently utilized novel preclinical models to provide definitive evidence that ASCT invokes myeloma-specific T cell immunity and the re-establishment of a state of immune equilibrium. Furthermore, we have demonstrated that disease progression after ASCT in these systems is a result of CD8 T cell exhaustion that is dependent on the accumulation of myeloid suppressive populations and the expression of multiple checkpoint molecules by CD8 T cells. These inhibitory pathways are highly amenable to immunotherapeutic approaches after ASCT that invoke long term survival. This proposal will utilize sophisticated protein and transcriptional based approaches to examine the relationship of T cell function in the peri-transplant period to subsequent survival and disease control in well-annotated clinical cohorts. A major focus will be the optimization of innovative immunotherapy approaches after ASCT in preclinical systems for clinical translation.

抽象的 多发性骨髓瘤是第二常见的血液恶性肿瘤，尽管患者病情有所改善 在新型药物时代的结果中，它在很大程度上仍然是无法治愈的。临床研究表明，自体干细胞 对于符合条件的患者和一小部分患者来说，移植（ASCT）仍然是一种有效的巩固治疗方法。 移植受者实现疾病的长期控制。目前，平台期的延长引起 ASCT 归因于清髓性化疗和细胞减灭术的使用。然而，ASCT 产生 炎症和严重的淋巴细胞耗竭，同时破坏骨髓微环境，所有这些都具有 诱导抗骨髓瘤免疫的潜力。我们最近利用新颖的临床前模型来提供 确凿的证据表明 ASCT 可以激发骨髓瘤特异性 T 细胞免疫并重建骨髓瘤状态 免疫平衡。此外，我们已经证明这些系统中 ASCT 后的疾病进展 是 CD8 T 细胞耗竭的结果，依赖于骨髓抑制细胞群的积累 CD8 T 细胞表达多个检查点分子。这些抑制途径高度 适合 ASCT 后的免疫治疗方法，从而实现长期生存。本提案将利用 基于复杂蛋白质和转录的方法来检查 T 细胞功能之间的关系 在注释良好的临床队列中，从围移植期到随后的生存和疾病控制。一大焦点 将是 ASCT 临床前系统中创新免疫治疗方法的优化，用于临床 翻译。