Optimizing myeloma-specific immunity after autologous stem cell transplantation

摘要 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， 在新药物时代的结果，它仍然在很大程度上无法治愈。临床研究表明，自体干细胞 移植（ASCT）仍然是合格患者的有效巩固治疗， 移植受者实现疾病的长期控制。目前，平台期的延长诱导 ASCT的发生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。我们最近利用新的临床前模型， 明确的证据表明，ASCT调用骨髓瘤特异性T细胞免疫和重建的状态， 免疫平衡此外，我们已经证明，在这些系统中，ASCT后的疾病进展 是CD8 T细胞耗竭的结果，其依赖于骨髓抑制性群体的积累 以及CD8 T细胞表达多个检查点分子。这些抑制途径是高度 在ASCT后适合于免疫疗法，其引起长期存活。该提案将利用 复杂的蛋白质和转录为基础的方法来检查T细胞功能的关系， 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。一个主要重点 将是临床前系统中ASCT后创新免疫治疗方法的优化， 翻译.

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.