Preventing Myeloma Relapse after Autologous Stem Cell Transplantation with Decoy Resistant IL-18

项目总结/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。在我们的母公司U 01中，我们利用了新的临床前模型， 提供了明确的证据表明，ASCT调用骨髓瘤特异性Th 1免疫和重建免疫系统。 免疫平衡状态。此外，我们已经证明，ASCT后的疾病进展， CD 8 T细胞耗竭依赖于骨髓抑制性T细胞的积累， 群体和CD 8 T细胞表达多个检查点分子。这项建议将研究 通过优化新的Th 1的给药而引起长期骨髓瘤特异性免疫控制的能力 诱导合成细胞因子DR-18。DR-18是诱饵抗性IL-18，其不被诱饵IL-18灭活 结合蛋白和初步数据表明，它在预防骨髓瘤进展方面非常有效。通过 与开发DR-18的Ring/Bosenberg U 01合作，这项补充合同的主要重点将是 在未来1-2年内，将这种疗法最优化用于骨髓瘤患者的临床治疗。

PROJECT SUMMARY/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. In our parent U01, we have utilized novel preclinical models to provide definitive evidence that ASCT invokes myeloma-specific Th1 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. This proposal will study the ability to invoke long term myeloma-specific immune control by optimizing the administration of a novel Th1 inducing synthetic cytokine, DR-18. DR-18 is a decoy resistant IL-18 that is not inactivated by the decoy IL-18 binding protein and preliminary data suggests it is highly effective in preventing myeloma progression. By working with the Ring/Bosenberg U01 that developed DR-18, the major focus of this supplementary award will be the optimization of this therapy for translation into the clinic in patients with myeloma over the next 1-2 years.