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

使用抗诱饵 IL-18 预防自体干细胞移植后骨髓瘤复发

• 批准号: 10286958
• 负责人: Geoffrey Roger HILL
• 金额: $ 16.56万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-11 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286958
• 关键词: African American; Agonist; Allogenic; Autologous Stem Cell Transplantation; Award; Blood; Bone Marrow; Bortezomib; CD8 Antigens; CD8-Positive T-Lymphocytes; Cell physiology; Clinic; Clinical Research; Clinical Trials; Clonal Evolution; Clonal Expansion; Computer Analysis; Data; Disease; Disease Progression; Epigenetic Process; Equilibrium; Event; Flow Cytometry; Genetic Heterogeneity; Genetic Transcription; Grant; Hematologic Neoplasms; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immunity; Immunologics; Immunomodulators; Immunotherapeutic agent; Immunotherapy; In complete remission; Incidence; Inflammation; Inflammatory; Interleukin-18; Maintenance Therapy; Malignant - descriptor; Marrow; Mediating; Melphalan; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Myeloablative Chemotherapy; Myelogenous; Neoadjuvant Therapy; Parents; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phenotype; Plasma Cells; Population; Pre-Clinical Model; Precancerous Conditions; Relapse; Resistance; System; T memory cell; T-Lymphocyte; Testing; Toxic effect; Translating; Translations; Transplant Recipients; Transplantation; Transplantation Conditioning; Treatment Protocols; Tumor Antigens; Tumor Immunity; base; checkpoint inhibition; clinical translation; cytokine; disorder control; effective therapy; exhaustion; graft vs leukemia effect; immunogenic cell death; improved; in vivo; innovation; interleukin-18 binding protein; lenalidomide; novel; parent grant; patient subsets; predictive signature; prevent; programs; standard care; stem cells; therapeutically effective; treatment optimization; tumor microenvironment; uptake

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.

项目摘要/摘要 多发性骨髓瘤是第二常见的血液系统恶性肿瘤，尽管患者病情有所改善 在新药时代的结果，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，移植(ASCT)仍然是一种有效的巩固治疗方法， 移植受者实现了疾病的长期控制。目前，平台期的延长引起 ASCT可归因于清髓化疗和细胞减少术的使用。但是，ASCT会生成 炎症和严重的淋巴衰竭，同时扰乱骨髓微环境，所有这些都有 有可能诱导抗骨髓瘤免疫。在我们的母公司U01中，我们利用新的临床前模型来 提供确凿证据表明，ASCT激活了骨髓瘤特异性Th1免疫并重建了 免疫平衡状态。此外，我们已经证明了ASCT后这些患者的疾病进展 系统是CD8 T细胞衰竭的结果，这依赖于髓系抑制的积累 CD8T细胞的群体和多种检查点分子的表达这项建议将研究 通过优化新型Th1的给药来激活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是一种抗诱饵的IL-18，不会被诱饵IL-18灭活 结合蛋白和初步数据表明，它在防止骨髓瘤进展方面非常有效。通过 与开发DR-18的Ring/Bosenberg U01合作，这一补充奖的主要重点将是 在未来1-2年内，这一疗法的优化将转化为骨髓瘤患者的临床应用。