Applying precision MEdicine to optimize desensitization with noveL bIOlogics or cellular theRApies in highly sensiTized kidney transplant patiEnts (AMELIORATE)

应用精准医学，通过新型生物制剂或细胞疗法对高度敏感的肾移植患者优化脱敏（AMELIORATE）

• 批准号: 10461851
• 负责人: Flavio Vincenti
• 金额: $ 81.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461851
• 关键词: Adverse event; Aftercare; Antibodies; Antigens; Autologous; B cell therapy; B-Lymphocytes; Biological Products; Biological Response Modifier Therapy; Bone Marrow; CAR T cell therapy; Cell Compartmentation; Cell Maturation; Cell Therapy; Cells; Cessation of life; Chronic; Clinical; Elements; Enrollment; Equipoise; Freedom; Frequencies; Genotype; Goals; Graft Survival; IL-6 inhibitor; Immunity; Incidence; Infection; Infusion procedures; Injury; Interleukin 6 Receptor; Interleukin-6; Intervention Studies; Kidney; Kidney Transplantation; Malignant Neoplasms; Measurement; Mediating; Memory B-Lymphocyte; Multiple Myeloma; Natural Killer Cells; Organ Transplantation; Outcome; Pathway interactions; Patients; Pharmacotherapy; Plasma Cells; Prevention; Randomized; Reaction; Receptor Gene; Regimen; Research Design; Safety; Severities; Specificity; Structure of germinal center of lymph node; Surface; System; T cell therapy; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Transplant Recipients; Transplantation; Work; antagonist; arm; base; cell killing; chimeric antigen receptor T cells; desensitization; efficacious treatment; high risk population; improved; killer immunoglobulin-like receptor; lymph nodes; molecular marker; novel; novel marker; novel therapeutics; open label; pathogen; patient stratification; post-transplant; precision medicine; prevent; prospective; response; success; treatment response

PROJECT ABSTRACT HLA sensitization is a significant barrier in organ transplantation. Kidney transplant candidates who are very highly sensitized (cPRA ≥99.9%) continue to have very poor access to a compatible donor and are more likely to be removed from the list or die than undergo transplantation. Desensitization has a clear survival benefit; however previous approaches have met with limited success especially in patients with the highest levels of HLA antibodies, and are hamstrung by the problem of antibody rebound. We hypothesize that durable reduction in HLA antibodies can be achieved by a two pronged approach: elimination of plasma cells plus prevention of the compensatory expansion of the germinal center. Both anti-CD38 antibodies and chimeric antigen receptor (CAR) T cells directed against plasma cells have emerged as novel therapeutic options in multiple myeloma. Germinal center activation can be inhibited by blockade of the IL-6 or CD40/CD40L pathway. Furthermore, we have identified a novel biomarker (specific HLA/KIR genotype combinations) which predicts poor plasma cell killing by NK cells in response to anti- CD38 antibodies. We propose to conduct a multicenter, prospective, open-label, interventional study in 68 patients with cPRA ≥99.9% who will be assigned to receive dual biologic therapy (n=60) or cellular therapy (n=8) for desensitization. Allocation into the dual biologic therapy or cellular therapy will be based on our novel biomarker using a precision medicine approach. Those assigned to dual biologic therapy will be further randomized to receive the anti-CD38 antibody, isatuximab, in combination with either VIB4920, a CD40L antagonist (n=30) or sarilumab, an IL- 6R antagonist (n=30). Those assigned to the cell therapy arm will receive a single infusion of ide- cel, a CAR T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of plasma cells. The primary efficacy endpoint is a ≥0.4% reduction in cPRA or receipt of transplant from a previously incompatible donor and is assessed at 16 weeks after completion of therapy. The primary safety endpoint is freedom from ≥grade 3 infusion reactions, ≥grade 3 or higher infections, and malignancy assessed at 16 weeks after completion of therapy or until receiving a transplant, whichever occurs earlier. Mechanistic analyses will focus on changes in the bone marrow and circulating T and B cell compartments after treatment, as well as in the lymph nodes of those who receive a transplant during the study. Transplanted subjects will receive additional study-directed therapy after transplant and be evaluated for post-transplant outcomes including freedom from rejection, graft loss and death.

项目摘要 HLA致敏是器官移植的一个重要障碍。肾移植候选人 高度敏感的人（cPRA ≥99.9%）仍然很难获得兼容的药物 捐赠者，比接受移植更有可能被从名单中删除或死亡。 脱敏具有明显的生存益处；然而，以前的方法效果有限 尤其是在 HLA 抗体水平最高的患者中，成功率很高，并且受到以下因素的阻碍： 抗体反弹的问题。我们假设 HLA 抗体的持久减少可以 通过双管齐下的方法来实现：消除浆细胞加预防 生发中心代偿性扩张。抗CD38抗体和嵌合抗原 针对浆细胞的受体（CAR）T细胞已成为新的治疗选择 在多发性骨髓瘤中。生发中心的激活可以通过阻断 IL-6 或 CD40/CD40L 途径。此外，我们还发现了一种新的生物标志物（特定的 HLA/KIR 基因型组合），预测 NK 细胞响应抗- CD38抗体。我们建议开展多中心、前瞻性、开放标签、介入性研究 对 68 名 cPRA ≥ 99.9% 的患者进行的研究，这些患者将被分配接受双重生物治疗 (n=60) 或细胞疗法 (n=8) 进行脱敏。分配至双重生物疗法或 细胞疗法将基于我们使用精准医学方法的新型生物标志物。那些 分配接受双重生物治疗的患者将进一步随机接受抗 CD38 抗体， isatuximab 与 VIB4920（一种 CD40L 拮抗剂）或 sarilumab（一种 IL- 6R 拮抗剂 (n=30)。那些被分配到细胞治疗组的人将接受单次理念输注。 cel，一种针对 B 细胞成熟抗原 (BCMA) 的 CAR T 细胞疗法，该抗原表达于 浆细胞表面。主要疗效终点是 cPRA 降低 ≥0.4% 或接受 来自先前不相容供体的移植，并在完成后 16 周进行评估 治疗。主要安全终点是不发生≥3级输注反应、≥3级或 治疗完成后 16 周或直至评估感染和恶性肿瘤较高 接受移植，以较早发生的为准。机制分析将重点关注变化 治疗后的骨髓和循环 T 细胞和 B 细胞区室，以及 研究期间接受移植的患者的淋巴结。移植的受试者将 移植后接受额外的研究导向治疗并接受移植后评估 结果包括免于排斥、移植物丢失和死亡。