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

项目摘要 人类白细胞抗原致敏是器官移植过程中的一个重要障碍。肾移植候选人 高度敏感者(CPRA≥99.9%)继续很难获得兼容的 捐献者和更有可能被从名单上删除或死亡，而不是接受移植。 脱敏有明显的生存益处；然而，以前的方法遇到了有限的 成功，尤其是在具有最高水平的人类白细胞抗原抗体的患者中，并受到 抗体反弹的问题。我们假设人类白细胞抗原抗体的持续减少可以 要通过双管齐下的方法来实现：消除浆细胞和预防 生发中心的代偿性扩张。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 多发性骨髓瘤。生发中心的激活可通过阻断IL-6或 CD40/CD40L途径。此外，我们还发现了一种新的生物标志物(特异性的人类白细胞抗原/KIR 基因组合)，预测NK细胞对抗-HBs的杀伤作用较差 CD38抗体。我们建议开展多中心、前瞻性、开放式、干预性 68例99.9%的慢性阻塞性肺疾病≥患者将被分配接受双重生物治疗的研究 脱敏治疗60例或细胞治疗8例。分配到双重生物疗法或 细胞治疗将基于我们的新生物标记物，使用精确医学方法。那些 分配给双重生物疗法的人将进一步随机接受抗CD38抗体， 伊索妥昔单抗与CD40L拮抗剂VIB4920(n=30)或沙利单抗(IL-1)联合应用。 6R拮抗剂(n=30)。那些被分配到细胞治疗组的人将接受一次IDE- CEL是一种针对B细胞成熟抗原(BCMA)的CAR T细胞疗法，表达于 浆细胞表面。主要疗效终点是CPRA降低≥0.4%或收到 来自以前血型不合的供者的移植，在完成移植后16周进行评估 心理治疗。主要安全终点是不出现≥3级输液反应、≥3级或 较高的感染和恶性程度在治疗结束后16周或 接受移植，以较早发生者为准。机械论分析将重点放在 治疗后的骨髓和循环中的T、B细胞亚群 在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指导治疗，并接受移植后的评估 结果包括免于排斥、移植物丢失和死亡。

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.