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

项目摘要 HLA致敏是器官移植中的重要障碍。肾移植候选人 非常高致敏（cPRA ≥ 99.9%）的患者仍然很难获得相容的 捐赠者和更有可能被从名单上删除或死亡比接受移植。 脱敏具有明显的生存益处;然而，先前的方法遇到了有限的问题。 尤其是在HLA抗体水平最高的患者中， 抗体反弹的问题。我们假设HLA抗体的持续减少可以 可以通过双管齐下的方法实现：消除浆细胞加上预防 补偿性扩张的脑中枢。抗CD38抗体和嵌合抗原 针对浆细胞的CAR受体T细胞已经成为新的治疗选择 多发性骨髓瘤通过阻断IL-6或IL-10， CD40/CD40L途径。此外，我们还发现了一种新的生物标志物（特异性HLA/KIR）， 基因型组合），其预测NK细胞应答抗- CD38抗体。我们建议进行一项多中心、前瞻性、开放标签、干预性研究， 在68例cPRA ≥ 99.9%的患者中进行的研究，这些患者将被分配接受双重生物制剂治疗 （n = 60）或细胞疗法（n = 8）用于脱敏。分配至双联生物治疗或 细胞疗法将基于我们使用精确医学方法的新型生物标志物。那些 被分配到双重生物治疗的患者将进一步随机接受抗CD38抗体， isatuximab，与VIB 4920（一种CD 40 L拮抗剂）（n = 30）或sar（一种IL- 6R拮抗剂组30例。那些被分配到细胞治疗组的人将接受一次ide- cel，一种靶向B细胞成熟抗原（BCMA）的CAR T细胞疗法，该抗原表达在 浆细胞表面。主要疗效终点是cPRA降低≥ 0.4%或接受 从以前不相容的供体移植，并在完成移植后16周进行评估。 疗法主要安全性终点是无≥ 3级输注反应，≥ 3级或 在完成治疗后16周或直至 接受移植，以较早发生者为准。机制分析将侧重于以下方面的变化： 治疗后的骨髓和循环T和B细胞区室，以及 在研究期间接受移植的人的淋巴结。移植受试者将 移植后接受额外的研究指导治疗，并接受移植后评估 结果包括免于排斥、移植物丢失和死亡。

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.