Autologous chimeric antigen receptor engineered T cell immunotherapy for desensitization in patients awaiting kidney transplantation

摘要 肾移植是终末期肾病（ESRD）患者的首选治疗方法， 它延长了生存时间，提高了生活质量，而且成本效益很高。然而，对于大约三分之一的 在等待名单上的患者中，预先存在的抗HLA抗体（即同种异体致敏）是主要的 成功移植的障碍。HLA抗体应答由记忆B细胞维持 （Bcb）和浆细胞（PC）。不幸的是，脱敏方法在很大程度上 由于同种异体特异性B细胞和PC的不完全消耗而无效。我们假设 临床上显著减少需要严格清除供体特异性B细胞和PC 同种异体抗体来实现成功的肾移植。我们已经证明 采用合成嵌合抗原受体（汽车）的工程化T细胞免疫疗法可 诱导B细胞谱系和浆细胞恶性肿瘤持久缓解。两个CAR-T细胞 靶向CD 19（CART-19）和B细胞成熟抗原（CART-BCMA）的疗法导致 恶性细胞以及生理性B细胞和PC的耗竭。重要的是，我们已经证明 CART-BCMA和CART-19可以安全地一起施用。根据这一经验， 我们的目标是利用这一创新平台，以BCN和PC为目标，促进减排 预先形成的抗HLA抗体，从而为移植提供了一个机会窗口。 具体来说，我们提出了一个单臂概念验证临床试验，结合CART-19 CART-BCMA作为一种新的脱敏措施，在肾移植候选人中， cPRA ≥ 99.9%。机制研究将评估细胞、体液和分子免疫 CART-19 + CART-BCMA免疫治疗在高致敏肾移植中的相关性 候选人这些都集中在CAR T细胞，T细胞和B细胞免疫（同种特异性和 保护性），以及在移植成功的情况下，同种异体移植生物学。传染 疾病研究提案将评估我们肾脏中的疫苗应答和免疫功能 包括我们的研究对象多中心团队（宾夕法尼亚大学，纽约大学，麻省理工学院） 汇集了在CART治疗，脱敏和 出色的实验室专业知识深度，以进行强大的机制研究。

Abstract Kidney transplant is the treatment of choice for patients with end-stage renal disease (ESRD), as it extends survival, improves quality of life and is highly cost-effective. However, for about a third of patients on the waitlist, pre-existing anti-HLA antibodies (i.e. allo-sensitization) presents a major barrier to successful transplant. HLA antibody responses are maintained by memory B cells (Bmem) and plasma cells (PC). Unfortunately, desensitization approaches have been largely ineffective due to incomplete depletion of allo-specific B cells and PCs. WE HYPOTHESIZE that stringent depletion of donor-specific B cells and PCs is required for a clinically significant reduction of allo-antibodies necessary to achieve successful kidney transplantation. We have shown that engineered T cell immunotherapies employing synthetic chimeric antigen receptors (CARs) can induce durable remission of B cell lineage and plasma cell malignancies. Two CAR-T cell therapies that target CD19 (CART-19) and B cell maturation antigen (CART-BCMA) result in depletion of malignant cells but also physiologic B cells and PCs. Importantly, we have shown that CART-BCMA and CART-19 can be safely administered together. Based on this experience, our GOAL is to leverage this innovative platform to target Bmem and PCs and promote reduction of preformed anti-HLA antibodies, thus providing a window of opportunity for transplantation. Specifically, we propose a single-arm proof-of-concept CLINICAL TRIAL that combines CART-19 with CART-BCMA as a novel desensitization measure in kidney transplant candidates with a cPRA ≥99.9%. MECHANISTIC studies will evaluate the cellular, humoral and molecular immune correlates of CART-19 + CART-BCMA immunotherapy in highly sensitized kidney transplant candidates. These are focused on the CAR T cells, T- and B-cell immunity (both allo-specific and protective) and, in the event of successful transplantation, the allograft biology. An INFECTIOUS DISEASE STUDY proposal will evaluate vaccine response and immune function in our renal transplant candidates, including our study cohort. The multi-center team (Penn, NYU, MGH) brings together investigators with extensive experience in CART therapy, desensitization, and outstanding depth of laboratory expertise to carry out robust mechanistic studies.