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

自体嵌合抗原受体工程化 T 细胞免疫疗法用于等待肾移植患者脱敏

• 批准号: 10472599
• 负责人: Vijay Bhoj
• 金额: $ 297.52万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472599
• 关键词: Address; Allografting; Antibodies; Antibody Repertoire; Antibody Response; Antigens; Autologous; B cell therapy; B-Lymphocytes; Biology; CAR T cell therapy; CD19 gene; Cell Lineage; Cell Maturation; Cell Therapy; Cells; Cellular Immunity; Clinical; Clinical Trials; Cohort Studies; Communicable Diseases; Disease remission; Disseminated Malignant Neoplasm; Dose; Dose-Limiting; Drug Kinetics; End stage renal failure; Europe; Event; Humoral Immunities; Immune; Immunity; Immunologic Deficiency Syndromes; Immunotherapy; Infusion procedures; Intravenous Immunoglobulins; Isoantibodies; Kidney; Kidney Transplantation; Laboratories; Leukapheresis; Malignant - descriptor; Malignant Neoplasms; Measures; Medical; Memory B-Lymphocyte; Methods; Molecular; Molecular Analysis; Multiple Myeloma; Outcome; Patients; Period Analysis; Pharmacodynamics; Phenotype; Physiological; Plasma Cells; Plasma Exchange; Proteasome Inhibitor; Quality of life; Refractory; Regimen; Research Personnel; Safety; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; Toxic effect; Transplantation; Waiting Lists; arm; base; cancer cell; chimeric antigen receptor; chimeric antigen receptor T cells; clinically significant; cohort; cost effective; desensitization; design; engineered T cells; experience; immune function; improved; in vivo; innovation; leukemia/lymphoma; longitudinal analysis; mortality; mortality risk; novel; organ allocation; pharmacokinetics and pharmacodynamics; pilot trial; risk mitigation; safety and feasibility; targeted treatment; treatment choice; vaccine evaluation; vaccine response

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.

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，而且性价比很高。然而，对于大约三分之一的人来说 在等待名单上的患者中，预先存在的抗人类白细胞抗原抗体(即同种异体致敏)是主要的 成功移植的障碍。人类白细胞抗原抗体反应由记忆B细胞维持 (Bmem)和浆细胞(PC)。不幸的是，脱敏方法在很大程度上 由于异体特异性B细胞和PC的不完全耗尽而无效。我们假设 需要严格去除供者特异性B细胞和PC，才能在临床上显著减少 成功进行肾移植所必需的同种异体抗体。我们已经证明了 使用合成嵌合抗原受体(CARS)的工程化T细胞免疫疗法可以 诱导B细胞系和浆细胞恶性肿瘤的持久缓解。两个CAR-T细胞 针对CD19(CART-19)和B细胞成熟抗原(CART-BCMA)的治疗导致 消耗恶性细胞，但也包括生理性B细胞和PC。重要的是，我们已经展示了 Cart-BCMA和Cart-19可以安全地一起管理。根据这一经验， 我们的目标是利用这一创新平台瞄准BMEM和PC，并促进减少 预制的抗人类白细胞抗原抗体，从而为移植提供了机会之窗。 具体地说，我们提出了一项结合CART-19的单臂概念验证临床试验 CART-BCMA作为一种新的脱敏措施应用于肾移植受者 CPRA≥为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。这些研究的重点是CAR T细胞、T细胞和B细胞免疫(包括同种异体特异性和 保护性)，以及在移植成功的情况下，同种异体移植生物学。一种传染性的 疾病研究计划将评估疫苗的反应和我们肾脏的免疫功能 移植候选者，包括我们的研究队列。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 具有卓越的实验室专业知识，可进行可靠的机械研究。