Department of Pathology & Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Cell Rep Med. 2023 Dec 19;4(12):101336. doi: 10.1016/j.xcrm.2023.101336.
Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation. We find that treatment of allo-sensitized hosts with CAR T cells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent islet allografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.
预先存在的抗人白细胞抗原（HLA）同种异体抗体是移植的主要障碍。由于无效耗尽同种特异性记忆 B 细胞（Bmems）和长寿浆细胞（LLPCs），目前的脱敏方法失败。我们评估了针对 CD19 和 B 细胞成熟抗原（BCMA）的嵌合抗原受体（CAR）T 细胞消除胰岛同种移植皮肤预致敏小鼠模型中同种抗体的疗效。我们发现，用针对 Bmems 和 LLPCs 的 CAR T 细胞治疗同种致敏宿主可消除供体特异性同种抗体（DSA）并减轻随后胰岛同种移植物的超急性排斥反应。然后，我们评估了针对先前存在 HLA 同种异体抗体的多发性骨髓瘤（MM）患者的 CAR T 治疗脱敏的临床疗效，这些患者接受了 CART-BCMA 和 CART-19 的联合治疗（ClinicalTrials.gov：NCT03549442），并观察到有临床意义的同种异体抗体减少。这些发现为在高度致敏候选者中进行基于 CAR T 的免疫治疗以促进成功移植的临床评估提供了合理的依据。
