Development of Chimeric Antigen Receptors Targeting Multiple Myeloma

我工作的一个重要重点是开发嵌合抗原受体T细胞治疗多发性骨髓瘤，这是一种通常无法治愈的浆细胞恶性肿瘤。发展car -表达t细胞治疗多发性骨髓瘤的主要障碍是缺乏合适的靶抗原。Anti-BCMA CARs：我最近设计并构建了两种特异性识别b细胞成熟抗原（BCMA）的car。BCMA在正常组织中的表达模式非常有限，但在多发性骨髓瘤的恶性浆细胞中表达我构建的BCMA特异性car在体外功能试验中特异性识别多发性骨髓瘤细胞系。表达抗bcma car的T细胞可以根除小鼠骨髓瘤肿瘤。利用免疫组织化学和定量PCR对正常人体组织中BCMA的表达进行了广泛的分析。除在正常浆细胞中表达外，免疫组化未在正常人体器官中检测到BCMA的表达。在过去的一年里，已经发表了一篇关于这个项目的论文和摘要。抗bcma - car转导T细胞治疗晚期多发性骨髓瘤的临床试验已经在过去的一个月开放招募。目前还没有患者接受治疗，但许多患者正在筛选该方案，医生对此也很感兴趣。其他靶向多发性骨髓瘤的car：除了开发抗bcma car外，我的目标是开发靶向多发性骨髓瘤细胞而非正常基本组织表达的其他抗原的car。一些有希望的候选抗原已经确定，这些抗原的初步评价已经开始。

An important focus of my work is development of chimeric antigen receptor T cell therapies for multiple myeloma, which is a usually incurable malignancy of plasma cells. A major obstacle to development of CAR-expressing T-cell therapies for multiple myeloma is the lack of suitable target antigens. Anti-BCMA CARs: I have recently designed and constructed two CARs that specifically recognize B-cell maturation antigen (BCMA). BCMA has a very restricted expression pattern in normal tissues, but BCMA is expressed on the malignant plasma cells of multiple myeloma.7 The BCMA specific CARs that I have constructed specifically recognize multiple myeloma cell lines in functional assays in vitro. Anti-BCMA CAR-expressing T cells can eradicate myeloma tumors in mice. An extensive analysis of BCMA expression in normal human tissues by immunohistochemistry and quantitative PCR has been conducted. Except for expression by normal plasma cells, BCMA expression was not detected in nomal human organs by immunohistochemistry. a paper and an abstract on this project have been published in the past year. A clinical trial of anti-BCMA-CAR-transduced T cells for treating advanced multiple myeloma has been opened for enrollment within the past month. No patient has yet been treated, but many patients are screening for the protocol, and interest among physicians is high. Other CARs targeting multiple myeloma: In addition to developing anti-BCMA CARs, I aim to develop CARs that target other antigens that are expressed by multiple myeloma cells but not normal essential tissues. Some promising candidate antigens have been identified, and initial evaluation of these antigens has begun.