Development of Chimeric Antigen Receptors Targeting Multiple Myeloma

我工作的一个重要重点是开发用于多发性骨髓瘤的嵌合抗原受体T细胞疗法，多发性骨髓瘤是一种通常无法治愈的浆细胞恶性肿瘤。开发用于多发性骨髓瘤的CAR表达T细胞疗法的主要障碍是缺乏合适的靶抗原。抗BCMA汽车：我最近设计并构建了两种特异性识别B细胞成熟抗原（BCMA）的汽车。BCMA在正常组织中的表达模式非常有限，但BCMA在多发性骨髓瘤的恶性浆细胞上表达。7我构建的BCMA特异性汽车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细胞可以根除小鼠中的骨髓瘤肿瘤。通过免疫组织化学和定量PCR对BCMA在正常人体组织中的表达进行了广泛的分析。免疫组化结果显示，除正常浆细胞外，BCMA在正常组织器官中均不表达。在过去一年中，发表了关于这一项目的论文和摘要。一项抗BCMA-CAR转导的T细胞治疗晚期多发性骨髓瘤的临床试验已在过去一个月内开放招募。目前还没有患者接受治疗，但许多患者正在筛选该方案，医生的兴趣很高。其他靶向多发性骨髓瘤的汽车：除了开发抗BCMA汽车外，我的目标是开发靶向多发性骨髓瘤细胞表达的其他抗原而不是正常必需组织的汽车。一些有希望的候选抗原已被确定，这些抗原的初步评估已经开始。

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.