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。Anti-BCMA CARs：我的团队是第一个设计和构建特异性识别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。我们构建的BCMA特异性car在体外特异性识别多发性骨髓瘤细胞系和原发性骨髓瘤细胞，并在小鼠体内根除骨髓瘤肿瘤。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。抗bcma - car转导T细胞治疗晚期多发性骨髓瘤的临床试验已于2014年9月开放入组。目前已有23名患者接受了治疗。这项试验取得了令人印象深刻的效果，这是CAR - T细胞消除可测量多发性骨髓瘤的第一个例子。这项工作于2016年发表在《血液》杂志上。与蓝鸟生物公司合作。我们已经开发了一种新的抗bcma CAR，蓝鸟从NCI获得了许可。这种新型CAR部分是在我的实验室开发的。这种新型CAR正在多中心试验中进行测试，我作为现场PI参与了该试验。NCI是该试验的主要招募站点。该试验显示出令人鼓舞的结果，大多数患者获得了客观的抗骨髓瘤反应。该试验最近在2017年6月的美国临床肿瘤学会会议上进行了报道。CAR - t细胞治疗多发性骨髓瘤的另一个研究领域是改进CAR - t细胞的设计。我们有一个项目研究car的铰链区域结构的变化如何在确定car的体内疗效方面发挥重要作用。我们已经证明，在抗bcma CAR - T细胞的铰链区域发生非常小的变化可以影响CAR - T细胞的体内功能。目前，我们正在为抗bcma CAR - T细胞设计新的全人抗原识别域。我们也在设计针对BCMA以外抗原的car，因为多发性骨髓瘤在许多情况下是一种表型异质性的恶性肿瘤，因此可能需要针对多种抗原来有效诱导多发性骨髓瘤的长期无进展间隔。

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. Anti-BCMA CARs: My group was the first to design and construct 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. The BCMA specific CARs that we have constructed specifically recognize multiple myeloma cell lines and primary myeloma cells in vitro and 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 clinical trial of anti-BCMA-CAR-transduced T cells for treating advanced multiple myeloma has been opened for enrollment since September, 2014. So far 23 patients have been treated. There have been impressive responses on this trial, which were the first demonstrated examples of elimination of measurable multiple myeloma by CAR T cells. This work led to a publication in the journal Blood in 2016. In conjunction with Bluebird Bio, Inc. We have developed a new anti-BCMA CAR that Bluebird licensed from the NCI. This new CAR was developed in part in my laboratory. This new CAR is being tested in a multicenter trial of which I participate as a site PI.. The NCI is a leading enrollment site for this trial. The trial is showing promising results with most patients treated obtaining objective anti-myeloma responses. This trial was most recently reported at the American Society of Clinical Oncology meeting in June, 2017. Another general area of research on CAR T-cell therapies for multiple myeloma is improving the design of CARs. We have a project looking at how changes in the structure of the hinge region of CARs can be quite important in determining in vivo efficacy of CARs. We have shown that very small changes in the hinge region of anti-BCMA CAR T cells can affect the in vivo function of CAR T cells. We are currently working on designing novel fully-human antigen-recognition domains for anti-BCMA CAR T cells. We are also designing CARs against antigens other than BCMA because multiple myeloma is a phenotypically heterogeneous malignancy in many cases, so targeting more than one antigen might be necessary to effectively induce long progression-free intervals of multiple myeloma.