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。抗BCMA汽车：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）的汽车的团队。BCMA在正常组织中具有非常有限的表达模式，但BCMA在多发性骨髓瘤的恶性浆细胞上表达。我们构建的BCMA特异性汽车在体外特异性识别多发性骨髓瘤细胞系和原代骨髓瘤细胞，并根除小鼠骨髓瘤肿瘤。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。自2014年9月以来，抗BCMA-CAR转导的T细胞用于治疗晚期多发性骨髓瘤的临床试验已经开放招募。到目前为止，已有23名患者接受了治疗。在这项试验中有令人印象深刻的反应，这是第一个证明CAR T细胞消除可测量的多发性骨髓瘤的例子。这项工作于2016年在《血液》杂志上发表。关于Bluebird Bio，Inc.我们开发了一种新的抗BCMA CAR，蓝鸟从NCI获得许可。这种新的汽车部分是在我的实验室里开发的。这种新的CAR正在一项多中心试验中进行测试，我作为研究中心PI参加了该试验。NCI是本试验的主要入组研究中心。该试验显示出有希望的结果，大多数接受治疗的患者获得了客观的抗骨髓瘤反应。这项试验最近于2017年6月在美国临床肿瘤学会会议上报告。关于多发性骨髓瘤的CAR T细胞疗法的另一个一般研究领域是改进汽车的设计。我们有一个项目，研究汽车铰链区结构的变化如何在确定汽车的体内功效方面非常重要。我们已经证明，抗BCMA CAR T细胞的铰链区的非常小的变化可以影响CAR T细胞的体内功能。我们目前正在为抗BCMA CAR T细胞设计新型全人类抗原识别结构域。我们还设计了针对BCMA以外抗原的汽车，因为多发性骨髓瘤在许多情况下是一种表型异质性恶性肿瘤，因此靶向一种以上抗原可能是有效诱导多发性骨髓瘤长时间无进展间隔所必需的。

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.