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。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的团队。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首个临床试验于2014年9月开放入组。James Kochenderfer是这项试验的首席研究员。26名患者接受了这项试验。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是在我的实验室研发的，由蓝鸟生物公司改造。这种新型CAR正在Celgene公司开展的全球I期和II期多中心试验中进行测试。我是该CAR第一阶段试验的现场PI。该试验持续时间最长的完全缓解持续时间为3年。他的试验结果于2019年5月发表在《新英格兰医学杂志》上；James Kochenderfer是这篇论文的资深作者。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。我们已经设计出具有全人类重链抗原识别结构域的新型car，其中一种名为FHVH33-CD8BBZ的car正在进行临床试验。我们假设，与具有单链可变片段抗原识别结构域的传统CAR - T细胞相比，全人源性仅重链抗bcma CAR - T细胞的免疫原性更低。25例患者接受了该临床试验，92%的患者有客观反应。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。我们设计了含有CAR靶向信号淋巴细胞激活分子家族成员7 （SLAMF7）的CAR结构。我们已经完成了一种编码抗slamf7 CAR和自杀基因的构建体的临床前开发。自杀基因允许按需消除表达car的T细胞。自杀基因是由一种叫做Rimiducid的二聚剂激活的。二聚化后，caspase 9被激活，导致表达car的T细胞凋亡。抗slamf7 p；我们的自杀基因构建被命名为IC9-Luc90-CD828Z。我们已经启动了IC9-Luc90-CD828Z T细胞的临床试验。SLAMF7 CAR - T细胞的临床试验没有产生任何反应。我们专注于寻找新的抗slamf7 CAR策略。

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. 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. The first clinical trial of anti-BCMA-CAR-transduced T cells for treating advanced multiple myeloma was opened for enrollment in September, 2014. James Kochenderfer was Principle Investigator of this trial. Twenty -six patients were treated on this trial. 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 my laboratory and modified by bluebird bio. This new CAR is being tested in a world-wide phase I and II multicenter trials conducted by Celgene, Inc. I am a site PI of the phase I trial of this CAR. The longest ongoing complete remission from this trial is 3 years in duration. Results from his trial were published in the New England Journal of Medicine in May 2019; James Kochenderfer was senior author of this paper. Another general area of research on CAR T-cell therapies for multiple myeloma is improving the design of CARs. We have designed novel CARs with fully-human heavy-chain-only antigen-recognition domains, and a clinical trial testing one of these CARs, designated FHVH33-CD8BBZ, is underway. We hypothesize that fully-human heavy-chain-only anti-BCMA CAR T cells will be less immunogenic than traditional CARs with single-chain variable fragment antigen-recognition domains. 25 patients have been treated on this clinical trial, and 92% of patients have had objective responses. 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. We have designed CAR constructs containing a CAR targeting signaling lymphocyte activation molecule family member 7 (SLAMF7). We have completed preclinical development of a construct that encodes an anti-SLAMF7 CAR and a suicide gene. The suicide gene allows on-demand elimination of the CAR-expressing T cells. The suicide gene is activated by a dimerizer agent called Rimiducid. After dimerization, caspase 9 is activated, which leads to apoptosis of the CAR-expressing T cells. The anti-SLAMF7 p;lus suicide gene construct is designated IC9-Luc90-CD828Z. We have initiated a clinical trial of IC9-Luc90-CD828Z T cells. The clinical trial of SLAMF7 CAR T cells did not yield any responses. We are focused on finding new anti-SLAMF7 CAR strategies.