Development of Chimeric Antigen Receptors Targeting Multiple Myeloma

针对多发性骨髓瘤的嵌合抗原受体的开发

• 批准号: 10262329
• 负责人: James Kochenderfer
• 金额: $ 125.16万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262329
• 关键词: Affect; Antigen Targeting; Antigens; Apoptosis; Area; B-Lymphocytes; Binding; Blood; CAR T cell therapy; CASP9 gene; Cell Line; Cell Maturation; Cells; Clinical Trials; Development; Dimerization; Disease remission; Enrollment; Family member; Genetic Engineering; Goals; Human; Immunohistochemistry; In Vitro; Industry; Journals; Laboratories; Malignant - descriptor; Malignant Neoplasms; Measurable; Medicine; Multicenter Trials; Multiple Myeloma; Mus; New England; Normal tissue morphology; Organ; Paper; Patients; Pattern; Phase; Phenotype; Plasma Cells; Publications; Publishing; Research; Research Personnel; SLAM protein; Site; Structure; T-Lymphocyte; Testing; Time; Work; cancer cell; chimeric antigen receptor; chimeric antigen receptor T cells; design; design and construction; dimer; human tissue; immunogenic; improved; in vivo; novel; phase I trial; preclinical development; response; suicide gene; tumor

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 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 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. 12 patients have been treated on this clinical trial, and 10 of the 12 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..

我工作的一个重要重点是用于多发性骨髓瘤的嵌合抗原受体T细胞疗法的发展，这是浆细胞的通常无法治愈的恶性肿瘤。我的小组是第一个设计和构建特定识别B细胞成熟抗原（BCMA）的汽车的人。 BCMA在正常组织中具有非常有限的表达模式，但是BCMA在多发性骨髓瘤的恶性血浆细胞上表达。我们已经构建的BCMA特异性汽车在体外和根除小鼠的骨髓瘤肿瘤中特异性识别多发性骨髓瘤细胞系和原发性骨髓瘤细胞。已经通过免疫组织化学和定量PCR对正常人体组织中的BCMA表达进行了广泛的分析。除非正常浆细胞表达外，在免疫组织化学中未检测到在人体器官中表达BCMA的表达。抗BCMA-CAR转录的T细胞的第一次临床试验于2014年9月开放为治疗高级多发性骨髓瘤。James Kochenderfer是该试验的主要研究者。在此试验中，对二十六个患者进行了治疗。该试验有令人印象深刻的反应，这是消除CAR T细胞消除可测量多发性骨髓瘤的第一个例子。这项工作导致了2016年《血液》杂志的出版物。与Bluebird Bio，Inc。一起，我们开发了一种新的抗BCMA汽车，该汽车是从NCI获得许可的蓝鸟。这辆新车是在我的实验室开发的，由Bluebird Bio进行了修改。这款新车正在全球范围内的I和II阶段II多中心试验中进行测试。该试验中最长的持续完全缓解是持续时间3年。他的审判结果于2019年5月发表在《新英格兰医学杂志》上；詹姆斯·科钦德（James Kochenderfer）是本文的高级作者。用于多发性骨髓瘤的汽车T细胞疗法研究的另一个一般研究是改善汽车的设计。我们有一个项目，研究汽车铰链区域结构的变化对于确定汽车的体内功效非常重要。我们已经表明，抗BCMA CAR T细胞的铰链区域的变化很小，会影响CAR T细胞的体内功能。我们已经设计了具有完全人类重链抗原识别域的新型汽车，并且正在进行其中一项指定为FHVH33-CD8BBZ的临床试验测试。我们假设完全人类的仅重链抗BCMA CAR T细胞比具有单链可变碎片抗原识别域的传统汽车的免疫原性。在这项临床试验中已经对12例患者进行了治疗，其中12名患者中有10例具有客观反应。我们还在针对BCMA以外的抗原设计汽车，因为在许多情况下，多发性骨髓瘤是一种表型异质性的恶性肿瘤，因此可能需要靶向多个抗原以有效地诱导多发性骨髓瘤的长期无进展间隔。我们设计了含有汽车靶向信号淋巴细胞活化分子家族成员7（SLAMF7）的汽车构建体。我们已经完成了编码抗Slamf7汽车和自杀基因的临床前开发。自杀基因允许按需消除表达汽车的T细胞。自杀基因被称为rimiducid的二聚体剂激活。二聚化后，激活了caspase 9，从而导致表达CAR的T细胞的凋亡。抗Slamf7 P; LUS自杀基因构建体被指定为IC9-LUC90-CD828Z。我们已经开始了IC9-LUC90-CD828Z T细胞的临床试验。