Novel targeted CAR-T multiple myeloma therapy

新型靶向 CAR-T 多发性骨髓瘤治疗

基本信息

批准号：
10821186
负责人：
Lovick Edward Cannon
金额：
$ 30.2万
依托单位：
NOVAB, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10821186
关键词：
Acceleration Adaptive Immune System Address Antibodies Antigen Receptors Antigen Targeting Antigens Autologous B-Cell Antigen Receptor B-Lymphocytes Binding Binding Sites Bispecific Antibodies Cell Line Cell Maturation Cell Surface Proteins Cells Cessation of life Clinical Clinical Trials Development Disease Progression Down-Regulation Engineering Engraftment Goals Growth Hagfish Hematologic Neoplasms Human Human Volunteers Immune Immune Targeting Immunoglobulins Immunologic Receptors Immunotherapy In Vitro Individual Lampreys Lentivirus Leucine-Rich Repeat Lymphocyte Malignant Neoplasms Modeling Monoclonal Antibodies Monoclonal Antibody Therapy Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Natural Killer Cells Normal Cell Patients Pharmacology and Toxicology Phase Plasma Cells Plasmablast Prior Therapy Production Refractory Refractory Disease Relapse Resistance Small Business Innovation Research Grant Source Specificity Surface Antigens T cell therapy T-Lymphocyte Therapeutic Toxic effect Tumor Cell Line Tumor-Derived Vertebrates antigen binding antitumor effect beta pleated sheet cell preparation cell type chimeric antigen receptor T cells cytotoxicity experience first-in-human humanized mouse immune modulating agents improved in vitro Assay in vivo in vivo evaluation monomer mouse model multicatalytic endopeptidase complex neoplastic neoplastic cell novel novel strategies novel therapeutics phase 1 study receptor recoverin protein relapse patients resistance mechanism response targeted treatment therapeutic target tumor

Acceleration Adaptive Immune System Address Antibodies Antigen Receptors Antigen Targeting Antigens Autologous B-Cell Antigen Receptor B-Lymphocytes Binding Binding Sites Bispecific Antibodies Cell Line Cell Maturation Cell Surface Proteins Cells Cessation of life Clinical Clinical Trials Development Disease Progression Down-Regulation Engineering Engraftment Goals Growth Hagfish Hematologic Neoplasms Human Human Volunteers Immune Immune Targeting Immunoglobulins Immunologic Receptors Immunotherapy In Vitro Individual Lampreys Lentivirus Leucine-Rich Repeat Lymphocyte Malignant Neoplasms Modeling Monoclonal Antibodies Monoclonal Antibody Therapy Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Natural Killer Cells Normal Cell Patients Pharmacology and Toxicology Phase Plasma Cells Plasmablast Prior Therapy Production Refractory Refractory Disease Relapse Resistance Small Business Innovation Research Grant Source Specificity Surface Antigens T cell therapy T-Lymphocyte Therapeutic Toxic effect Tumor Cell Line Tumor-Derived Vertebrates antigen binding antitumor effect beta pleated sheet cell preparation cell type chimeric antigen receptor T cells cytotoxicity experience first-in-human humanized mouse immune modulating agents improved in vitro Assay in vivo in vivo evaluation monomer mouse model multicatalytic endopeptidase complex neoplastic neoplastic cell novel novel strategies novel therapeutics phase 1 study receptor recoverin protein relapse patients resistance mechanism response targeted treatment therapeutic target tumor

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项目摘要

PROJECT SUMMARY Multiple myeloma (MM), a malignancy of plasma cells (PCs), is responsible for over 12,500 deaths in the US and over 117,000 deaths worldwide annually. Over 91,000 individuals in the US and over 300,000 worldwide currently live with MM. In spite of major therapeutic advances in the past two decades, MM remains incurable and most MM patients succumb to the underlying malignancy. Recent therapies redirecting T cells via chimeric antigen receptor-T cells (CAR-Ts) or bispecific antibodies that target B Cell Maturation Antigen (BCMA) have significantly improved survival of patients with disease refractory to prior therapies. However, nearly all MM patients experience disease progression and become refractory to these BCMA-targeted T cell therapies. There is therefore an urgent unmet need to develop new targets for these potent T cell-directed MM therapies. This phase 1 SBIR application addresses that need with a novel monoclonal antibody (mAb) designated MM3. MM3 belongs to a new class of antibodies, Variable Lymphocyte Receptor B (VLRB) antibodies produced by the B cells of jawless vertebrates, lamprey and hagfish, and specifically binds to a distinctive form of a well-validated MM therapeutic target, multimeric forms of the CD38 cell surface protein, with no detectable binding to CD38 monomers. CD38 multimers are uniquely expressed by PCs and MM tumors, whereas CD38 monomers are expressed by numerous other normal cell types, including NK and T cell immune effectors. CAR-T cells that utilize MM3 as target recognition domain therefore avoid potential “on-target/off-tumor” toxicity associated with binding to monomeric CD38, “fratricide” among CAR-T cells that express both monomeric CD38 and CAR antigen binding domains that bind monomeric CD38, and depletion of NK and T cell immune effectors. Multimeric CD38 is highly expressed by the tumor cells of relapsed-refractory MM (RRMM) patients refractory to proteasome and/or immunomodulator drugs. Although downregulation of CD38 expression is one of several mechanisms of resistance to anti-CD38 mAb therapy, e.g., daratumumab, high levels of CD38 and multimeric CD38 expression return within 3 to 6 months of anti-CD38 mAb therapy discontinuation, and MM tumor cells of over 87% of RRMM patients express high levels of CD38 multimers detected with MM3. MM3 human CAR-T cells have been produced and shown with in vitro assays to direct CAR-T killing only to cells that express multimeric CD38. This application will extend those results by: (1) producing MM3 CAR-T cells with T cell preparations derived from healthy human volunteers and from patients relapsed following anti-BCMA CAR-T therapy and evaluating in vitro target-specific activation and cytotoxicity against a MM cell line and autologous MM tumor cells from anti-BCMA CAR-T relapsed MM patients, and (2) evaluating the in vivo anti-tumor efficacy of MM3 CAR-T cells with MISTRG6 “humanized” mice engrafted with a human MM tumor cell line. These phase 1 studies will be followed by phase 2 in vivo evaluations of MM3 CAR-Ts produced with RRMM patient T cells against tumors from those same patients in the MISTRG6 model and by GMP production of MM3 CAR lentivirus and MM3 CAR-T cells, and IND-enabling pharmacology/toxicology studies to support first in human clinical trials of this new CAR-T therapy for MM patients that have failed all other therapies.

项目摘要多发性骨髓瘤（MM）是浆细胞（PC）的恶性肿瘤，在美国及以上造成12,500多人死亡全球117,000人死亡。美国超过91,000个人，目前在全球范围内有超过30万人毫米。尽管在过去的二十年中取得了重大治疗进展，但MM仍然无法治愈，大多数MM患者屈服于潜在的恶性肿瘤。最近的疗法通过嵌合抗原受体T细胞（CAR-TS）重定向T细胞或靶向B细胞成熟抗原（BCMA）的双特异性抗体（BCMA）显着提高了患者的存活率对先前疗法难治性的疾病。但是，几乎所有MM患者都经历了疾病的进展并成为对这些靶向BCMA的T细胞疗法的难治性。因此，紧迫的未满足需要为这些潜在的T细胞指导的MM疗法。此阶段1 SBIR应用程序解决了新型单克隆的需求抗体（MAB）指定的MM3。 MM3属于新的抗体，可变的淋巴细胞受体B（VLRB）由颌脊椎动物，lamp和hag鱼的B细胞产生的抗体，特别结合了独特的形式 CD38细胞表面蛋白的验证良好的MM治疗靶标的多种形式的形式，没有可检测的结合到CD38单体。 CD38多聚体由PC和MM肿瘤唯一表达，而CD38单体是由许多其他正常细胞类型表达，包括NK和T细胞免疫作用。使用MM3作为的CAR-T细胞因此，目标识别域避免了与与单体结合有关的潜在“靶向/非肿瘤”毒性 CD38，CAR-T细胞中的“ Fratricide”，这些细胞表达单体CD38和CAR抗原结合结构域的CD38 单体CD38，以及NK和T细胞免疫作用的耗竭。多聚体CD38由肿瘤高度表达继发性侵蚀性MM（RRMM）患者的细胞对蛋白酶体和/或免疫调节剂药物难治性。虽然 CD38表达的下调是抗CD38 MAB治疗的几种机制之一，例如 daratumumab，高水平的CD38和多媒体CD38表达在抗CD38 MAB治疗3至6个月内停用的RRMM患者中有超过87％的MM肿瘤细胞表达了高水平的CD38多聚体。 MM3。 MM3人CAR-T细胞已被生成并用体外测定法显示，以直接杀死细胞那个表达的多药CD38。该应用将通过以下方式扩展这些结果：（1）用T细胞产生MM3 CAR-T细胞源自健康的人类志愿者和抗BCMA CAR-T疗法的患者的准备工作评估对MM细胞系和自体MM肿瘤细胞的体外靶标特异性激活和细胞毒性抗BCMA CAR-T传递MM患者，（2）评估MM3 CAR-T细胞的体内抗肿瘤效率 Mistrg6“人源化”小鼠植入了人类MM肿瘤细胞系。这些第1阶段的研究将随后进行阶段 2用RRMM患者T细胞对来自同一患者的肿瘤产生的MM3 CAR-TS的体内评估 MISTRG6模型以及GMP生产MM3 CAR慢病毒和MM3 CAR-T细胞，以及成分药理学/毒理学研究首先支持这种新的CAR-T治疗的MM患者的人类临床试验所有其他疗法都无法通过。