Novel targeted CAR-T multiple myeloma therapy

新型靶向 CAR-T 多发性骨髓瘤治疗

• 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
• 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

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.

项目总结 多发性骨髓瘤(MM)是一种浆细胞(PC)的恶性肿瘤，在美国造成超过12,500人死亡 全球每年有11.7万人死亡。目前，美国超过91,000人和全球超过30万人生活在一起 尽管在过去的二十年里，多发性骨髓瘤的治疗取得了重大进展，但多发性骨髓瘤仍然是不治之症，而且大多数多发性骨髓瘤患者 屈从于潜在的恶毒。最近的治疗通过嵌合抗原受体-T细胞(CAR-TS)重定向T细胞 或针对B细胞成熟抗原(BCMA)的双特异性抗体显著提高了患者的存活率 以前的治疗方法难以治愈的疾病。然而，几乎所有的多发性骨髓瘤患者都会经历疾病的进展并成为 对这些BCMA靶向T细胞疗法无效。因此，迫切需要为以下目标制定新的目标 这些有效的T细胞导向多发性骨髓瘤疗法。这一阶段的SBIR应用通过一种新的单抗满足了这一需求 指定为MM3的抗体(MAb)。MM3属于一类新的抗体，可变淋巴细胞受体B(VLRB) 由无颌脊椎动物、七鳃鳗和七鳃鳗的B细胞产生的抗体，并与一种独特的形式特异结合 有效的MM治疗靶点，CD38细胞表面蛋白的多聚体，没有检测到结合 至CD38单体。CD38多聚体在PC和MM肿瘤中有独特表达，而CD38单体在PC和MM肿瘤中有独特表达 由许多其他正常细胞类型表达，包括NK和T细胞免疫效应器。CAR-T细胞利用MM3作为 因此，靶标识别结构域避免了与单体结合相关潜在“靶上/肿瘤外”毒性 CD38，同时表达单体CD38和结合CAR抗原结合域的CAR-T细胞中的“兄弟杀虫” 单体CD38与NK和T细胞免疫效应器的耗竭。肿瘤高表达多聚体CD38 复发难治性多发性骨髓瘤(RRMM)患者的细胞对蛋白酶体和/或免疫调节剂药物无效。虽然 CD38表达下调是抵抗抗CD38单抗治疗的几种机制之一，例如， 抗CD38单抗治疗后3-6个月内，高水平CD38和多聚体CD38表达恢复 停药后，87%以上的RRMM患者的MM肿瘤细胞表达高水平的CD38多聚体 Mm~3。MM3人CAR-T细胞已经被制造出来，并在体外实验中显示只对细胞有直接的CAR-T杀伤作用 表达多聚体CD38。本应用将通过以下方式扩展这些结果：(1)用T细胞生产MM3CAR-T细胞 来自健康志愿者和抗BCMA CAR-T治疗后复发患者的制剂 体外靶向杀伤骨髓瘤细胞系和自体骨髓瘤细胞的研究 抗BCMA CAR-T细胞对复发MM患者的体内抗肿瘤作用 MISTRG6“人源化”小鼠移植了人MM肿瘤细胞系。这些第一阶段研究之后将分阶段进行。 2用RRMM患者T细胞产生的MM3抗体对同一患者体内肿瘤的抑制作用 MISTRG6模型和GMP生产MM3CAR慢病毒和MM3CAR-T细胞，以及IND使能 药理学/毒理学研究支持首次对MM患者进行这种新的CAR-T疗法的人体临床试验 所有其他疗法都失败了。