Allogeneic BAFF Ligand Based CAR T Cells as a Novel Therapy for B Cell Malignancies

基于同种异体 BAFF 配体的 CAR T 细胞作为 B 细胞恶性肿瘤的新疗法

基本信息

批准号：
10698759
负责人：
Hunter Ramsdell Gibbons
金额：
$ 39.79万
依托单位：
LUMINARY THERAPEUTICS, 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：
2023-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698759
关键词：
Address Adoption Affinity Allogenic Animals Antigen Targeting Antigens Autologous B lymphoid malignancy B-Cell Activation B-Lymphocytes Benefits and Risks Binding Biological Assay CAR T cell therapy CD19 gene Cell Line Cell Therapy Cells Cellular biology Chemistry Clinical Coculture Techniques Complex DNA DNA Transposons Data Development Documentation Dose Drug Kinetics Engineering Evaluation Family Generations Genetic Genetic Engineering Human Immunocompromised Host Immunotherapeutic agent Immunotherapy In Vitro Interleukin 4 Receptor Life Ligands Longevity MS4A1 gene Malignant - descriptor Malignant Neoplasms Mantle Cell Lymphoma Mature B-Lymphocyte Memory Messenger RNA Methods Mus Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase Population Positioning Attribute Process Production Property Protocols documentation Qualifying Quality Control Recommendation Recurrent disease Relapse Reproducibility Residual state Running Safety Signal Transduction Source Specific qualifier value System T cell therapy T-Lymphocyte Technology Transfer Testing Therapeutic Intervention Time Toxic effect Toxicity Tests Tumor Antigens Validation Viral Work Xenograft procedure cancer cell cell killing chimeric antigen receptor chimeric antigen receptor T cells commercialization cost cost effective cytotoxic cytotoxicity design efficacy evaluation engineered T cells experience good laboratory practice graft vs host disease improved improved outcome in vivo in vivo evaluation innovation manufacture manufacturing process mouse model neoplastic novel novel therapeutics patient subsets pre-clinical preclinical evaluation preservation prevent product development receptor receptor expression response safety study safety testing targeted treatment therapeutic development timeline tumor tumor xenograft γδ T cells

Address Adoption Affinity Allogenic Animals Antigen Targeting Antigens Autologous B lymphoid malignancy B-Cell Activation B-Lymphocytes Benefits and Risks Binding Biological Assay CAR T cell therapy CD19 gene Cell Line Cell Therapy Cells Cellular biology Chemistry Clinical Coculture Techniques Complex DNA DNA Transposons Data Development Documentation Dose Drug Kinetics Engineering Evaluation Family Generations Genetic Genetic Engineering Human Immunocompromised Host Immunotherapeutic agent Immunotherapy In Vitro Interleukin 4 Receptor Life Ligands Longevity MS4A1 gene Malignant - descriptor Malignant Neoplasms Mantle Cell Lymphoma Mature B-Lymphocyte Memory Messenger RNA Methods Mus Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase Population Positioning Attribute Process Production Property Protocols documentation Qualifying Quality Control Recommendation Recurrent disease Relapse Reproducibility Residual state Running Safety Signal Transduction Source Specific qualifier value System T cell therapy T-Lymphocyte Technology Transfer Testing Therapeutic Intervention Time Toxic effect Toxicity Tests Tumor Antigens Validation Viral Work Xenograft procedure cancer cell cell killing chimeric antigen receptor chimeric antigen receptor T cells commercialization cost cost effective cytotoxic cytotoxicity design efficacy evaluation engineered T cells experience good laboratory practice graft vs host disease improved improved outcome in vivo in vivo evaluation innovation manufacture manufacturing process mouse model neoplastic novel novel therapeutics patient subsets pre-clinical preclinical evaluation preservation prevent product development receptor receptor expression response safety study safety testing targeted treatment therapeutic development timeline tumor tumor xenograft γδ T cells

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项目摘要

ABSTRACT Since the first FDA approval of chimeric antigen receptor (CAR) T cell therapy in 2017, the use of engineered T cells expressing specific CARs to treat cancer has generated durable cures for many patients. Nevertheless, a significant subset of patients with B cell malignancies relapse following treatment due to lack of CAR T cell persistence and the ability of cancer cells to change with time and evade therapeutic interventions. Autologous T cell therapies also carry significant timeline and cost burdens, making widespread adoption difficult. In this application, we propose a novel allogeneic CAR T cell therapy aimed at improving outcomes for patients with mantle cell lymphoma (MCL) by overcoming deficiencies present in current generation CD19 targeted therapeutics. B cell activating factor (BAFF) provides critical survival signals to both normal and neoplastic B cells through a family of receptors (BAFF receptor, TACI, and BCMA) thus mitigating potential for antigen escape. BAFF and its receptors have remained underexplored in the context of B cell malignancies where strategies have relied overwhelmingly on pan B cell antigens such as CD19 and CD20. Since BAFF binds its receptors with moderate affinity, we believe this will increase the ability of these cells to form memory populations and engage in serial killing. We will leverage this ligand-based CAR design in an allogeneic gamma delta (γδ) T cell platform, as γδ T cells have been shown to have high replicative properties in vitro and do not mediate graft versus host disease in new hosts. We have produced preliminary data that confirms our ability to use the non- viral TcBuster DNA transposon system to generate T cells with BAFF-CAR expression. The overall objective of this proposal is to further develop and evaluate our γδ BAFF-CAR T cell therapy for the treatment of MCL in IND enabling studies. In doing so, our allogeneic BAFF-CAR T cell therapy supports an urgently needed shift in therapeutic development toward new tumor antigens that protect against antigen escape while reducing the manufacturing burden associated with cellular therapies through use of a readily available cell source.

抽象的自2017年首次FDA批准嵌合抗原受体（CAR）T细胞疗法以来表达特定汽车治疗癌症的细胞为许多患者产生了持久的治疗方法。然而，由于缺乏CAR T细胞，治疗后B细胞恶性继电器患者的显着子集持久性和癌细胞随时间变化并逃避治疗干预措施的能力。自体 T细胞疗法还具有大量的时间表和成本伯恩斯的成本，使得宽度的采用变得困难。在这个应用，我们提出了一种新型的同种异体汽车T细胞疗法，旨在改善通过克服当前一代CD19中存在的缺陷靶标的地幔细胞淋巴瘤（MCL）。疗法。 B细胞激活因子（BAFF）为正常和肿瘤B提供了关键的生存信号细胞通过一个受体家族（BAFF受体，TACI和BCMA），从而减轻抗原逃生的潜力。在B细胞恶性肿瘤的背景下，Baff及其接收器在策略的情况下仍未得到充实绝大多数依赖于PAN B细胞抗原，例如CD19和CD20。由于Baff绑定了其接收器有了中等亲和力，我们认为这将增加这些细胞形成记忆种群的能力，并进行连环杀戮。我们将利用这种基于配体的汽车设计在同种异体伽玛三角洲（γδ）T细胞中平台，由于γδT细胞已显示出体外具有高复制特性，并且不介导移植物与新宿主中的宿主疾病相对于宿主疾病。我们已经产生了初步数据，证实了我们使用非 - 病毒TCBUSTER DNA转座子系统可生成带有BAFF-CAR表达的T细胞。总体目标该建议是进一步开发和评估我们的γδBaff-CAR T细胞疗法，用于在IND中治疗MCL 启用研究。这样，我们的同种异体baff-car T细胞疗法支持急需的转变对新的肿瘤抗原的治疗发育，可防止抗原逃逸，同时减少通过使用易于使用的细胞来源，制造与细胞疗法相关的Burnen。