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

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 FDA 首次批准嵌合抗原受体 (CAR) T 细胞疗法以来，工程化 T 细胞的使用表达特定 CAR 来治疗癌症的细胞已经为许多患者带来了持久的治愈。由于缺乏 CAR T 细胞，相当一部分 B 细胞恶性肿瘤患者在治疗后复发癌细胞的持久性和随时间变化并逃避自体治疗干预的能力。 T 细胞疗法还具有重大的时间安排和成本负担，使得广泛采用变得困难。在应用中，我们提出了一种新型同种异体 CAR T 细胞疗法，旨在改善患有套细胞淋巴瘤 (MCL) 通过克服当前一代 CD19 靶向存在的缺陷 B 细胞激活因子 (BAFF) 为正常和肿瘤性 B 细胞提供关键的生存信号。通过一系列受体（BAFF 受体、TACI 和 BCMA）与细胞结合，从而减轻抗原逃逸的可能性。 BAFF 及其受体在 B 细胞恶性肿瘤的背景下仍未得到充分研究，其中策略由于 BAFF 与其受体结合，因此绝大多数依赖于 CD19 和 CD20 等泛 B 细胞抗原。具有中等亲和力，我们相信这将增加这些细胞形成记忆群体的能力我们将在同种异体 γ δ (γδ) T 细胞中利用这种基于配体的 CAR 设计。平台，因为 γδ T 细胞已被证明在体外具有高复制特性并且不介导移植我们已经产生了初步数据，证实了我们使用非-宿主疾病的能力。病毒 TcBuster DNA 转座子系统产生具有 BAFF-CAR 表达的 T 细胞。该提案旨在进一步开发和评估我们的 γδ BAFF-CAR T 细胞疗法用于治疗 IND 中的 MCL 在此过程中，我们的同种异体 BAFF-CAR T 细胞疗法支持了迫切需要的转变。开发新的肿瘤抗原，可以治疗性地防止抗原逃逸，同时减少通过使用现成的细胞来源，与细胞疗法相关的制造负担。