Novel anti-CD19 CAR-T cells for lupus nephritis treatment

用于狼疮性肾炎治疗的新型抗 CD19 CAR-T 细胞

• 批准号: 10434944
• 负责人: Si-Yi Chen
• 金额: $ 20.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434944
• 关键词: Ablation; Antibodies; Antitumor Response; Autoimmune Diseases; B-Lymphocytes; CAR T cell therapy; CD19 gene; Cell surface; Cells; Clinical Trials; Development; Engineering; Epidermal Growth Factor Receptor; Failure; Generations; Immunoglobulin G; Immunoglobulin M; In Vitro; Lupus; Lupus Nephritis; Lymphoma; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Multiple Sclerosis; Mus; Nature; Nephritis; Outcome; Pathogenesis; Patients; Pilot Projects; Proliferating; Refractory; Rheumatoid Arthritis; Serum; Signal Transduction; Systemic Lupus Erythematosus; Testing; Therapeutic; anti-CD20; chimeric antigen receptor T cells; cytokine; cytokine release syndrome; efficacy testing; innovation; mortality; neurotoxicity; novel; novel strategies; rituximab; tositumomab

Project Summary Lupus nephritis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). SLE, a classic B cell-mediated autoimmune disease, is still difficult to treat and about 60% of lupus patients will eventually develop nephritis. Approaches that inactivate or deplete B cells offer attractive strategies for SLE therapy. B cell depletion with a monoclonal antibody against the B cell surface marker, such as anti-CD20 Rituximab, has shown therapeutic promise in rheumatoid arthritis and multiple sclerosis, but was unsuccessful in several clinical trials for SLE. Transient and incomplete nature of B cell depletion by anti-CD20 antibodies may have contributed to its failure to achieve satisfactory outcomes. Hence, new approaches to deplete B cells are needed for the treatment of refractory SLE. Recently, we generated a re-engineered anti-CD19 CAR (CD19- BBz(86)) derived from the classic second-generation CD19-BBz(71) CAR. We found that the re-engineered CD19-BBz(86) CAR-T cells produced lower levels of cytokines and proliferated at a slower rate than the classic CD19-BBz(71) CAR T cells, while they retained potent cytolytic activity. A clinical trial of CD19-BBz(86) CAR-T cells in advanced-stage lymphomas showed durable antitumor responses without causing cytokine release syndrome (CRS) or neurotoxicity, representing a safe and potent therapy for lymphoma (Ying Z et al. Nature Med 25: 947-953, 2019). Importantly, CD19-BBz(86) CAR-T cell therapy caused sustained B cell depletion and reduction of serum IgG and IgM levels in the patients with lymphoma, which suggests that the safer CD19- BBz(86) CAR-T cells could be used for the treatment of refractory SLE as well. In this pilot study, we aim to develop a safe and long-lasting anti-CD19 CAR-T cell therapy for lupus nephritis. The hypothesis of this study is that the novel re-engineered CD19-BBz(86) CAR-T cells co-expressing a cell ablation marker tEGFR have a safe and long-lasting cytolytic activity to deplete CD19+ B cells and reduce serum Ig levels in a sustained manner, resulting in the lasting alleviation of lupus pathogenesis. The specific aims of this study are: Aim 1. To test the efficacy of the re-engineered mouse CD19-BBz(86) CAR-T cells that co-express a cell ablation marker tEGFR to deplete B-cells and alleviate SLE pathogenesis in a mouse SLE model. Aim 2. To test whether anti-EGFR antibody administration depletes mCD19-BBz(86) CAR-T cells coexpressing tEGFR to reverse B cell aplasia in mice. Aim 3. To mechanistically investigate the CAR-triggered signaling of the novel re-engineered mouse CD19- BBz(86) CAR-T cells in comparison with the classic second-generation mCD19-BBz(71) CAR-T cells in vitro. This proposed study is highly significant and novel, since this study will lead to the development of a novel, safe and long-lasting anti-CD19 CAR-T cell therapy for lupus nephritis.

项目概要 狼疮性肾炎是系统性红斑狼疮（SLE）患者发病和死亡的主要原因。 SLE 是一种经典的 B 细胞介导的自身免疫性疾病，目前仍难以治疗，约 60% 的狼疮患者会出现以下症状： 最终发展成肾炎。灭活或消耗 B 细胞的方法为 SLE 提供了有吸引力的策略 治疗。使用针对 B 细胞表面标志物（例如抗 CD20）的单克隆抗体消除 B 细胞 利妥昔单抗已显示出治疗类风湿关节炎和多发性硬化症的前景，但并未成功 参与多项 SLE 临床试验。抗 CD20 抗体造成的 B 细胞消耗的瞬时性和不完全性可能 导致其未能取得令人满意的结果。因此，消耗 B 细胞的新方法是 治疗难治性 SLE 所需。最近，我们生成了重新设计的抗CD19 CAR（CD19- BBz(86))源自经典的第二代CD19-BBz(71) CAR。我们发现重新设计的 CD19-BBz(86) CAR-T 细胞产生的细胞因子水平较低，增殖速度比经典细胞更慢 CD19-BBz(71) CAR T 细胞，同时保留了有效的细胞溶解活性。 CD19-BBz(86) CAR-T临床试验 晚期淋巴瘤中的细胞表现出持久的抗肿瘤反应，而不引起细胞因子释放 综合征（CRS）或神经毒性，代表了一种安全有效的淋巴瘤治疗方法（Ying Z 等人，Nature 医学 25：947-953，2019）。重要的是，CD19-BBz(86) CAR-T 细胞疗法导致 B 细胞持续耗竭， 淋巴瘤患者血清 IgG 和 IgM 水平降低，这表明 CD19- 更安全 BBz(86) CAR-T细胞也可用于治疗难治性SLE。在这项试点研究中，我们的目标是 开发一种安全、持久的抗 CD19 CAR-T 细胞疗法治疗狼疮肾炎。本研究的假设 是共表达细胞消融标记物 tEGFR 的新型重新设计的 CD19-BBz(86) CAR-T 细胞具有 安全且持久的细胞溶解活性，可持续消耗 CD19+ B 细胞并降低血清 Ig 水平， 从而持久缓解狼疮发病机制。本研究的具体目的是： 目的 1. 测试 共表达细胞消融标记物 tEGFR 的重新设计的小鼠 CD19-BBz(86) CAR-T 细胞的功效 在小鼠 SLE 模型中消耗 B 细胞并减轻 SLE 发病机制。目的2.测试是否抗EGFR 抗体给药消耗共表达 tEGFR 的 mCD19-BBz(86) CAR-T 细胞，以逆转 B 细胞发育不全 老鼠。目标 3. 从机制上研究新型重组小鼠 CD19- 的 CAR 触发信号传导 BBz(86) CAR-T 细胞与经典的第二代 mCD19-BBz(71) CAR-T 细胞在体外的比较。 这项拟议的研究非常重要且新颖，因为这项研究将导致开发一种新颖的、安全的 以及针对狼疮性肾炎的长效抗 CD19 CAR-T 细胞疗法。