CAR-T cell control through orthogonal antibody-based switches

通过基于正交抗体的开关控制 CAR-T 细胞

• 批准号: 10001984
• 负责人: Travis Scott Young
• 金额: $ 32.7万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-12 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001984
• 关键词: Acute Lymphocytic Leukemia; Adoptive Transfer; Adverse event; Affect; Antibodies; Antigen Targeting; Antigens; B lymphoid malignancy; B-Cell Leukemia; B-Cell Neoplasm; B-Lymphocytes; CAR T cell therapy; CD19 gene; Cell Therapy; Cells; Cicatrix; Clinic; Clinical Trials; Development; Dose; Engineering; Goals; Human; Immune system; In complete remission; Investigation; Knowledge; Malignant - descriptor; Mediating; Medical; Memory; Methods; Mission; Mus; Outcome; Patients; Phase I Clinical Trials; Phenotype; Public Health; Recombinant Antibody; Recurrent disease; Refractory; Relapse; Reporting; Research; Safety; Specificity; Standardization; Structure; T-Lymphocyte; Testing; Therapeutic; Therapeutic Index; Therapeutic antibodies; Time; Titrations; Toxic effect; Treatment Protocols; Tumor Antigens; Tumor Burden; Tumor Lysis Syndrome; United States National Institutes of Health; Work; Xenograft procedure; advanced disease; antibody engineering; base; bench to bedside; cancer cell; cancer clinical trial; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; cost; cytokine; cytokine release syndrome; design; human disease; immunological synapse; improved; in vivo; in vivo Model; leukemia; leukemia treatment; leukemia/lymphoma; method development; mouse model; prevent; resistance mutation; safety study; side effect; tumor

Project Summary/Abstract: Chimeric antigen receptor T (CAR-T) cell therapy has produced remarkable results in clinical trials for cancer; providing complete remissions in patients with relapsed refractory acute lymphoblastic leukemia, and offering patients a realistic hope for a cure. However, challenges related to the inability to control CAR-T cells once infused into the patient pose significant safety concerns. This includes permanent B cell aplasia and fatal cases of cytokine release syndrome. Additionally, loss of antigen expression on malignant cells renders conventional CAR-T cells ineffective against relapsed disease and has been attributed to a significant number of relapses in early stage clinical trials for ALL and CLL leukemia. Correspondingly, the development of mechanisms to control CAR-T cells represents a critical and urgent unmet medical need which warrants thorough investigation to provide a safe and efficacious CAR-T cell therapy for patients. Towards this end, this proposal describes a method of engineering antibody-based switches which enables tunable control over CAR-T cell activity. These switches mediate formation of an orthogonal immunological synapse between the target cell, switch, and CAR-T cell which is structurally, stoichiometrically, and temporally defined to enable a level of control which has not been reported previously. The long term goal of this work is to understand how these switches can improve safety and versatility in the clinic. The overall objective of this proposal is to investigate the use of switches to control activity of CAR-T cells in the context of leukemia and lymphoma using mouse models. Our central hypothesis is that antibody-based switches which control the specificity and duration of CAR-T cell activity in vivo will enable control over the efficacy, persistence, and safety of adoptively transferred CAR-T cells. The rationale for this research is that a sCAR-T cell which functions orthogonally within the patient’s immune system is safer than conventional CAR-T cell therapy because it is controlled by, and entirely dependent on, dosing of the antibody-based switch. To test the central hypothesis, aim 1 will determine the redirection of switchable CAR-T cells to more than one antigen in mouse models which mimic disease relapse. Aim 2 will determine how switch-based control effects CAR-T cell phenotype which is significant because persistent phenotypes are strongly associated with complete remissions in clinical trials. Aim 3 will use a unique mouse model which recapitulates the toxicity associated with conventional CART-19 therapy to demonstrate switch-based control over severe adverse side effects. The proposed research is a significant step in the development of a universal CAR construct which would obviate the need to reconstruct a new CAR for each antigen target. This is expected to substantially lower the cost and time of “bench to bedside” development, as well as provide a standardized treatment regimen which is not yet possible with conventional CAR-T cells.

项目摘要/摘要： 嵌合抗原受体T（CAR-T）细胞疗法在癌症临床试验中取得了显著成果； 为复发难治性急性淋巴细胞白血病患者提供完全缓解，并提供 患者对治愈的现实希望。然而，一旦出现无法控制 CAR-T 细胞的挑战 输注到患者体内会带来重大的安全问题。这包括永久性 B 细胞再生障碍和致命病例 细胞因子释放综合征。此外，恶性细胞上抗原表达的丧失使得传统的 CAR-T 细胞对复发性疾病无效，并且已被归因于大量复发 ALL 和 CLL 白血病的早期临床试验。相应地，建立控制机制 CAR-T 细胞代表了一个关键而紧迫的未满足的医疗需求，需要进行彻底的调查 为患者提供安全有效的CAR-T细胞治疗。 为此，该提案描述了一种工程化基于抗体的开关的方法，该方法使得 对 CAR-T 细胞活性的可调控制。这些开关介导正交免疫学的形成 靶细胞、开关和 CAR-T 细胞之间的突触在结构上、化学计量上和时间上是一致的 定义为实现以前未报告过的控制级别。这项工作的长期目标是 了解这些开关如何提高诊所的安全性和多功能性。本次活动的总体目标 该提案的目的是研究在白血病和白血病的背景下使用开关来控制 CAR-T 细胞的活性 使用小鼠模型进行淋巴瘤。我们的中心假设是基于抗体的开关控制 CAR-T细胞体内活性的特异性和持续时间将能够控制功效、持久性和安全性 过继转移的 CAR-T 细胞。这项研究的基本原理是 sCAR-T 细胞具有功能 患者免疫系统内的正交疗法比传统的 CAR-T 细胞疗法更安全，因为它 由基于抗体的开关的剂量控制并完全依赖于该剂量。 为了检验中心假设，目标 1 将确定可切换 CAR-T 细胞的重定向超过 模拟疾病复发的小鼠模型中的一种抗原。目标 2 将确定如何基于开关进行控制 影响 CAR-T 细胞表型，这一点很重要，因为持久表型与 临床试验中完全缓解。 Aim 3 将使用独特的小鼠模型来概括毒性 与传统 CART-19 疗法相关，以证明对严重不良反应的基于开关的控制 影响。拟议的研究是开发通用 CAR 结构的重要一步， 将消除为每个抗原靶标重建新 CAR 的需要。预计这将大幅降低 “从实验室到临床”开发的成本和时间，以及提供标准化的治疗方案 传统的 CAR-T 细胞尚无法实现这一点。

项目成果

Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory.

• DOI: 10.1073/pnas.1810060115
• 发表时间: 2018-11-13
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Viaud S;Ma JSY;Hardy IR;Hampton EN;Benish B;Sherwood L;Nunez V;Ackerman CJ;Khialeeva E;Weglarz M;Lee SC;Woods AK;Young TS
• 通讯作者: Young TS