A New Approach to Modulating CAR T Cell Activity

调节 CAR T 细胞活性的新方法

基本信息

批准号：
10709301
负责人：
Ulrike Lorenz
金额：
$ 18.61万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709301
关键词：
Acute Lymphocytic Leukemia Admission activity Adolescent Adult Auxins B lymphoid malignancy B-Lymphocytes B-cell precursor acute lymphoblastic leukemia cell Beauty Brain Edema CAR T cell therapy CD19 gene Cell Compartmentation Central Nervous System Diseases Characteristics Chemotherapy and/or radiation Child Chronic Clinic Clinical Clinical Data Clinical Trials Confusion Development Diagnosis Dose Effector Cell Face Fever Future Goals Heart Rate Hematopoietic Stem Cell Transplantation High Dose Chemotherapy Hispanic Human Hypotension Immune Immunoglobulins In Vitro Incidence Infusion procedures Length of Stay Life Long-Term Survivors Malignant Neoplasms Medical Medication Management Medicine Modeling Morbidity - disease rate Mus Neurologic Neurotoxicity Syndromes PTPN6 gene Patients Pharmaceutical Preparations Plant Growth Regulators Plants Prevention Property Protein Tyrosine Phosphatase Proteins Refractory Refractory Disease Regulation Relapse Resolution Risk Safety Savings Seizures Signal Transduction Solid Neoplasm Specificity System T-Cell Activation T-Lymphocyte Technology Testing Tissues Toxic effect Translating Work Xenograft procedure attenuation base cancer diagnosis cancer immunotherapy chemotherapy chimeric antigen receptor chimeric antigen receptor T cells cytokine release syndrome cytotoxicity efficacy evaluation experience in vivo leukemia mortality risk mouse model neoplastic cell neurotoxicity novel novel strategies overexpression pediatric patients pre-clinical prevent protein degradation public health relevance side effect tool young adult

项目摘要

Abstract Chimeric antigen receptor (CAR) T cells targeting CD19 are highly effective in children with refractory/relapsed acute lymphoblastic leukemia (ALL), including those with primary refractory or CNS disease. Current CAR T cell therapies infuse patients with T cells constitutively expressing CARs, which are not susceptible to any controllable regulation. Cytokine release syndrome (CRS) and CAR-associated neurotoxicity (CAN), both of which can be fatal, arise from uncontrolled CAR T cell activation and expansion. While a few pharmacological management approaches have been attempted to overcome this issue, they are often suboptimal. In addition, chronic B-cell aplasia from persistent CD19 CAR T cells requires monthly infusions of immunoglobulin, which is burdensome and expensive, especially for pediatric patients facing potentially a lifetime need. Here, we propose to develop a system for controllable CAR T cells that can be turned on and off as needed. We have previously demonstrated that exogenous expression of the tyrosine phosphatase SHP-1 acts as a negative regulator to dampen T cell activation. Recently, we have developed an inducible and reversible protein degradation system for SHP-1 by adapting the plant Auxin-induced degron (AID) system for T cells. Combining these two tools in Aim 1, we propose to develop CD19 CAR T cells that will be kept basally dormant through overexpression of SHP-1. However, upon administration of Auxin, the CAR T cells can be temporarily and reversibly activated through the degradation of SHP-1. As the doses of Auxin sufficient to activate the AID system had no significant toxicities in humans, we do not foresee a problem translating this system into the clinic. In Aim 2, we will examine the efficacy of this novel CAR T cell system in a murine model of ALL. In Aim 3, we will expand the studies to test whether this regulatable CAR T cells system can control and/or limit CAR T cell-associated toxicities using a muring model of ALL, CRS and neurotoxicity. Such an exogenously regulatable CAR T cell system may provide clinicians a tool to avoid/limit severe CRS and CAN, and allow repopulation of the B-cell compartment after a sufficient treatment course. This approach will greatly enhance the safety of CD19 CAR T cells and is likely applicable to CARs for other malignancies, including solid tumors, where on-target, off-tissue cytotoxicity is more problematic.

抽象的靶向 CD19 的嵌合抗原受体 (CAR) T 细胞对患有以下疾病的儿童非常有效难治性/复发性急性淋巴细胞白血病（ALL），包括原发性白血病难治性或中枢神经系统疾病。目前的 CAR T 细胞疗法为患者注入 T 细胞组成型表达的 CAR，不受任何可控调控的影响。细胞因子释放综合征 (CRS) 和 CAR 相关神经毒性 (CAN)，两者均由于不受控制的 CAR T 细胞激活和扩增而可能致命。虽然有几个已尝试药理管理方法来克服这个问题，他们往往不是最理想的。此外，持久性 CD19 CAR T 细胞导致慢性 B 细胞再生障碍需要每月输注免疫球蛋白，这是繁重且昂贵的，尤其是适用于面临潜在终生需求的儿科患者。在这里，我们建议开发一个系统用于可根据需要打开和关闭的可控 CAR T 细胞。我们之前有过证明酪氨酸磷酸酶 SHP-1 的外源表达充当抑制 T 细胞活化的负调节因子。最近，我们开发了一种诱导型和通过适应植物生长素诱导的降解决定子来实现 SHP-1 的可逆蛋白质降解系统 T 细胞 (AID) 系统。结合目标 1 中的这两个工具，我们建议开发 CD19 CAR T 细胞将通过 SHP-1 的过度表达保持基本休眠。然而，施用生长素后，CAR T 细胞可以暂时且可逆地激活通过 SHP-1 的降解。由于生长素的剂量足以激活 AID 系统对人类没有显着的毒性，我们预计翻译该系统不会出现问题进入诊所。在目标 2 中，我们将检查这种新型 CAR T 细胞系统在小鼠体内的功效全部的模型。在目标 3 中，我们将扩大研究范围，测试这种可调节 CAR T 细胞是否系统可以使用 ALL 的 muring 模型来控制和/或限制 CAR T 细胞相关的毒性， CRS 和神经毒性。这种外源性可调节的 CAR T 细胞系统可以提供临床医生避免/限制严重 CRS 和 CAN 并允许 B 细胞重新增殖的工具经过足够的疗程后。这种方法将大大提高安全性 CD19 CAR T 细胞，并可能适用于其他恶性肿瘤的 CAR，包括实体瘤肿瘤，其中的靶向、组织外细胞毒性更成问题。