A New Approach to Modulating CAR T Cell Activity

调节 CAR T 细胞活性的新方法

• 批准号: 10365202
• 负责人: Ulrike Lorenz
• 金额: $ 2.83万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365202
• 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

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细胞在患有儿童的儿童中非常有效 难治性/复发性急性淋巴细胞白血病（全部），包括主要的白血病 难治性或中枢神经系统疾病。当前的CAR T细胞疗法注入T细胞患者 组成性表达汽车，这些汽车不容易受到任何可控法规的影响。 细胞因子释放综合征（CRS）和与CAR相关的神经毒性（CAN） 可能是致命的，是由不受控制的汽车T细胞激活和扩张引起的。而几个 药理学管理方法已试图克服这个问题，他们 通常是最佳的。此外，来自持久性CD19 CAR T细胞的慢性B细胞植物 需要每月的免疫球蛋白输注，这是繁重且昂贵的，尤其是 对于可能面临终生需求的小儿患者。在这里，我们建议开发一个系统 对于可以根据需要打开和关闭的可控汽车T单元。我们以前有 证明酪氨酸磷酸酶SHP-1的外源表达充当 负调控因子抑制T细胞激活。最近，我们开发了一个可诱导的 通过适应植物生长素诱导的DEGRON，用于SHP-1的可逆蛋白质降解系统 （AID）T细胞系统。将这两个工具结合在AIM 1中，我们建议开发CD19 通过SHP-1的过表达，基本将处于休眠状态的CAR T细胞。然而， 生长素给药后，可以暂时和可逆地激活CAR T细胞 通过SHP-1的降解。由于生长素的剂量足以激活辅助系统 在人类中没有明显的毒性，我们没有预见到翻译该系统的问题 进入诊所。在AIM 2中，我们将检查这种新型汽车T细胞系统在鼠中的功效 所有模型。在AIM 3中，我们将扩展研究以测试是否可调节的CAR T细胞 系统可以使用所有介绍模型来控​​制和/或限制与CAR T细胞相关的毒性， CRS和神经毒性。这种外源可调节的汽车T细胞系统可能会提供 临床医生是避免/限制严重CR的工具，并允许重新填充B细胞 足够的治疗课程后隔间。这种方法将大大提高安全性 CD19 CAR T细胞的大量，可能适用于其他恶性肿瘤的汽车，包括固体 攻击性，离组织的细胞毒性的肿瘤更有问题。