A New Approach to Modulating CAR T Cell Activity

调节 CAR T 细胞活性的新方法

• 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
• 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

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.

摘要 针对CD19的嵌合抗原受体(CAR)T细胞对儿童白血病非常有效 难治性/复发性急性淋巴细胞白血病(ALL)，包括原发 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 构成表达的汽车，不受任何可控监管的影响。 细胞因子释放综合征(CRS)和CAR相关神经毒性(CAN)，两者都 可能是致命的，由不受控制的CAR T细胞激活和扩张引起。虽然有几个 已经尝试了药理学管理方法来克服这个问题，他们 往往是次优的。此外，持续性CD19 CAR T细胞的慢性B细胞再生障碍性疾病 需要每月注射免疫球蛋白，这是负担和昂贵的，特别是 对于可能面临终生需求的儿科患者。在这里，我们建议开发一个系统 用于可控的CAR T细胞，可根据需要打开和关闭。我们之前已经 证明了酪氨酸磷酸酶SHP-1的外源表达是一种 抑制T细胞活化的负性调节因子。最近，我们开发了一种可诱导和 适应植物生长素诱导降解的SHP-1可逆蛋白质降解系统 T细胞(辅助)系统。在目标1中结合这两个工具，我们建议开发CD19 通过过度表达SHP-1而保持基本休眠的CAR T细胞。然而， 在给予生长素后，CAR T细胞可以被暂时和可逆地激活 通过对SHP-1的降解。因为足够激活AID系统的生长素剂量 在人类身上没有明显的毒性，我们预计翻译这个系统不会有问题 送进诊所。在目标2中，我们将检查这种新的CAR T细胞系统在小鼠身上的有效性 所有人的典范。在目标3中，我们将扩展研究以测试这种可调节的CAR T细胞 系统可以使用混合模型控制和/或限制CAR T细胞相关的毒性， CRS和神经毒性。这种外源可调节CAR T细胞系统可提供 临床医生提供了避免/限制严重CRS和CAN的工具，并允许B细胞重新繁殖 经过充分的治疗疗程后进入隔室。这种方法将大大提高安全性。 CD19 CAR T细胞，并可能适用于包括实体瘤在内的其他恶性肿瘤的CARS 肿瘤，在靶点上，组织外的细胞毒性更有问题。