Prognostic and Therapeutic Implications of IFNAR1 Signaling on CAR T Cell Therapy for Cancer

IFNAR1 信号传导对癌症 CAR T 细胞治疗的预后和治疗意义

基本信息

批准号：
10215845
负责人：
Matthew John Atherton
金额：
$ 15.37万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10215845
关键词：
Adoptive Cell Transfers Antigens Autologous Award B lymphoid malignancy B-Cell Lymphomas B-Cell Neoplasm B-Lymphocytes Biological Blood Component Removal CD19 gene Cancer Patient Canis familiaris Cell Count Cell Therapy Cell surface Cells Cessation of life Chronic Lymphocytic Leukemia Classification Clinical Clinical Trials Data Development Development Plans Down-Regulation Enrollment Exposure to Fc Receptor Fever Foundations Future Generations Genetic Human IFNAR1 gene Immune response Immunologics Immunology Immunotherapeutic agent In Vitro In complete remission Infusion procedures Interferon Receptor Interferon Type I Interferons Knowledge Malignant Neoplasms Malignant lymphoid neoplasm Measurable Mediating Memory Modeling Mus Neoplasms Oncologist Outcome Patient-Focused Outcomes Patients Pennsylvania Pharmacology Phenotype Pilot Projects Play Pre-Clinical Model Primary Neoplasm Prognostic Marker Publishing Refractory Research Rodent Safety Scientist Secure Signal Transduction Solid Surface T cell therapy T memory cell T-Cell Activation T-Cell Development T-Cell Proliferation T-Cell Receptor T-Lymphocyte Techniques Testing Therapeutic Time Traction Training Treatment Efficacy Tumor-Infiltrating Lymphocytes Ubiquitination Universities anti-tumor immune response blood product cancer therapy career development chimeric antibody clinical predictors cytokine release syndrome efficacy evaluation genetic signature improved improved outcome in vivo inhibitor/antagonist innovation insight large cell Diffuse non-Hodgkin&apos s lymphoma mouse model mutant p38 Mitogen Activated Protein Kinase pilot trial pre-clinical pre-clinical assessment preclinical efficacy prognostic prognostic significance response success trait trial design tumor tumor progression type I interferon receptor

项目摘要

Adoptive cellular therapy (ACT) has revolutionized the treatment of certain malignancies and responses in refractory B cell tumors treated with chimeric antibody receptor (CAR)-expressing T cells have been remarkable. However, ACT is not consistently curative even in these particularly responsive cancers, highlighting the critical need for innovative approaches to improve this powerful therapeutic approach. Type I interferon (IFN) signaling through the type I interferon receptor (IFNAR) plays a key role in the activation, differentiation and function of T cells. Importantly, degradation of the type I interferon receptor chain subunit 1 (IFNAR1) in anti-tumor T cells favors tumor progression whereas its genetic or pharmacologic (by p38 inhibition) stabilization improves anti-tumor T cell activity in mouse models. While rodent studies have yielded much preclinical insight into CAR T cells, they fail to accurately predict clinical safety and efficacy. However, genetically outbred and immunologically intact canine cancer patients that develop tumors spontaneously are rapidly gaining traction as an invaluable preclinical model. In exciting new preliminary data, we infused CAR T cells treated with the IFNAR1 stabilizing p38 inhibitor ralimetinib into a canine B cell lymphoma patient. Following treatment, we observed signs associated with CAR T cell mediated anti-tumor activity that have not been previously observed in canine patients treated with CAR T cells. Furthermore, in human chronic lymphocytic leukemia patients, an active type I IFN gene signature was associated with improved outcomes following CAR T cell therapy. Together, these data support the hypothesis that stabilization of IFNAR1 on the surface of CAR T cells will improve their therapeutic efficacy for the treatment of B cell malignancies. We will perform the following studies to test this: 1. Canine cancer patients with spontaneous diffuse large B cell lymphoma currently being enrolled in a pilot trial will be used to determine the safety and efficacy of IFNAR1-stabilized CART cells. 2. CART cells derived from multiple species will be evaluated in vitro and in vivo to ascertain the mechanism by which genetic and pharmacologic IFNAR1 stabilization enhances the anti-tumor activity of CART cells. 3. The prognostic significance of IFNAR1 and downstream signaling in T cell apheresis products used to manufacture CAR T cells and CAR T cells themselves will be evaluated in patients with B cell malignancies. We anticipate that IFNAR1 stabilization will safely enhance the activity of CAR T cells. As a veterinary oncologist with doctoral training in immunology I have a solid foundation of the knowledge and skillsets required to undertake these studies. The proposed research on the application of CART cell therapy for the treatment of B cell neoplasia will be performed under the expert guidance of Ors. Fuchs and Mason and represents a field for which the University of Pennsylvania is globally renowned.

过继细胞疗法 (ACT) 彻底改变了某些恶性肿瘤的治疗和反应在用表达嵌合抗体受体 (CAR) 的 T 细胞治疗的难治性 B 细胞肿瘤中，非常了不起。然而，即使在这些特别敏感的癌症中，ACT 也不能始终有效，强调迫切需要创新方法来改进这种强大的治疗方法。 Ⅰ型通过 I 型干扰素受体 (IFNAR) 的干扰素 (IFN) 信号传导在激活中发挥关键作用， T 细胞的分化和功能。重要的是，I 型干扰素受体链亚基的降解抗肿瘤 T 细胞中的 1 (IFNAR1) 有利于肿瘤进展，而其遗传或药理学（通过 p38 抑制）稳定性可提高小鼠模型中的抗肿瘤 T 细胞活性。虽然啮齿动物研究已取得成果尽管对 CAR T 细胞的临床前了解很多，但它们无法准确预测临床安全性和有效性。然而，基因远交且免疫完整的犬类癌症患者自发产生肿瘤作为一种宝贵的临床前模型迅速获得关注。在令人兴奋的新初步数据中，我们注入了 CAR T 将用 IFNAR1 稳定 p38 抑制剂 ralimetinib 处理的细胞注入犬 B 细胞淋巴瘤患者体内。治疗后，我们观察到与 CAR T 细胞介导的抗肿瘤活性相关的迹象，而这些迹象并未出现。此前曾在接受 CAR T 细胞治疗的犬类患者中观察到这一现象。此外，在人类慢性淋巴细胞白血病患者中，活跃的 I 型 IFN 基因特征与改善预后相关 CAR T 细胞治疗后。总之，这些数据支持这样的假设：IFNAR1 在 CAR T细胞表面的修饰将提高其治疗B细胞恶性肿瘤的疗效。我们将进行以下研究来测试这一点： 1. 目前正在招募患有自发性弥漫性大 B 细胞淋巴瘤的犬癌症患者进行试点试验将用于确定 IFNAR1 稳定的 CART 细胞的安全性和有效性。 2. 来自多个物种的CART细胞将在体外和体内进行评估，以确定其机制通过遗传和药理学 IFNAR1 稳定增强 CART 细胞的抗肿瘤活性。 3. IFNAR1 和 T 细胞单采产品中下游信号传导的预后意义制造 CAR T 细胞，并且 CAR T 细胞本身将在 B 细胞恶性肿瘤患者中进行评估。我们预计 IFNAR1 的稳定性将安全地增强 CAR T 细胞的活性。作为一名兽医接受过免疫学博士培训的肿瘤学家我对所需的知识和技能有坚实的基础进行这些研究。拟议的CART细胞疗法在治疗中的应用研究 B细胞瘤形成将在Ors的专家指导下进行。福克斯和梅森代表了一个领域其中宾夕法尼亚大学享誉全球。