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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：
10657328
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/10657328
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 Separation Cell Therapy Cell surface Cells Cessation of life Chronic Lymphocytic Leukemia Classification Clinical Clinical Trials Data Development Development Plans Down-Regulation Engraftment 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 Persons Phenotype Pilot Projects Play Pre-Clinical Model Primary Neoplasm Proliferating 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 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 innovation insight large cell Diffuse non-Hodgkin&apos s lymphoma manufacture mouse model mutant p38 Mitogen Activated Protein Kinase pharmacologic pilot trial pre-clinical pre-clinical assessment preclinical efficacy prognostic prognostic indicator prognostic significance response safety assessment skills 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)使某些恶性肿瘤的治疗和反应发生了革命性的变化。在嵌合抗体受体(CAR)表达的T细胞瘤治疗难治性B细胞肿瘤中不同凡响。然而，ACT即使在这些特别敏感的癌症中也不是始终如一的治愈，强调迫切需要创新的方法来改进这一强大的治疗方法。第I类通过I型干扰素受体(IFNAR)传递的干扰素信号在激活过程中起着关键作用， T细胞的分化和功能。重要的是，I型干扰素受体链亚单位的降解 1(IFNAR1)在抗肿瘤T细胞中促进肿瘤进展，而它的遗传或药物作用(通过p38 抑制)稳定可提高小鼠模型中抗肿瘤T细胞的活性。虽然对啮齿动物的研究已经产生了许多临床前对CAR T细胞的洞察，它们无法准确预测临床安全性和有效性。然而，基因繁殖和免疫功能正常的犬癌患者自发发展为肿瘤作为一种无价的临床前模型，它迅速获得了吸引力。在令人兴奋的新的初步数据中，我们注入了CAR T 用IFNAR1稳定p38抑制剂雷米美替尼治疗的细胞转化为犬B细胞淋巴瘤患者。治疗后，我们观察到与CAR T细胞介导的抗肿瘤活性相关的体征，但尚未观察到以前在接受CAR T细胞治疗的犬类患者中观察到了这种情况。此外，在人类慢性疾病中淋巴细胞白血病患者活跃的I型干扰素基因签名与改善预后相关在接受CAR T细胞治疗后。总之，这些数据支持这样的假设，即IFNAR1在 CAR T细胞表面修饰可提高其治疗B细胞恶性肿瘤的疗效。我们会执行以下研究来测试这一点： 1.患有自发性弥漫性大B细胞淋巴瘤的犬癌患者目前正在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.多种来源的CART细胞将在体外和体内进行评估，以确定其作用机制通过基因和药物的IFNAR1稳定性增强CART细胞的抗肿瘤活性。 3.IFNAR1及其下游信号在T细胞分离产品中的预后意义制造CAR T细胞和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的稳定将安全地增强CAR T细胞的活性。作为一名兽医我是受过免疫学博士训练的肿瘤学家，具备扎实的所需知识和技能基础来进行这些研究。CART细胞疗法在慢性粒细胞白血病治疗中的应用 B细胞瘤将在ORS的专家指导下进行。Fuchs和Mason，并代表一个领域宾夕法尼亚大学享誉全球。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer.

DOI：
10.1038/s41467-022-34428-w
发表时间：
2022-11-04
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Lu, Zhen;Chen, Jinyun;Yu, Pengfei;Atherton, Matthew J.;Gui, Jun;Tomar, Vivek S.;Middleton, Justin D.;Sullivan, Neil T.;Singhal, Sunil;George, Subin S.;Woolfork, Ashley G.;Weljie, Aalim M.;Hai, Tsonwin;Eruslanov, Evgeniy B.;Fuchs, Serge Y.
通讯作者：
Fuchs, Serge Y.

Genetic re-direction of canine primary T cells for clinical trial use in pet dogs with spontaneous cancer.