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.

收养细胞疗法（ACT）已彻底改变了某些恶性肿瘤和反应的治疗在用嵌合抗体受体（CAR）表达T细胞处理的难治性B细胞肿瘤中非常了不起。但是，即使在这些特别响应的癌症中，ACT也不是一贯的治疗方法，强调对创新方法的批判性需求，以改善这种强大的治疗方法。类型I。通过I型干扰素受体（IFNAR）的干扰素（IFN）信号传导在激活中起关键作用， 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）有利于肿瘤进展抑制作用）稳定改善了小鼠模型中的抗肿瘤T细胞活性。啮齿动物的研究产生了对汽车T细胞的临床前洞察力很大，他们无法准确预测临床安全性和功效。然而，自发发展肿瘤的遗传近代和免疫学完整的犬类癌患者迅速成为宝贵的临床前模型。在令人兴奋的新初步数据中，我们注入了汽车用IFNAR1处理的细胞将p38抑制剂ralimetinib稳定成犬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以前是在用汽车T细胞治疗的犬类患者中观察到的。此外，在人类慢性淋巴细胞性白血病患者，一种活跃的I型IFN基因签名与改善的预后有关遵循汽车T细胞疗法。这些数据共同支持以下假设 CAR T细胞的表面将提高其治疗B细胞恶性肿瘤的治疗功效。我们将进行以下研究以测试以下研究： 1。自发性弥漫性大B细胞淋巴瘤目前正在招募的犬类癌症患者试验将用于确定IFNAR1稳定的CART细胞的安全性和功效。 2。将在体外和体内评估来自多种物种的推车细胞以确定机制遗传和药理IFNAR1稳定化可以增强CART细胞的抗肿瘤活性。 3。ifnAR1和下游信号传导在T细胞形成产物中的预后意义 B细胞恶性肿瘤患者将评估制造CAR T细胞和CAR T细胞本身。我们预计IFNAR1稳定将安全增强CAR T细胞的活性。作为兽医肿瘤学家接受免疫学博士培训，我为所需的知识和技能奠定了坚实的基础进行这些研究。提出的关于采用CART细胞疗法在治疗的研究 B细胞肿瘤将在ORS的专家指导下进行。福克斯和梅森代表一个领域宾夕法尼亚大学在全球著名。

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.