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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：
10370427
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/10370427
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 Persons Pharmacology Phenotype Pilot Projects Play Pre-Clinical Model Primary Neoplasm 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 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 indicator 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）已经彻底改变了某些恶性肿瘤的治疗和反应