Combination antigen sensing engineered T cell for precise recognition and enhanced elimination of solid tumors

组合抗原传感工程 T 细胞可精确识别并增强实体瘤的消除

基本信息

批准号：
10651062
负责人：
BIN LIU
金额：
$ 66.61万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-04 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651062
关键词：
Address Affinity Alkaline Phosphatase Antibodies Antigen Targeting Antigens B lymphoid malignancy Bacteriophages Binding Biological Markers CAR T cell therapy CAR receptor CD8B1 gene Cell Therapy Cell surface Clinic Clinical Collaborations Credentialing DNA Binding Domain Development Engineering Family Generations Genes Goals Human Immune Immune response Immunoglobulin Fragments In Vitro Laboratories Libraries Logic Malignant Neoplasms Malignant mesothelioma Mesothelioma Modeling Nature Normal tissue morphology Patient-Focused Outcomes Patients Placenta Preclinical Testing Prognosis Proteolysis Rare Diseases Refractory Relapse Reporting Research Sampling Seminoma Signal Transduction Site Solid Neoplasm Specificity Specimen Surface Antigens System T cell therapy T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Testing Tissues Toxic effect Transactivation Transcriptional Activation Translations Treatment Efficacy Tumor Antigens Viral Proteins Work Xenograft Model antibody engineering antigen binding chimeric antigen receptor T cells clinical efficacy clinical translation cytokine design engineered T cells exhaustion extracellular flexibility human DNA human monoclonal antibodies human tissue immunoregulation improved in vivo member mesothelin neoplastic cell notch protein novel novel strategies novel therapeutics patient biomarkers patient stratification receptor research clinical testing success synthetic antibodies therapeutic development translational potential trophoblast tumor tumor microenvironment yeast protein

项目摘要

Abstract: The goal of this proposal is to develop an engineered T cell therapy with potential of translation into human testing. We will develop a clinically optimized combination antigen sensing prime-and-kill circuit T cell for precise recognition and enhanced elimination of mesothelioma, a rare disease with poor prognosis. The work is built on our recent progress in T cell engineering and novel tumor antigen discovery: (1) a prime-and-kill dual antigen AND-gated circuit with fully human components (dubbed as SNIPR for SyNthetic Intramembrane Proteolysis Receptors) that facilitate clinical translation. (2) A novel tumor specific cell surface antigen ALPPL2 (aka ALPG) that is expressed in mesothelioma but not any of the normal human tissues except for the placenta. Paired with the credentialed mesothelioma antigen mesothelin, the ALPPL2 SNIPR → CAR circuit T cell enables precise temporal and spatial control of T cell activation at the site of the tumor, minimizes on-target off-tumor toxicity, reduces tonic signaling and T cell exhaustion, and maintains multifunctional T cell states. The circuit design is modular and flexible and can be induced to locally deliver additional immune modulatory payloads such as cytokines to further improve efficacy. In addition, our research has shown that SNIPR → CAR circuit T cells are capable of effectively targeting antigens that are heterogeneously expressed in tumors, a common pitfall for therapeutic efficacy. We propose to perform translation-enabling studies: (Aim 1) Optimize antibodies for SNIPR T cell construction, and develop biomarker for patient stratification. (Aim 2) Engineer and evaluate humanized clinical grade SNIPR → AND logic T cells in vitro and in vivo. (Aim 3) Evaluate SNIPR-engineered prime-and- kill circuit T cells in killing tumor with heterogeneous target antigen expression. Successful completion of the project will enable us to move the SNIPR → CAR circuit T cell to translational development and identify via the biomarker appropriate mesothelioma patients for clinical testing.

抽象的：该提案的目标是开发一种具有转化为人类潜力的工程化 T 细胞疗法我们将开发一种临床优化的组合抗原感应启动和杀伤电路 T 细胞，以进行精确的测试。间皮瘤是一种预后不良的罕见疾病，并且加强对其的识别和消除。我们在T细胞工程和新型肿瘤抗原发现方面的最新进展：（1）引发和杀死双抗原具有完全人为组件的与门电路（称为 SNIPR，用于合成膜内蛋白水解） (2) 一种新型肿瘤特异性细胞表面抗原ALPPL2（又名ALPG）它在间皮瘤中表达，但在除胎盘之外的任何正常人体组织中不表达。经过认证的间皮瘤抗原间皮素、ALPPL2 SNIPR → CAR 电路 T 细胞可实现精确肿瘤部位 T 细胞激活的时间和空间控制，最大限度地减少靶向肿瘤外毒性，该电路设计旨在减少强直信号传导和 T 细胞耗竭，并维持多功能 T 细胞状态。模块化且灵活，可以诱导局部传递额外的免疫调节有效负载，例如此外，我们的研究表明，SNIPR→CAR电路T细胞是可以进一步提高疗效的。能够有效地靶向肿瘤中异质表达的抗原，这是肿瘤治疗的常见陷阱我们建议进行翻译研究：（目标 1）优化 SNIPR 抗体。 T 细胞构建，并开发用于患者分层的生物标志物（目标 2）设计和评估人源化。体外和体内临床级 SNIPR → AND 逻辑 T 细胞（目标 3）评估 SNIPR 工程设计的prime-and-。杀伤电路T细胞在杀伤具有异质靶抗原表达的肿瘤中的成功完成。该项目将使我们能够将 SNIPR → CAR 电路 T 细胞进行转化开发并通过生物标志物适合间皮瘤患者进行临床测试。