Precise tumor targeting with logic CAR circuits

利用逻辑 CAR 电路精确肿瘤靶向

基本信息

批准号：
10330301
负责人：
Yolonda L Colson
金额：
$ 58.23万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
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：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10330301
关键词：
Adaptor Signaling Protein Address Affect Animals Antigen Targeting Antigens B-Lymphocytes Binding Biocompatible Materials Bioinformatics Blood Blood group antigen S CAR T cell therapy Cells Clinical Collaborations Data Devices Dimensions Engineering Experimental Designs Fiber Future Hepatotoxicity Human Immunology Implant Infection Leucine Zippers Liver Location Logic Malignant Neoplasms Modeling Monitor Mus Nature Outcome Publishing ROR1 gene Receptor Signaling Signal Pathway Signal Transduction Site Solid Neoplasm Specificity System T-Cell Activation T-Lymphocyte Testing Therapeutic Tissues Toxic effect Tumor Biology Tumor Burden Work base cancer cell chimeric antigen receptor chimeric antigen receptor T cells clinical implementation design efficacy evaluation experimental study extracellular immunoengineering improved in vivo in vivo evaluation mouse model neoplastic cell novel ovarian neoplasm prevent programs receptor success synthetic biology targeted treatment therapy development tool transgene expression tumor tumor specificity

项目摘要

Project Summary This proposal describes a unique SUPRA CAR system in human T cells to address in vivo off-tumor toxici- ty, using an established liver transgene expression mouse model. We will use our recently developed split, universal and programmable (SUPRA) CAR system that simultaneously encompasses multiple critical up- grades, such as the ability to finely tune T cell activation strength, sense and logically respond to multiple antigens, and independently regulate two T cell subtypes simultaneously. Specifically, we will evaluate two types of circuits: (1) AND and (2) NIMPLY (A AND NOT B) logic CAR circuits, which have been determined bioinformatically as the best type for circuits for discriminating tumors from healthy cells. The proposed exper- iments will test the hypotheses that (1) our modular and tunable logic CAR T systems are uniquely suited for preventing on-target off-tumor toxicity in vivo, even when healthy tissues expressing a tar- get antigen are near the tumor, and (2) the tumor specificity and activity of our SUPRA CAR systems is enhanced by controlled delivery. Importantly, preliminary data support these hypotheses, and well- characterized materials and rigorous experimental designs are established in this proposal with essential cross-disciplinary collaborations and expertise that encompass synthetic biology, immunology, animal tumor biology, and biomaterials. The specific aims of this five-year proposal are as follows: Aim 1 evaluates AND log- ic SUPRA CAR specificity in vivo. Aim 2 investigate the tumor specificity and toxicity of NIMPLY logic SUPRA CAR in vivo. Aim 3 determine the effect of adaptor protein delivery mechanism on tumor-targeting specificity. Outcomes from this work will establish the clinical potential of logic CAR systems and expand their use to addi- tional cancers, including solid tumors.

项目概要该提案描述了人类 T 细胞中独特的 SUPRA CAR 系统，以解决体内肿瘤外毒性问题 ty，使用已建立的肝脏转基因表达小鼠模型。我们将使用我们最近开发的分裂，通用和可编程（SUPRA）CAR系统，同时包含多个关键up- 等级，例如微调 T 细胞激活强度、感知和逻辑响应多种能力的能力抗原，并同时独立调节两种 T 细胞亚型。具体来说，我们将评估两个电路类型：（1）AND和（2）NIMPLY（A AND NOT B）逻辑CAR电路，已确定生物信息学上认为这是区分肿瘤和健康细胞的最佳电路类型。拟议的经验我们的实验将检验以下假设：(1) 我们的模块化和可调逻辑 CAR T 系统是独一无二的适用于防止体内的脱靶毒性，即使健康组织表达焦油- 获得的抗原靠近肿瘤，并且（2）我们的 SUPRA CAR 系统的肿瘤特异性和活性是通过控制下交付得到加强。重要的是，初步数据支持这些假设，而且该提案中建立了特征材料和严格的实验设计，并具有必要的跨学科合作和专业知识，涵盖合成生物学、免疫学、动物肿瘤生物学和生物材料。该五年提案的具体目标如下：目标 1 评估并记录- ic SUPRA CAR 体内特异性。目标 2 研究 NIMPLY 逻辑 SUPRA 的肿瘤特异性和毒性体内CAR。目标 3 确定接头蛋白递送机制对肿瘤靶向特异性的影响。这项工作的成果将确立逻辑 CAR 系统的临床潜力，并将其用途扩展到其他领域自然癌症，包括实体瘤。