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.

项目摘要该提案描述了人类T细胞中独特的Supra汽车系统，以解决体内肿瘤的毒性。 TY，使用已建立的肝转基因表达小鼠模型。我们将使用我们最近开发的拆分，通用和可编程（同上）汽车系统，同时涵盖了多个关键的上等级，例如能够细分T细胞激活强度的能力，感官和逻辑上响应多个抗原，并同时独立调节两个T细胞亚型。具体来说，我们将评估两个电路类型：（1）和（2）nimply（a而不是b）逻辑汽车电路，已确定生物信息是将肿瘤与健康细胞区分开的电路类型。提出的实验 Iments将测试（1）我们的模块化和可调逻辑车系统的假设是唯一的适用于在体内防止靶向非肿瘤毒性的靶向，即使健康的组织表达焦油 GET抗原在肿瘤附近，（2）我们上car系统的肿瘤特异性和活性是通过受控交付增强。重要的是，初步数据支持这些假设以及良好的在本提案中建立了特征的材料和严格的实验设计，必要跨学科合作和专业知识，包括合成生物学，免疫学，动物肿瘤生物学和生物材料。该五年提案的具体目的如下：AIM 1评估和日志 - 体内IC Supra Car的特异性。 AIM 2研究Nimply Logic Supra的肿瘤特异性和毒性体内汽车。 AIM 3确定衔接蛋白递送机制对靶向肿瘤的特异性的影响。这项工作的结果将确定逻辑汽车系统的临床潜力，并将其用途扩展到附加癌症，包括实体瘤。