Directing the metabolic fate of CAR T cells

指导 CAR T 细胞的代谢命运

基本信息

批准号：
10364746
负责人：
CARL H. JUNE
金额：
$ 42.37万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10364746
关键词：
Acidosis Acute leukemia Address Adenocarcinoma Adoptive Cell Transfers Arginine Autologous B lymphoid malignancy Biogenesis Biological Assay CD19 gene CD28 gene CTLA4 gene Carbon Carcinoma Cell Culture Techniques Cell physiology Cell surface Cellular Metabolic Process Characteristics Citric Acid Cycle Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Custom Data Development Electroporation Enzymes Epidemic Epigenetic Process Future Genes Genetic Glucose Glycolysis Goals Guide RNA Hematologic Neoplasms Human Hypoxia Immunotherapy In Vitro Institution Label Laboratories Lentivirus Vector Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Memory Messenger RNA Metabolic Metabolism Mitochondria NADP Organoids Oxidoreductase Patients Population Pre-Clinical Model Proteins Receptor Signaling Resistance Role Signal Transduction Solid Specific qualifier value Structure Supplementation T-Lymphocyte Technology Testing To specify United States Woman advanced pancreatic cancer aerobic glycolysis antitumor effect cancer immunotherapy cancer therapy cellular engineering chimeric antigen receptor chimeric antigen receptor T cells deprivation design enantiomer exhaust experience experimental study fatty acid oxidation first-in-human gain of function mutation genome editing hyperkalemia improved innovation interest leukemia relapse leukemia/lymphoma loss of function men metabolic profile metabolome neoplastic cell next generation pancreatic cancer model preclinical study programmed cell death protein 1 programs receptor synthetic biology tool translational goal tumor tumor microenvironment tumor-immune system interactions virtual

项目摘要

Project Summary / Abstract The goal of this project is to develop the next generation of targeted T-cells with chimeric antigen receptors (CARs) for use in carcinomas and hematologic malignancies. Therefore, these studies address the cancer epidemic that afflicts the population in the United States. CAR T cells are now beginning to show activity in a number of pilot clinical trials and they have significant potential for therapy of many cancers that are currently incurable. However two issues have emerged that provide a barrier to further rapid progress in the field: 1) the persistence of CAR T cells in patients with solid cancer has been limited, unlike the case with CARs that target CD19; 2) T cells become exhausted, become anergic or die in the toxic tumor microenvironment, unlike the case of hematologic malignancies, where CAR T cells have continued to function for at least 5 years in responding patients. Our preliminary data indicates that the metabolic profiles of CAR T cells can be altered at will by changing the design of the signaling domain in the CAR construct. In this project, we will use the principles of synthetic biology and the tools of lentiviral vector technology, mRNA electroporation technology, and clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR associated protein 9 (Cas9) technology to adapt the metabolism of T cells in order to promote survival in harsh tumor microenvironments. The theme of the project is that T cells with more potent and sustained antitumor effects can be designed to resist metabolic checkpoints such as hypoxia, hyperkalemia, acidosis, and glucose deprivation. In summary, these overlapping studies will test the central hypothesis that synthetically enhanced CAR T cells will improve CAR immunotherapy compared to therapy with currently available CAR T cells. At the conclusion of this project, a next generation of metabolically enhanced CAR T cells will be available for testing in pilot clinical trials in patients with advanced pancreatic cancer.

项目概要/摘要该项目的目标是开发具有嵌合体的下一代靶向T细胞抗原受体（CAR）用于癌症和血液恶性肿瘤。所以，这些研究针对的是困扰美国人口的癌症流行问题。车 T 细胞现在开始在一些试点临床试验中表现出活性，并且它们已经治疗许多目前无法治愈的癌症的巨大潜力。然而两个已经出现的问题阻碍了该领域的进一步快速进展：1）与实体瘤患者不同的是，CAR T 细胞在实体瘤患者体内的持久性有限。靶向CD19的CAR； 2) T细胞在毒性肿瘤中变得精疲力尽、变得无反应或死亡与血液恶性肿瘤的情况不同，CAR T 细胞具有在有反应的患者中持续发挥作用至少 5 年。我们的初步数据表明通过改变细胞的设计，可以随意改变 CAR T 细胞的代谢特征 CAR 结构中的信号传导域。在这个项目中，我们将使用合成原理生物学和慢病毒载体技术、mRNA电穿孔技术等工具成簇规则间隔短回文重复序列 (CRISPR) 和 CRISPR 相关蛋白 9 (Cas9) 技术可适应 T 细胞的代谢，以促进生存恶劣的肿瘤微环境。该项目的主题是T细胞具有更强大和更有效的能力。持续的抗肿瘤作用可以被设计来抵抗代谢检查点，例如缺氧，高钾血症、酸中毒和葡萄糖缺乏。总之，这些重叠的研究将测试综合增强的 CAR T 细胞将改善 CAR 的中心假设免疫疗法与目前可用的 CAR T 细胞疗法相比。结束时该项目中，下一代代谢增强型 CAR T 细胞将可供测试在晚期胰腺癌患者中进行试点临床试验。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Citius, Altius, Fortius: Performance in a Bottle for CAR T-Cells.

DOI：
10.33696/haematology.1.015
发表时间：
2020
期刊：
Journal of clinical haematology
影响因子：
0
作者：
Ayari A;O'Connor RS
通讯作者：
O'Connor RS

Engineered cellular immunotherapies in cancer and beyond.

DOI：
10.1038/s41591-022-01765-8
发表时间：
2022-04
期刊：
NATURE MEDICINE
影响因子：
82.9
作者：
Finck, Amanda V.;Blanchard, Tatiana;Roselle, Christopher P.;Golinelli, Giulia;June, Carl H.
通讯作者：
June, Carl H.

In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL.

DOI：
10.1158/1535-7163.mct-20-1089
发表时间：
2021-07
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Safarzadeh Kozani P;Safarzadeh Kozani P;O'Connor RS
通讯作者：
O'Connor RS

Testing the Specificity of Compounds Designed to Inhibit CPT1A in T Cells.

DOI：
10.1007/978-1-0716-0203-4_5
发表时间：
2020
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
O'Connor RS;Milone MC
通讯作者：
Milone MC

Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy.

DOI：
10.1158/1078-0432.ccr-20-1739
发表时间：
2020-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Huarte E;O'Connor RS;Peel MT;Nunez-Cruz S;Leferovich J;Juvekar A;Yang YO;Truong L;Huang T;Naim A;Milone MC;Smith PA
通讯作者：
Smith PA