Directing the metabolic fate of CAR T cells

指导 CAR T 细胞的代谢命运

• 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
• 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

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.

项目总结/摘要 该项目的目标是开发下一代具有嵌合T细胞的靶向T细胞。 抗原受体（汽车）用于癌症和血液恶性肿瘤。因此，我们认为， 这些研究针对的是折磨美国人口的癌症流行病。车 T细胞现在开始在一些试点临床试验中显示出活性， 对于目前无法治愈的许多癌症的治疗具有显著的潜力。然而，两个 出现了一些问题，阻碍了该领域的进一步快速进展： 实体癌患者中CAR T细胞的持久性有限，与实体癌患者不同， 靶向CD 19的汽车; 2）T细胞在毒性肿瘤中耗尽，变得无反应性或死亡 微环境，不像血液恶性肿瘤的情况，其中CAR T细胞具有 在有反应的患者中持续发挥作用至少5年。我们的初步数据显示 CAR T细胞的代谢谱可以通过改变细胞的设计来随意改变。 CAR构建体中的信号传导结构域。在这个项目中，我们将使用合成的原理， 生物学和慢病毒载体技术，mRNA电穿孔技术， 成簇规则间隔短回文重复序列（CRISPR）和CRISPR相关的 蛋白9（Cas9）技术来适应T细胞的代谢，以促进T细胞的存活。 恶劣的肿瘤微环境。该项目的主题是，T细胞具有更强大的， 可设计持续的抗肿瘤作用以抵抗代谢检查点如缺氧， 高钾血症酸中毒和葡萄糖缺乏总之，这些重叠的研究将 测试中心假设，即合成增强的CAR T细胞将改善CAR 与目前可用的CAR T细胞的治疗相比，免疫疗法。结束时 在这个项目中，下一代代谢增强的CAR T细胞将可用于测试。 在晚期胰腺癌患者中进行初步临床试验。

项目成果

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

Citius，Altius，Fortius：在汽车T细胞的瓶子中的性能。

• DOI: 10.33696/haematology.1.015
• 发表时间: 2020
• 期刊: Journal of clinical haematology
• 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.

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.)
• 作者: O'Connor RS;Milone MC
• 通讯作者: Milone MC

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

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
• 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