Biomanufacturing next generation T cells

生物制造下一代 T 细胞

• 批准号: 1705464
• 负责人: Navin Varadarajan
• 金额: $ 50.95万
• 依托单位: University of Houston
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1705464&HistoricalAwards=false
• 关键词: Biomanufacturing; next; generation; cells

Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults and is responsible for more than 10,000 deaths annually in the United States. Immunotherapy has revolutionized the treatment of cancers. T-cell based therapy involving the infusion of genetically modified cells has the potential to deliver long-lasting remissions, eventually leading to cures. Despite this promise, treatments remain unpredictable, so newer methods are required to assist the biomanufacturing of immune cells with defined properties. This research project aims to deliver on data-driven engineering methods to rapidly engineer the potency of T cells for the treatment of AML and to test these in mice. Additionally, students at all levels will be trained through the development and delivery of animation-based tutorials and interactive games that teach immunotherapy, cell metabolism, T-cell function, and cellular responses to cancer. The educational outreach is also advancing student engagement in immunotherapy through research experiences for K-12, undergraduate and graduate students. Adoptive cell therapy (ACT) based on the transfer of chimeric antigen receptor (CAR) T cells has demonstrated significant anti-tumor effects in patients with refractory B-cell malignancies. The remarkable clinical success of CAR+ T cells has spurred the development of this approach for other leukemias and solid tumors. In spite of the clinical potential of ACT, its efficacy remains unpredictable, and newer approaches are required to define the key components of the efficacy of CAR+ T cells. The incomplete understanding of the role of metabolism in the anti-tumor efficacy of cells has severely limited the biomanufacturing T cells with predictable potency, and this is a fundamental limitation. The objective of this research project is to quantify the dynamic metabolic profile, the complete transcriptome, and the functional competency of CAR+ T cells targeting the sialoadhesin receptor 3 (CD33), at single-cell resolution, and to determine if directly altering T-cell metabolism provides new avenues to immunotherapeutic treatment or treatment enhancement. A suite of innovative high-throughput single-cell methodologies that have been developed and implemented, including real-time metabolic profiling, Timelapse Imaging Microscopy in Nanowell Grids (TIMING), and single-cell RNA-seq, are being utilized. The ability of these engineered CAR+ T-cell populations to control the growth of human tumors is being tested in immunodeficient mice. This work will establish the heterogeneity and correlation between fundamental T-cell processes like metabolism, function, and phenotype, and thus will have a broad impact on T-cell immunology.

急性髓样白血病（AML）是影响成年人的最常见急性白血病，在美国每年造成10,000多人死亡。免疫疗法彻底改变了癌症的治疗。基于T细胞输注基因修饰细胞的T细胞治疗具有延长持久缓解的潜力，最终导致治疗方法。尽管有希望，但治疗仍然无法预测，因此需要更新的方法来帮助具有定义特性的免疫细胞的生物制造。该研究项目旨在提供数据驱动的工程方法，以迅速设计T细胞的效力以治疗AML并在小鼠中测试这些方法。此外，各级学生将通过开发和提供基于动画的教程和互动游戏的培训，这些教程和交互式游戏教授免疫疗法，细胞代谢，T细胞功能以及对癌症的细胞反应。教育外展活动还通过针对K-12，本科生和研究生的研究经验来推进学生参与免疫疗法的参与。基于嵌合抗原受体（CAR）T细胞转移的过养细胞疗法（ACT）对难治性B细胞恶性肿瘤患者表现出显着的抗肿瘤作用。 CAR+ T细胞的显着临床成功促使这种方法开发了其他白血病和实体瘤。尽管具有ACT的临床潜力，但其功效仍然无法预测，并且需要更新的方法来定义CAR+ T细胞功效的关键组成部分。对新陈代谢在细胞抗肿瘤功效中的作用的不完全理解严重限制了具有可预测效力的生物制造T细胞，这是一个基本限制。该研究项目的目的是量化靶向唾液粘着蛋白受体3（CD33），单细胞分辨率的CAR+ T细胞的动态代谢谱，完整的转录能力以及功能能力，并确定是否直接改变T细胞代谢为免疫治疗或治疗增强的新途径。已经开发和实施的一组创新的高通量单细胞方法，包括实时代谢分析，纳米维尔电网中的时间元素化成像显微镜（时机）和单细胞RNA-seq。这些工程的汽车+ T细胞种群控制人类肿瘤生长的能力正在免疫缺陷小鼠中进行测试。这项工作将建立新代谢，功能和表型等基本T细胞过程之间的异质性和相关性，从而对T细胞免疫学产生广泛的影响。

项目成果

Automated Classification of Apoptosis in Phase Contrast Microscopy Using Capsule Network

• DOI: 10.1109/tmi.2019.2918181
• 发表时间: 2020-01-01
• 期刊: IEEE TRANSACTIONS ON MEDICAL IMAGING
• 影响因子: 10.6
• 作者: Mobiny, Aryan;Lu, Hengyang;Varadarajan, Navin
• 通讯作者: Varadarajan, Navin

Single-cell technologies for profiling T cells to enable monitoring of immunotherapies

• DOI: 10.1016/j.coche.2018.01.003
• 发表时间: 2018-03-01
• 期刊: CURRENT OPINION IN CHEMICAL ENGINEERING
• 影响因子: 6.6
• 作者: An, Xingyue;Varadarajan, Navin
• 通讯作者: Varadarajan, Navin

Small-molecule inducible transcriptional control in mammalian cells.

• DOI: 10.1080/07388551.2020.1808583
• 发表时间: 2020-12
• 期刊: Critical reviews in biotechnology
• 影响因子: 9
• 作者: Doshi A;Sadeghi F;Varadarajan N;Cirino PC
• 通讯作者: Cirino PC

Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils

• DOI: 10.1073/pnas.2015618118
• 发表时间: 2021-03-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Yang, David S.;Saeedi, Arash;Vekilov, Peter G.
• 通讯作者: Vekilov, Peter G.

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses.

• DOI: 10.1172/jci159402
• 发表时间: 2022-09-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Romain, Gabrielle;Strati, Paolo;Rezvan, Ali;Fathi, Mohsen;Bandey, Irfan N.;Adolacion, Jay R. T.;Heeke, Darren;Liadi, Ivan;Marques-Piubelli, Mario L.;Solis, Luisa M.;Mahendra, Ankit;Vega, Francisco;Cooper, Laurence J. N.;Singh, Harjeet;Mattie, Mike;Bot, Adrian;Neelapu, Sattva S.;Varadarajan, Navin
• 通讯作者: Varadarajan, Navin