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Label-free imaging of CAR T cell metabolism

CAR T 细胞代谢的无标记成像

基本信息

批准号：
10751581
负责人：
Christian Capitini
金额：
$ 66.2万
依托单位：
MORGRIDGE INSTITUTE FOR RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751581
关键词：
Antitumor Response Autologous B-Cell Lymphomas Benchmarking Biological Assay Biological Markers CAR T cell therapy CD19 gene Cancer Patient Cell physiology Cells Cellular Metabolic Process Clinical Clinical Trials Combined Modality Therapy Cytolysis Dasatinib Data Disease remission FDA approved Flow Cytometry Frequencies Genetic Engineering Goals Human Hypoxia Image Imaging technology Immunofluorescence Immunologic In Vitro Infiltration Infusion procedures Intervention Knowledge Label Malignant Neoplasms Measurement Measures Memory Metabolic Methods Modeling Monitor Neuroblastoma Optics Patient Selection Patients Phenotype Process Production Resolution Resources Sampling Solid Neoplasm Source Specificity Spleen T cell response T cell therapy T memory cell T-Lymphocyte Technology Technology Assessment Testing Time Xenograft procedure alternative treatment cancer cell cancer therapy cellular imaging chimeric antigen receptor chimeric antigen receptor T cells cytokine exhaust exhaustion fitness fluorescence imaging improved in vivo manufacture metabolic imaging mouse model neoplastic cell patient screening predictive modeling process optimization response response biomarker single cell technology stem cells therapy development tumor

项目摘要

PROJECT SUMMARY / ABSTRACT The goal of this proposal is to develop non-invasive single-cell technologies to improve the potency of T cell therapies against cancer. The first 6 chimeric antigen receptor (CAR) T cell therapies were recently approved and >800 CAR and T cell therapies are in clinical trials. However, barriers remain in achieving durable remissions (>1 year) for ~50% of patients who receive CAR T cell therapy. Due to the rapid development of these therapies and a great need for process optimization, we focus on improving three translational roadblocks to effective CAR T cell therapy: (1) screening patients whose T cells are unfit for CAR T cell manufacturing, (2) optimizing in vitro CAR T cell production for higher potency, and (3) identifying metabolic features of potent CAR T cells in vivo. CAR T cell therapy could be improved by enriching for naïve and stem cell memory (SCM) T cells in starting materials and final products. Deficiencies in naïve and SCM T cells occurs in ~50% of untreated cancer patients, and manufacturing autologous CAR T cell products from these sources has been unsuccessful. Even if SCM T cells can be isolated, after CAR incorporation, the expansion process typically diminishes potency through T cell exhaustion. After infusion, the presence of memory-like phenotypes in vivo correlate with better responses. To date, there are no robust, non-destructive technologies to monitor CAR T cell manufacturing to optimize production and assess potency in vivo at a single-cell level. These issues limit the impact of CAR T cell therapy. Current approaches to measure T cell function are labor-intensive, destructive, or lack single-cell resolution, which limits the frequency or specificity of these measurements. For CAR T cell therapy to realize its clinical potential, new methods are needed to monitor T cells for optimal potency throughout manufacturing and post- infusion. Changes in cell metabolism provide an attractive yet under-explored assay to track T cell potency. Previous studies, including our own, show that T cells undergo drastic metabolic changes with activation, and that naïve, exhausted, and memory-like T cells have distinct metabolic features. Our preliminary data shows that non-invasive single-cell imaging of the fluorescence intensity and lifetime of NAD(P)H and FAD (optical metabolic imaging, or OMI) can predict CAR T cell manufacturing conditions that produce a more vs. less potent anti-tumor response in vivo. Given these metabolic features of CAR T cell potency, we propose to determine whether label-free OMI of T cell autofluorescence and multivariate models can identify patient T cell fitness, optimal in vitro expansion conditions, and in vivo cell biomarkers of potent and persistent CAR T cell response. Overall, these technologies will streamline processes and interventions for consistently potent T cell therapy and increase our knowledge of CAR T cell metabolism in vitro and in vivo.

项目摘要/摘要