用功能磁共振成像评估嵌合抗原受体 T 细胞疗法治疗脑胶质瘤的血氧水平依赖反应：一项在小鼠模型中的研究。
Assessing Oximetry Response to Chimeric Antigen Receptor T-cell Therapy against Glioma with F MRI in a Murine Model.
机构信息
Department of Biomedical Engineering, University of Kentucky, Lexington, Ky (F.C.); Department of Radiology (B.I.L., D.L., E.T.A.), Department of Biostatistics and Bioinformatics (R.C.), and Department of Family Medicine and Public Health (K.M.), University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093; Department of Neurologic Surgery, University of California San Francisco, San Francisco, Calif (H.O.); and Parker Institute for Cancer Immunotherapy, San Francisco, Calif (H.O.).
出版信息
Radiol Imaging Cancer. 2021 Jan 22;3(1):e200062. doi: 10.1148/rycan.2021200062. eCollection 2021 Jan.
PURPOSE
To assess the cell-specific, intracellular partial pressure of oxygen (Po) dynamics of both tumor and chimeric antigen receptor (CAR) T cells in a murine immunotherapy model.
MATERIALS AND METHODS
Human glioblastoma cells or human T cells were intracellularly labeled with perfluorocarbon nanoemulsion droplet sensors prior to in vivo injection in severe combined immunodeficient mice to measure Po in the two cell types in response to treatment. Two main sets of experiments were performed: mice were injected in the flank with perfluorocarbon-labeled human glioblastoma cells and were then inoculated with either CAR T cells or untransduced T cells or were untreated 5 days after tumor inoculation; and mice with unlabeled glioblastoma tumors were inoculated with perfluorocarbon-labeled CAR T cells or untransduced T cells 5 days after tumor inoculation. Longitudinal fluorine 19 (F) spin-lattice relaxation time measurements of the tumor mass were used to ascertain absolute Po in vivo. Results were analyzed for significance using an analysis of variance, a linear mixed-effect model, and a Pearson correlation coefficient test, as appropriate.
RESULTS
The intracellular tumor cell Po temporal dynamics exhibited delayed, transient hyperoxia at 3 days after infusion of CAR T cells, commensurate with significant tumor cell killing and CAR T-cell infiltration, as observed by bioluminescence imaging and histologic findings. Conversely, no significant changes were detected in CAR or untransduced T-cell intracellular Po over time in tumor using these same methods. Moreover, it was observed that the total F tumor cell signal quenches with treatment, consistent with rapid tissue clearance of probe from apoptotic tumor cells.
CONCLUSION
Cell-specific Po measurements using perfluorocarbon probes can provide insights into effector cell function and tumor response in cellular immunotherapeutic cancer models. Animal Studies, MR-Imaging, MR-Spectroscopy, Molecular Imaging-Cancer, Molecular Imaging-Immunotherapy © RSNA, 2021See also commentary by Bulte in this issue.
目的
在小鼠免疫治疗模型中评估肿瘤和嵌合抗原受体（CAR）T 细胞的细胞特异性、细胞内局部氧分压（Po）动态。
材料与方法
在体内注射入严重联合免疫缺陷小鼠前，用人氟碳纳米乳液液滴传感器对人神经胶质瘤细胞或人 T 细胞进行细胞内标记，以测量两种细胞类型对治疗的反应时的 Po。进行了两组主要实验：将氟碳标记的人神经胶质瘤细胞注射到小鼠的侧腹，然后接种 CAR T 细胞或未转导的 T 细胞，或在肿瘤接种后 5 天未处理；以及在肿瘤接种后 5 天，将未标记的神经胶质瘤肿瘤的小鼠接种氟碳标记的 CAR T 细胞或未转导的 T 细胞。肿瘤质量的纵向氟 19（F）自旋晶格弛豫时间测量用于确定体内绝对 Po。使用方差分析、线性混合效应模型和 Pearson 相关系数检验适当地对结果进行分析。
结果
细胞内肿瘤细胞 Po 的时间动态表现为 CAR T 细胞输注后 3 天出现延迟、短暂的氧合过度，与肿瘤细胞杀伤和 CAR T 细胞浸润相一致，如生物发光成像和组织学发现所示。相反，使用相同的方法，在肿瘤中，未观察到 CAR 或未转导的 T 细胞的细胞内 Po 随时间的显著变化。此外，观察到随着治疗，总 F 肿瘤细胞信号猝灭，与探针从凋亡肿瘤细胞中的快速组织清除一致。
结论
使用氟碳探针进行的细胞特异性 Po 测量可以提供关于细胞免疫治疗癌症模型中效应细胞功能和肿瘤反应的深入了解。动物研究、磁共振成像、磁共振光谱学、分子成像-癌症、分子成像-免疫疗法 © RSNA，2021 也请参见本期 Bulte 的评论。
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