肿瘤细胞治疗研究
英文原题：Direct and Indirect Chimeric Antigen Receptor T-Cell Imaging with PET/MRI in a Tumor Xenograft Model.
Direct and Indirect Chimeric Antigen Receptor T-Cell Imaging with PET/MRI in a Tumor Xenograft Model.
结果 89Zr-DFO 标记的 CAR T 细胞在所有评估的时间点均可通过 PET/MRI 扫描在小鼠（n = 4）的肝脏和肺部观察到。
背景 嵌合抗原受体 (CAR) T 细胞是一种有前景的癌症疗法；然而，在体内追踪和监测 CAR T 细胞的可靠且可重复的方法仍研究不足。 目的 探讨用于追踪 CAR T 细胞生物分布并监测其在靶肿瘤中治疗效果的直接和间接成像策略。 材料与方法 由人外周血单个核细胞生成共表达肿瘤靶向基因（anti-CD19 CAR）和人生长抑素受体亚型 2 (hSSTr2) 报告基因的 CAR T 细胞。用锆 89 (89Zr)-p-异硫氰酸苄基-去铁胺 (DFO) 直接标记后，将 CAR T 细胞经静脉注射到免疫缺陷小鼠体内，小鼠左、右侧腹分别植有 CD19 阳性和 CD19 阴性人肿瘤异种移植瘤。PET/MRI 用于在第 0、1、3 和 7 天对 89Zr-DFO 标记的 CAR T 细胞进行直接体内成像，并在第 6、9 和 13 天使用放射性标记的生长抑素受体靶向配体镓 68 (68Ga)-DOTA-Tyr3-奥曲肽 (DOTATOC) 进行间接细胞成像。第 13 天，处死小鼠，并切除组织和肿瘤。 结果 在所有评估时间点，PET/MRI 扫描均在小鼠 (n = 4) 的肝脏和肺中观察到 89Zr-DFO 标记的 CAR T 细胞。然而，即使在 第 7 天，也未在 CD19 阳性或 CD19 阴性肿瘤中显像。连续 68Ga-DOTATOC PET/MRI 显示，从第 6 天到第 13 天，CAR T 细胞在 CD19 阳性肿瘤中积聚，但在 CD19 阴性肿瘤中无积聚。值得注意的是，CD19 阳性肿瘤中 68Ga-DOTATOC 的积聚在第 9 天最高（平均注射剂量百分比 [%ID]，3.7% 1.0 [SD]），并在第 13 天下降（平均 %ID，2.6% 0.7) 与肿瘤生长受抑制组中肿瘤体积的减小同步（第9天：平均195 mm3 27；第13天：平均127 mm3 43）。在切除的CD19阳性肿瘤组织中，还观察到分化簇3（CD3）和hSSTr2的免疫组织化学染色增强。结论 PET/MRI直接和间接细胞成像能够在动物模型中实现对CAR T细胞的体内追踪和监测。RSNA，2024本文有补充材料可供获取。另请参见本期Bulte的社论。
Background Chimeric antigen receptor (CAR) T cells are a promising cancer therapy; however, reliable and repeatable methods for tracking and monitoring CAR T cells in vivo remain underexplored. Purpose To investigate direct and indirect imaging strategies for tracking the biodistribution of CAR T cells and monitoring their therapeutic effect in target tumors. Materials and Methods CAR T cells co-expressing a tumor-targeting gene (anti-CD19 CAR) and a human somatostatin receptor subtype 2 (hSSTr2) reporter gene were generated from human peripheral blood mononuclear cells. After direct labeling with zirconium 89 ( 89 Zr)-p-isothiocyanatobenzyl-desferrioxamine (DFO), CAR T cells were intravenously injected into immunodeficient mice with a CD19-positive and CD19-negative human tumor xenograft on the left and right flank, respectively. PET/MRI was used for direct in vivo imaging of 89 Zr-DFO-labeled CAR T cells on days 0, 1, 3, and 7 and for indirect cell imaging with the radiolabeled somatostatin receptor-targeted ligand gallium 68 ( 68 Ga)-DOTA-Tyr3-octreotide (DOTATOC) on days 6, 9, and 13. On day 13, mice were euthanized, and tissues and tumors were excised. Results The 89 Zr-DFO-labeled CAR T cells were observed on PET/MRI scans in the liver and lungs of mice ( n = 4) at all time points assessed. However, they were not visualized in CD19-positive or CD19-negative tumors, even on day 7. Serial 68 Ga-DOTATOC PET/MRI showed CAR T cell accumulation in CD19-positive tumors but not in CD19-negative tumors from days 6 to 13. Notably, 68 Ga-DOTATOC accumulation in CD19-positive tumors was highest on day 9 (mean percentage injected dose [%ID], 3.7% 1.0 [SD]) and decreased on day 13 (mean %ID, 2.6% 0.7) in parallel with a decrease in tumor volume (day 9: mean, 195 mm 3 27; day 13: mean, 127 mm 3 43) in the group with tumor growth inhibition. Enhanced immunohistochemistry staining of cluster of differentiation 3 (CD3) and hSSTr2 was also observed in excised CD19-positive tumor tissues. Conclusion Direct and indirect cell imaging with PET/MRI enabled in vivo tracking and monitoring of CAR T cells in an animal model. RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bulte in this issue.
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