Abstract：
Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.
摘要：
嵌合抗原受体(CAR)细胞疗法利用CAR将免疫细胞重定向到表达特异性抗原如人表皮生长因子受体2(HER2)的癌细胞。尽管有潜力,CART细胞疗法在一些患者中表现出可变的应答率和不良反应。非侵入性分子成像可以通过跟踪给药后输注的细胞来帮助预测患者结果。CAR-T细胞通常是自体的，增加制造复杂性和成本。另一种方法涉及开发CAR自然杀伤（CAR-NK）细胞作为现成的同种异体产品。在这项研究中,我们设计了HER2靶向的共表达正电子发射断层扫描(PET)报告基因人碘化钠转运体(NIS)的CAR-NK细胞,并在HER2卵巢癌小鼠模型中评估了其治疗效果和PET成像能力.NK-92细胞被遗传修饰以表达HER2靶向的CAR，生物发光成像记者Antares,和NIS。将表达HER2的卵巢癌细胞工程化以表达生物发光报道萤火虫荧光素酶(Fluc)。共培养实验表明,与幼稚NK细胞相比,CAR-NK细胞的细胞毒性显著增强。涉及具有表达Fluc的肿瘤的小鼠的体内研究显示,与对照相比,用CAR-NK细胞处理的那些表现出降低的肿瘤负荷和延长的存活。纵向生物发光成像显示了随着时间的推移来自CAR-NK细胞的稳定信号。使用NIS靶向示踪剂18F-四氟硼酸酯([18F]TFB)的PET成像在用表达NIS的CAR-NK细胞处理的小鼠中显示出显著更高的PET信号。总的来说,我们的研究展示了HER2靶向CAR-NK细胞在侵袭性卵巢癌模型中的治疗潜力,并强调了在患者中使用人源PET报告基因成像非侵入性监测这些细胞的可行性.
