Lundberg Johan, Jussing Emma, Liu Zhenjiang, Meng Qingda, Rao Martin, Samén Erik, Grankvist Rikard, Damberg Peter, Dodoo Ernest, Maeurer Markus, Holmin Staffan
Cell Transplant. 2017 Feb 16;26(2):283-292. doi: 10.3727/096368916X693347. Epub 2016 Oct 7.
Glioblastoma multiforme (GBM) is the most common and most severe form of malignant gliomas. The prognosis is poor with current combinations of pharmaceutical, radiotherapy, and surgical therapy. A continuous search for new treatments has therefore been ongoing for many years. Therapy with tumor-infiltrating lymphocytes (TILs) is a clinically promising strategy to treat various cancers, including GBM. An endovascular intra-arterial injection of TILs as a method of delivery may, instead of intravenous infusion, result in better retention of effector cells within the tumor. Prior to clinical trials of intra-arterial injections with any cells, preclinical safety data with special emphasis on embolic-ischemic events are necessary to obtain. We used native rabbits as a model for intra-arterial injections with routine clinical catheter material and a clinical angiography suite. We selectively infused a total dose of 20 million activated T cells at a cell concentration of 4,000 cells/μl over 8 min of injection time. The rabbits were evaluated for ischemic lesions by 9.4 T magnetic resonance imaging (MRI) (n = 6), and for tracking of injected cells, single-photon emission computed tomography/computed tomography (SPECT/CT) was used (n = 2). In this study, we show that we can selectively infuse activated T cells to a CNS volume of 3.5 cm3 (estimated from the volumetric MRI) without catastrophic embolic-ischemic adverse events. We had one adverse event with a limited basal ganglia infarction, probably due to catheter-induced mechanical occlusion of one of the lateral lenticulostriatal arteries. The cells pass through the native brain without leaving SPECT signals. The cells then, over the first hours, end up in the liver to a large extent and to a lesser degree by the spleen, pancreas, and kidneys. Virtually no uptake could be detected in the lungs. This indicates a difference in biodistribution as opposed to other cell types when infused intravenously.
多形性胶质母细胞瘤（GBM）是恶性胶质瘤中最常见、最严重的类型。目前药物治疗、放疗和手术治疗联合使用的情况下，预后较差。因此，多年来一直在不断寻找新的治疗方法。肿瘤浸润淋巴细胞（TILs）治疗是一种治疗包括GBM在内的各种癌症的具有临床前景的策略。作为一种给药方法，经血管内动脉注射TILs，而非静脉输注，可能会使效应细胞在肿瘤内更好地留存。在进行任何细胞的动脉内注射临床试验之前，必须获得特别强调栓塞性缺血事件的临床前安全性数据。我们使用天然兔作为动脉内注射的模型，采用常规临床导管材料和临床血管造影设备。我们在8分钟的注射时间内，以4000个细胞/μl的细胞浓度选择性输注了总量为2000万个活化T细胞。通过9.4 T磁共振成像（MRI）对兔子进行缺血性病变评估（n = 6），并使用单光子发射计算机断层扫描/计算机断层扫描（SPECT/CT）对注入细胞进行追踪（n = 2）。在本研究中，我们表明我们可以将活化T细胞选择性地输注到3.5 cm³的中枢神经系统区域（根据容积MRI估计），而不会发生灾难性的栓塞性缺血不良事件。我们发生了1例不良事件，基底节梗死范围有限，可能是由于导管导致外侧豆纹动脉之一机械性闭塞。细胞穿过天然脑组织，未留下SPECT信号。然后，在最初的几个小时内，细胞大部分最终进入肝脏，较少程度地进入脾脏、胰腺和肾脏。在肺部几乎未检测到摄取。这表明与静脉输注其他细胞类型相比，生物分布存在差异。
