German Cancer Consortium (DKTK), Partner Site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany.
Department of Nuclear Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, TU, Dresden, Germany.
Radiother Oncol. 2021 Feb;155:285-292. doi: 10.1016/j.radonc.2020.11.013. Epub 2020 Nov 21.
Systemic molecular radiotherapy utilizes internal irradiation by radionuclide-labeled tumor-targeting agents with the potential to destroy (micro-)metastases. However, doses that are applicable in solid tumors do not reach the levels nessecary for tumor control. Thus, the combination of molecular and external radiotherapy is a promising treatment strategy, as enhanced tumor doses can be delivered with and without minor overlapping toxicities. Here, we combined a Y-labeled anti-EGFR antibody (Cetuximab) with clinically relevant fractionated radiotherapy in a preclinical trial using head and neck squamous cell carcinoma xenograft tumors.
To model Y-Cetuximab uptake for treatment schedule optimization, FaDu-bearing mice were injected with near-infrared-labeled-Cetuximab at different time points during radiotherapy with differing doses. Cetuximab uptake was longitudinally followed by in vivo-optical imaging. Tumor control probability experiments with fractionated radiotherapy (30 fx, 6 weeks, 8 dose groups/ arm) in combination with Y-Cetuximab were performed to test the curative potential.
Imaging of near-infrared-labeled-Cetuximab uptake revealed that low to moderate external beam doses can enhance antibody uptake. Using the optimized schedule, combination of molecular and external radiotherapy using Y-Cetuximab at a dose that did not result in permanent tumor inactivation in previous experiments, led to substantially increased tumor control compared to radiotherapy alone.
Our results indicate that combination of radiolabeled therapeutics with clinically relevant fractionated radiotherapy has a remarkable potential to improve curative treatment outcome. Application of some radiation dose prior to injection may improve drug uptake and enable patient stratification and treatment personalization via a corresponding PET-tracer during therapy.
全身分子放射治疗利用放射性核素标记的肿瘤靶向药物进行内照射，具有破坏（微）转移灶的潜力。然而，适用于实体瘤的剂量并不能达到控制肿瘤所需的水平。因此，分子和外部放射治疗的联合是一种很有前途的治疗策略，因为可以在不增加轻微重叠毒性的情况下提供更高的肿瘤剂量。在这里，我们结合了一种 Y 标记的抗 EGFR 抗体（西妥昔单抗）与临床相关的分割放射治疗，在头颈部鳞状细胞癌异种移植肿瘤的临床前试验中进行了研究。
为了模拟 Y-Cetuximab 的摄取，以便优化治疗方案，在不同剂量的放射治疗过程中，将近红外标记的 Cetuximab 注射到 FaDu 荷瘤小鼠体内，并在不同的时间点进行。通过体内光学成像对 Cetuximab 的摄取进行了纵向跟踪。采用分割放射治疗（30 fx，6 周，8 个剂量组/臂）与 Y-Cetuximab 联合进行肿瘤控制概率实验，以测试其治疗潜力。
对近红外标记的 Cetuximab 摄取的成像研究表明，低到中等的外照射剂量可以增强抗体摄取。使用优化的方案，在之前的实验中，Y-Cetuximab 的分子和外部放射治疗联合使用，其剂量不会导致肿瘤永久性失活，与单纯放射治疗相比，肿瘤控制率显著提高。
我们的结果表明，放射性标记治疗药物与临床相关的分割放射治疗相结合，具有显著提高治疗效果的潜力。在注射前应用一定剂量的辐射可能会改善药物摄取，并通过治疗过程中的相应 PET 示踪剂实现患者分层和治疗个体化。
