Bäck Tom, Chouin Nicolas, Lindegren Sture, Kahu Helena, Jensen Holger, Albertsson Per, Palm Stig
Department of Radiation Physics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
LUNAM Université, Oniris, AMaROC, Nantes, France.
J Nucl Med. 2017 Apr;58(4):598-604. doi: 10.2967/jnumed.116.178327. Epub 2016 Sep 29.
The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Mice bearing subcutaneous tumors (50 mm, NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with At-MX35-F(ab') at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Effects on tumor growth after fractionated α-radioimmunotherapy with At-MX35-F(ab') was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival.
本研究的目的是调查除了已确定的治疗微转移和微小病灶的作用外，靶向α治疗是否可用于成功治疗大肿瘤。我们在小鼠皮下肿瘤模型中使用了α放射免疫疗法的静脉分次给药方案。我们旨在评估根除肿瘤和监测肿瘤生长所需的吸收剂量水平，以及评估治疗后的长期生存率。给患有皮下肿瘤（50 mm，NIH:OVCAR-3）的小鼠反复注射（1-3次静脉注射，间隔7-10天，以使骨髓恢复）不同活性的At-MX35-F(ab')（接近急性骨髓毒性）。根据生物分布数据估计肿瘤和器官的平均吸收剂量，并将各分次剂量相加。治疗后监测肿瘤生长100天，生存1年。毒性分析包括体重、白细胞计数和血细胞比容。用At-MX35-F(ab')进行分次α放射免疫治疗后对肿瘤生长的影响强烈且呈剂量依赖性。肿瘤剂量为12.4和16.4 Gy时出现完全缓解（无瘤率100%）。给药活性较高，长期毒性作用（≤60周）明显。高于1 MBq时，中位生存期随注射活性呈线性下降，从44周降至11周。体重减轻也显示出毒性。α放射免疫治疗后的白细胞计数分析表明低活性组骨髓恢复，而高活性组白细胞减少接近急性骨髓毒性。在较晚的时间段（治疗后34-59周）观察到血细胞比容下降。健康状况不佳的主要外部表现是脱水。在观察到实体瘤异种移植完全根除后，我们得出结论，靶向α治疗方案可能超出微转移疾病的范围，对大肿瘤也有根除作用。我们的观察表明至少需要10 Gy。这与计算出的肿瘤控制概率非常吻合。考虑到相对生物效应为5，这个剂量水平似乎是合理的。然而，首次在接近致死的活性水平时实现了完全缓解，并且伴随着降低长期生存率的生物学效应。
