Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
J Nucl Med. 2023 Sep;64(9):1439-1445. doi: 10.2967/jnumed.122.265095. Epub 2023 Jun 22.
Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). On day 0, 10 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 Ac-PRIT (37 kBq/cycle as Ac- DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups ( = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Treatment of EOC PC-tumor-bearing mice with anti-HER2 Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 Ac-PRIT system is a potential treatment for otherwise incurable EOC.
上皮性卵巢癌（EOC）通常无症状，临床上表现为广泛的腹膜显微镜下疾病，通常认为手术无法治愈。用α-发射放射性核素 Ac（半衰期为 9.92 天）进行靶向α-治疗是一种对小体积疾病甚至单细胞有效的高线性能量转移治疗方法。在这里，我们报告了使用人表皮生长因子受体 2（HER2）Ac 预靶向放射免疫疗法（PRIT）治疗作为腹膜癌病（PC）生长的人类 EOC SKOV3 异种移植物的小鼠模型。在第 0 天，将转导荧光素酶报告基因的 10 个 SKOV3 细胞腹膜内植入裸鼠中，并通过生物发光成像（BLI）验证肿瘤植入。在第 15 天，使用 1 或 2 个 3 步抗 HER2 Ac-PRIT（每个循环 37 kBq 作为 Ac-DOTA）开始治疗，间隔 1 周。监测了长达 154 天的疗效和毒性。未经治疗的 PC-荷瘤裸鼠的中位生存期为 112 天。我们使用了 2 种独立的反应评估方法来评估 Ac-PRIT 的疗效。首先，与对照组（9/27，33%）相比，更多接受治疗的小鼠（1 个周期的 9/10 只和 2 个周期的 8/10 只；总共有 17/20 只；85%）长期存活，并且记录到明显的生存延长（对数秩[Mantel-Cox] = 0.0042）。其次，使用 BLI，在对照组和治疗组之间观察到到 98 天的综合 BLI 信号区域有显著差异（= 0.0354）。在接受尸检评估的 2 个周期治疗组（共 8 只小鼠，总剂量为 74 kBq）中，肾放射性毒性轻微，无临床症状（正常血清尿素氮和肌酐）。对肿瘤和肾脏进行每 37 kBq 给药的剂量估计（相对生物效应加权剂量，相对生物效应= 5）分别为 56.9 和 16.1 Gy。1 个周期和 2 个周期的治疗同样有效。通过免疫组织化学，在两个治疗组中都观察到归因于α毒性的轻微管状变化。用抗 HER2 Ac-PRIT 治疗上皮性卵巢癌 PC-荷瘤小鼠可导致组织学治愈和延长生存期，且毒性最小。使用抗 HER2 Ac-PRIT 系统进行靶向α-治疗可能是治疗无法治愈的上皮性卵巢癌的一种方法。
