64Cu-Intraperitoneal Radioimmunotherapy: A Novel Approach for Adjuvant Treatment in a Clinically Relevant Preclinical Model of Pancreatic Cancer
64Cu-Intraperitoneal Radioimmunotherapy: A Novel Approach for Adjuvant Treatment in a Clinically Relevant Preclinical Model of Pancreatic Cancer
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DOI：
10.2967/jnumed.118.225045
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发表时间：
2019-10-01
影响因子：
9.3
通讯作者：
Higashi, Tatsuya
中科院分区：
文献类型：
--
作者：
Yoshii, Yukie;Matsumoto, Hiroki;Higashi, Tatsuya
胰腺癌（PC）的预后非常差。手术是可切除PC患者的主要治疗方法;然而，即使在广泛手术后，也经常发生局部复发、肝转移和腹膜播散。辅助化疗，通常与吉西他滨，已在临床上使用，但只有适度的生存获益。为了获得更好的结果，我们研究了Cu-64-腹膜内放射免疫治疗（ipRIT）与Cu-64-标记的抗表皮生长因子受体抗体西妥昔单抗作为PC手术后使用原位异种移植小鼠模型的辅助治疗的疗效。方法：在携带xPA-1-DC细胞的原位异种移植物的人PC小鼠模型中研究佐剂Cu-64-ipRIT的功效。为了再现临床情况，当胰腺肿瘤容易可见但没有转移性肿瘤时，手术切除PC异种移植物。腹膜内注射增加剂量的Cu-64-西妥昔单抗，并监测小鼠的毒性以确定安全治疗剂量。对于佐剂Cu-64-ipRIT，在肿瘤切除后的第二天，腹膜内给予小鼠22.2MBq的Cu-64-PCTA-西妥昔单抗，并将存活率与仅手术的对照进行比较。为了进行比较，还使用相同的模型检查了吉西他滨辅助化疗。结果如下：小鼠模型不仅在胰腺中产生原发性肿瘤，而且随后在手术后再现局部复发、肝转移和腹膜播散，这与人类PC发生的表现相似。在该模型中，手术后辅助Cu-64-ipRIT与Cu-64标记的西妥昔单抗有效地抑制了局部复发、肝转移和腹膜播散。与仅接受手术的对照小鼠相比，佐剂Cu-64-ipRIT实现了存活率的显著改善和最小的毒性。吉西他滨辅助化疗名义上延长了生存期，但效果无统计学意义。结论：Cu-64-ipRIT联合西妥昔单抗可作为前列腺癌术后有效的辅助治疗。
Pancreatic cancer (PC) has a very poor prognosis. Surgery is the primary treatment for patients with resectable PC; however, local recurrence, hepatic metastasis, and peritoneal dissemination often occur even after extensive surgery. Adjuvant chemotherapy, typically with gemcitabine, has been used clinically but with only a modest survival benefit. To achieve a better outcome, we investigated the efficacy of Cu-64-intraperitoneal radioimmunotherapy (ipRIT) with Cu-64-labeled antiepidermal growth factor receptor antibody cetuximab as an adjuvant treatment after PC surgery using an orthotopic xenografted mouse model. Methods: The efficacy of adjuvant Cu-64-ipRIT was investigated in a human PC mouse model harboring orthotopic xenografts of xPA-1-DC cells. To reproduce the clinical situation, PC xenografts were surgically resected when pancreatic tumors were readily visible but not metastatic tumors. Increasing doses of Cu-64-cetuximab were intraperitoneally injected, and the mice were monitored for toxicity to determine the safe therapeutic dose. For adjuvant Cu-64-ipRIT, the day after tumor resection, the mice were intraperitoneally administered 22.2 MBq of Cu-64-PCTA-cetuximab and the survival was compared with that in surgery-only controls. For comparison, adjuvant chemotherapy with gemcitabine was also examined using the same model. Results: The mouse model not only developed primary tumors in the pancreas but also subsequently reproduced local recurrence, hepatic metastasis, and peritoneal dissemination after surgery, which is similar to the manifestations that occur with human PC. Adjuvant Cu-64-ipRIT with Cu-64-labeled cetuximab after surgery effectively suppressed local recurrence, hepatic metastasis, and peritoneal dissemination in this model. Significant improvement of the survival with minimal toxicity was achieved by adjuvant Cu-64-ipRIT compared with that in control mice that underwent surgery only. Adjuvant chemotherapy with gemcitabine nominally prolonged the survival, but the effect was not statistically significant. Conclusion: Cu-64-ipRIT with cetuximab can be an effective adjuvant therapy after PC surgery.