10月13-16日，第14届国际妇科肿瘤学会双年会（IGCS 2012）在加拿大温哥华举行。IGCS 2012一如既往地为参会者奉上妇科肿瘤学领域最新研究进展，提供发布、讨论和争辩最新科学信息的良机。金宝搏网站登录技巧 对本届年会进行了专题报道（http://zt.cmt.com.cn/zt/igcs2012/index.html）。

　　会上，美国阿拉巴马大学的Fauci博士等报告的一项体外研究表明，单克隆抗体（mAb）376.96单独应用或与舒尼替尼联用均可抑制对化疗敏感或耐药的卵巢癌细胞。重要的是，联合用药可抑制癌症起源细胞（CIC）。腹膜内给予小鼠212Pb-376.96是一种可行的局部区域给药方法，在卵巢癌治疗中具有特殊意义。

       研究摘要：

Monoclonal Antibody-Based Immunotherapy of Ovarian Cancer: Targeting of Differentiated and Cancer-Initiating Cells With the B7-H3-Specific mAb 376.96 and Sunitinib

Background: The high rate of relapse after surgical debulking and adjuvant chemotherapy in advanced ovarian cancer likely reflects the chemoresistance of cancer-initiating cells (CICs), which play a crucial role in disease recurrence. This possibility has prompted us to develop therapy to target not only differentiated ovarian cancer cells but also CICs. To this end, we combine the monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope with selective expression on malignant
cells including ovarian carcinoma cells, with the tyrosine kinase inhibitor sunitinib. We show that this combination targets not only differentiated ovarian cancer cells but also CICs. In addition, we show that the mAb 376.96 is amenable to an intraperitoneal delivery method.

Methods: Eight ovarian cancer cell lines including 2 chemoresistant cell lines A2780.cp20 and SKOV3ip2.TR were stained with mAb376.96 and analyzed by flow cytometry to establish expression. In vitro studies to assess the effect of mAb376.96 with or without chemotherapy with or without sunitinib were performed on chemosensitive (SKOV3.ip1) and chemoresistant (SKOV3ip2.TR and A2780.cp20) cell lines. The effect of mAb376.96 on CICs was evaluated via analysis
of aldehyde dehydrogenase (ALDHbright) activity using an ALDEFLUOR kit. Cells isolated from a patient with ovarian cancer were intraperitoneally (IP) injected into immunodeficient mice and radiolabeled mAb376.96 (technetium-99m [99mTc]-376.96) was IP injected, and localization of antibody was assessed after 24 hours.
 

Results: The B7-H3 epitope recognized by mAb 376.96 is expressed by both chemosensitive and chemoresistant ovarian cancer cell lines. In vitro treatment of A2780.cp20 and SKOV3ip2.TR cells with single agent mAb376.96 revealed cell growth inhibition of 30% and 45%, respectively. Combination treatment of SKOV3.ip1 cells with sunitinib and mAb376.96 resulted in 28% cell growth inhibition versus 10% inhibition with sunitinib alone. Analysis of CICs revealed that treatment with sunitinib and mAb376.96 reduced the proportion of CICs by one third compared with untreated cells. In vivo studies showed that 24 hours after IP
dosing, 99mTc-376.96 showed higher uptake in tumors grown in mice (n = 3) after IP injection of human ovarian cancer pleural fluid compared to 99mTc-labeled isotype control mAb (3 tumors had values of 15.1%, 24.1%, and 11.8% injected dose per gram, vs. 4.3 T 1.4% injected dose per gram in isotype control). Additionally, 99mTc-376.96 was retained in the tumors in peritoneal cavity.
 

Conclusion: In vitro studies using mAb376.96 showed an inhibitory effect against chemosensitive and chemoresistant ovarian cancer cells alone and in combination with sunitinib. Importantly, the combination treatment inhibits CICs. Intraperitoneal 212Pb-376.96 is a feasible method for locoregional treatment delivery, which is of particular interest in the treatment of ovarian cancer.