10月13-16日，第14屆國際婦科腫瘤學會雙年會（IGCS 2012）在加拿大溫哥華舉行。IGCS 2012一如既往地為參會者奉上婦科腫瘤學領域最新研究進展，提供發布、討論和爭辯最新科學信息的良機。醫學論壇網對本屆年會進行了專題報道（http://zt.cmt.com.cn/zt/igcs2012/index.html）。
會上，美國阿拉巴馬大學的Fauci博士等報告的一項體外研究表明，單克隆抗體（mAb）376.96單獨應用或與舒尼替尼聯用均可抑製對化療敏感或耐藥的卵巢癌細胞。重要的是，聯合用藥可抑製癌症起源細胞（CIC）。腹膜內給予小鼠212Pb-376.96是一種可行的局部區域給藥方法，在卵巢癌治療中具有特殊意義。
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.
