Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy./nMethods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo./nResults: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models./nConclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.

中文翻译：

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与B7H3重定向的双特异性抗体和索拉非尼的联合治疗可增强协同的抗肿瘤功效。

理由：由于晚期诊断和高复发性，当前的传统治疗选择常常不能有效抵抗卵巢癌。因此，迫切需要开发新型治疗剂。B7H3是一种免疫检查点蛋白，在各种癌症中都高度表达，代表着它是癌症免疫疗法的有希望的靶标。尽管近年来通过双特异性T细胞接合抗体（BiTE）靶向B7H3在血液系统恶性肿瘤中取得了成功，但将其用于治疗实体癌的尝试却不太理想，部分原因是肿瘤的异质性。索拉非尼是多种激酶的非选择性抑制剂，目前正在临床试验中针对多种肿瘤（包括卵巢癌）进行测试，这些肿瘤表现出有限的活性，并且对于卵巢癌的治疗具有不可避免的副作用。方法：我们使用在线数据库评估了B7H3在卵巢癌中的表达，并通过免疫组织化学染色验证了其在肿瘤组织中的表达。然后，通过流式细胞术确定B7H3表达和索拉非尼对卵巢癌细胞系的影响。此外，建立2D和3D卵巢癌模型以测试体外联合治疗效果。最后，单独B7H3×CD3的BiTE的效率及其与索拉非尼组合都进行了评价在体外和体内./n结果：我们的数据显示，与正常样品相比，B7H3在卵巢癌中高表达。索拉非尼治疗抑制卵巢癌细胞增殖并诱导B7H3表达水平明显上调。进一步的研究表明，B7H3×CD3 BiTE可以有效地介导T细胞对癌细胞的杀伤作用。结论：总的来说，我们的研究表明，索拉非尼与B7H3×CD3 BiTE联合治疗可能是卵巢癌进一步研究的新治疗选择。 OC的临床前治疗。