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B7H3 导向双特异性抗体与索拉非尼联合治疗可产生增强的协同抗肿瘤疗效。

Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy.

机构信息

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan province, China.

Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan province, China.

出版信息

Theranostics. 2020 Aug 21;10(23):10498-10512. doi: 10.7150/thno.49480. eCollection 2020.

DOI:10.7150/thno.49480
PMID:32929362
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7482810/
Abstract

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. 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 . Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both and . 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. 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.

摘要

目前，由于卵巢癌诊断较晚且复发率较高，传统的治疗方法往往无效。因此，迫切需要开发新的治疗药物。B7H3 是一种免疫检查点蛋白，在多种癌症中高度表达，代表其是癌症免疫治疗的一个有前途的靶点。尽管近年来双特异性 T 细胞接合抗体（BiTE）靶向 B7H3 在血液恶性肿瘤中取得了成功，但将其用于实体瘤的治疗并不理想，部分原因是肿瘤的异质性。索拉非尼是一种多激酶的非选择性抑制剂，目前正在临床试验中用于多种肿瘤的治疗，包括卵巢癌，但对卵巢癌的治疗效果有限且不可避免地存在副作用。然而，它能够增强抗肿瘤免疫反应，这表明索拉非尼可能会提高免疫治疗的效率。

我们使用在线数据库评估了卵巢癌中 B7H3 的表达，并通过免疫组化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了 B7H3 的表达和索拉非尼对卵巢癌细胞系的影响。此外，建立了 2D 和 3D 卵巢癌模型来测试联合治疗效果。最后，评估了 B7H3×CD3 BiTE 单独使用及其与索拉非尼联合使用的效果。

我们的数据表明，与正常样本相比，B7H3 在卵巢癌中高度表达。索拉非尼治疗抑制了卵巢癌细胞的增殖，并诱导了 B7H3 表达水平的显著上调。进一步的研究表明，B7H3×CD3 BiTE 可有效介导 T 细胞杀伤癌细胞。索拉非尼和 B7H3×CD3 BiTE 的联合治疗在卵巢癌模型中具有协同的抗肿瘤作用。

总之，我们的研究表明，索拉非尼和 B7H3×CD3 BiTE 的联合治疗可能是进一步研究 OC 临床前治疗的一种新的治疗选择。

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