Targeting Tissue Factor for Immunotherapy of Triple-Negative Breast Cancer Using a Second-Generation ICON.
Targeting Tissue Factor for Immunotherapy of Triple-Negative Breast Cancer Using a Second-Generation ICON.
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DOI：
10.1158/2326-6066.cir-17-0343
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发表时间：
2018-06
影响因子：
10.1
通讯作者：
Carson WE 3rd
中科院分区：
文献类型：
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作者：
Hu Z;Shen R;Campbell A;McMichael E;Yu L;Ramaswamy B;London CA;Xu T;Carson WE 3rd
三阴性乳腺癌（TNBC）是乳腺癌死亡的主要原因，通常与BRCA 1和BRCA 2突变有关。由于缺乏经验证的靶分子，没有批准用于TNBC的靶向疗法。组织因子（TF）是包括乳腺癌在内的几种实体癌中癌细胞、肿瘤血管内皮细胞和癌干细胞的常见而特异的表面靶受体。在这里，我们报告的证据支持TF是TNBC的表面靶点的想法。我们使用了体外癌症细胞系和小鼠体内肿瘤异种移植物，所有这些细胞都具有BRCA 1或BRCA 2突变，来自患者的肿瘤。我们发现，TF在50%至85%的TNBC患者（n = 161）中的TNBC细胞和肿瘤新生血管系统上以及在来自小鼠的TNBC细胞系来源的异种移植物（CDX）和患者来源的异种移植物（PDX）中过表达，但在邻近的正常乳腺组织中未检测到。然后，我们描述了第二代TF靶向免疫偶联物（称为L-ICON 1，用于更轻或轻链ICON）的开发，与原始ICON相比，其疗效和安全性有所改善。我们表明，L-ICON 1通过抗体依赖性细胞介导的细胞毒性在体外杀死TNBC细胞，并且可用于在原位小鼠模型中在体内治疗人和鼠TNBC CDX以及PDX。因此，TF可能是一个有用的目标，用于开发TNBC患者的免疫治疗，有或没有BRCA 1和BRCA 2突变。
Triple-negative breast cancer (TNBC) is a leading cause of breast cancer death and is often associated with BRCA1 and BRCA2 mutation. Due to the lack of validated target molecules, no targeted therapy for TNBC is approved. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells and cancer stem cells in several types of solid cancers including breast cancer. Here we report evidence supporting the idea that TF is a surface target in TNBC. We used in vitro cancer lines and in vivo tumor xenografts in mice, all with BRCA1 or BRCA2 mutations, derived from patients’ tumors. We showed that TF is over-expressed on TNBC cells and tumor neovasculature in 50% to 85% of TNBC patients (n = 161) and in TNBC cell line–derived xenografts (CDX) and patient-derived xenografts (PDX) from mice, but was not detected in adjacent normal breast tissue. We then describe the development of a second-generation TF-targeting immunoconjugate (called L-ICON1, for lighter or light chain ICON) with improved efficacy and safety profiles compared to the original ICON. We showed that L-ICON1 kills TNBC cells in vitro via antibody-dependent cell-mediated cytotoxicity and can be used to treat human and murine TNBC CDX as well as PDX in vivo in orthotopic mouse models. Thus TF could be a useful target for the development of immunotherapeutics for TNBC patients, with or without BRCA1 and BRCA2 mutations.