Development of an Ad5-CEA/Brachyury Vector Approach for Cancer Treatment

用于癌症治疗的 Ad5-CEA/Brachyury 载体方法的开发

• 批准号: 8780459
• 负责人: Frank R. Jones
• 金额: $ 20.27万
• 依托单位: ETUBICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780459
• 关键词: Adenoviruses; Adverse effects; Animals; Antibodies; Antigen Targeting; Biological Assay; Biological Markers; Boxing; Brachyury protein; CD8B1 gene; Cancer Patient; Carcinoembryonic Antigen; Cell-Mediated Cytolysis; Characteristics; Clinical; Collaborations; Colorectal Cancer; Complement; Cytolysis; DNA Binding Domain; Development; Dose; Down-Regulation; Epithelial; Family; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Interferon Type II; Interleukin-2; Intravenous; Lead; Lymphocyte Activation; Maintenance; Malignant Epithelial Cell; Mesenchymal; Mesoderm; Modality; Monitor; Mus; National Cancer Institute; Neoplasm Metastasis; Patients; Phase; Play; Primary Neoplasm; Radiation; Recombinants; Regimen; Resistance; Role; Safety; Serotyping; Serum; Small Business Innovation Research Grant; T-Lymphocyte; Technology; Testing; Therapeutic; Transgenes; Tumor Antigens; Up-Regulation; Vaccines; Viral Vector; base; cancer stem cell; cancer therapy; cell motility; chemotherapy; cytotoxic; design; granzyme B; immunogenic; immunogenicity; member; metastatic colorectal; neoplastic cell; prevent; public health relevance; response; small molecule; transcription factor; tumor; tumor growth; vector

DESCRIPTION (provided by applicant): With the discovery of new biomarkers associated with tumor development, many of these tumor-associated antigens (TAA) are being utilized in immunotherapeutic modalities designed to induce anti-tumor directed cytotoxic immune responses. It is increasingly clear that not any one of these TAA is sufficient, as a single entity to develop an immunotherapeutic treatment agent. Consequently, our efforts are being focused on developing multi-targeted immunotherapeutic approach against TAA. The overall goal of the current project is to expand our immunotherapeutic approach for the treatment of metastatic colorectal cancer (mCRC) using a multiple targeted approach. Drs. Jeffery Schlom and James Gully at the National Cancer Institute have agreed to collaborate with us to reach this goal. We have achieved safety, dose response, and an increased overall survival in mCRC patients using our Ad5 [E1-, E2b-]-CEA(6D) (ETBX-011) immunotherapeutic as a single agent. We believe that adding an anti-cancer stem cell (CSC) approach can lead to increased efficacy particularly against tumor metastases. Thus, we have added Brachyury as a TAA CSC target. Brachyury represents a relatively new but attractive target for immunotherapy. It is a member of the T-box family of transcription factors that play key roles during early development, mostly in the formation and differentiation of normal mesoderm and is characterized by a highly conserved DNA-binding domain designated as T-domain. Recently, epithelial-mesenchymal transition (EMT) has been recognized as a key step during the progression of primary tumors into a metastatic state in which Brachyury plays a crucial role. Tumor EMT has been demonstrated to be associated with the acquisition of CSC-like features that includes acquisition and maintenance of CSC-like characteristics, resistance to conventional therapeutics, chemotherapy and radiation, and to some small-molecule targeted therapies. Over-expression of Brachyury in human carcinoma cells induces changes characteristic of EMT, including up-regulation of mesenchymal markers, down-regulation of epithelial markers, and an increase in cell migration and invasion. Importantly, Brachyury is immunogenic and Brachyury-specific CD8+ T cells expanded in vitro can lyse Brachyury expressing tumor cells. These features make it one of the more attractive TAA that can be utilized broadly for immunotherapeutic purposes but especially for mCRC. Brachyury is incorporated into our recombinant Ad5 [E1-, E2b-] platform for use in the multiple immunotherapy approach to treat mCRC. We believe that this platform will enable multiple immunizations that will functionally boost the immune response to this target and may prevent metastases. We will incorporate Brachyury into our recombinant Ad5 [E1-, E2b-] platform to produce a new and more potent immunotherapeutic for mCRC that will target primary and mCRC stem cells. We believe these two TAA targets as a single delivery immunotherapeutic agent, will enhance the clinical responses of our Ad5 [E1-, E2b-]- CEA(6D) approach by targeting CSC and will result in an increased overall survival of patients with mCRC.

描述（由申请人提供）：随着与肿瘤发展相关的新生物标志物的发现，许多这些肿瘤相关抗原（TAA）被用于旨在诱导抗肿瘤定向细胞毒性免疫反应的免疫治疗方式。越来越清楚的是，这些 TAA 中的任何一种都不足以作为单一实体来开发免疫治疗剂。因此，我们的工作重点是开发针对 TAA 的多靶点免疫治疗方法。当前项目的总体目标是使用多靶向方法扩展我们治疗转移性结直肠癌（mCRC）的免疫治疗方法。博士。美国国家癌症研究所的 Jeffery Schlom 和 James Gully 已同意与我们合作实现这一目标。我们使用 Ad5 [E1-, E2b-]-CEA(6D) (ETBX-011) 免疫治疗作为单一药物，在 mCRC 患者中实现了安全性、剂量反应并提高了总体生存率。我们相信，添加抗癌干细胞（CSC）方法可以提高疗效，特别是针对肿瘤转移。因此，我们将 Brachyury 添加为 TAA CSC 目标。 Brachyury 代表了一个相对较新但有吸引力的免疫治疗靶点。它是 T-box 转录因子家族的成员，在早期发育过程中发挥关键作用，主要是在正常中胚层的形成和分化中，其特征是高度保守的 DNA 结合结构域（称为 T 结构域）。最近，上皮-间质转化（EMT）被认为是原发性肿瘤进展为转移状态的关键步骤，其中 Brachyury 发挥着至关重要的作用。肿瘤 EMT 已被证明与 CSC 样特征的获得相关，包括 CSC 样特征的获得和维持、对常规治疗、化疗和放疗以及一些小分子靶向治疗的耐药性。 Brachyury 在人类癌细胞中的过度表达会诱导 EMT 特征的变化，包括间充质标记物的上调、上皮标记物的下调以及细胞迁移和侵袭的增加。重要的是，Brachyury 具有免疫原性，体外扩增的 Brachyury 特异性 CD8+ T 细胞可以裂解表达 Brachyury 的肿瘤细胞。这些特性使其成为更具吸引力的 TAA 之一，可广泛用于免疫治疗目的，尤其是 mCRC。 Brachyury 被纳入我们的重组 Ad5 [E1-, E2b-] 平台，用于治疗 mCRC 的多重免疫疗法。我们相信，该平台将实现多重免疫，从而在功能上增强对该目标的免疫反应，并可能预防转移。我们将把 Brachyury 整合到我们的重组 Ad5 [E1-, E2b-] 平台中，以生产一种新的、更有效的 mCRC 免疫疗法，该疗法将靶向原代干细胞和 mCRC 干细胞。我们相信，这两个 TAA 靶标作为单一递送免疫治疗剂，将通过靶向 CSC 来增强我们的 Ad5 [E1-, E2b-]- CEA(6D) 方法的临床反应，并将导致 mCRC 患者的总生存期增加。