A Novel Symbiotic Approach for Ovarian Cancer

治疗卵巢癌的新共生方法

• 批准号: 10511945
• 负责人: Jogender Tushir-Singh
• 金额: $ 38.14万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511945
• 关键词: Novel; Symbiotic; Approach; Ovarian; Cancer

The overall cancer death rates are down ~20% in past 25 years, however they remained unchanged for late stage ovarian cancer (OvCa) patients, making it the deadliest gynecological disease. Cancer immunotherapy makes use of antibody-based approaches to activate immune cells against the cancer cells and have proven effective in blood cancers and melanomas. Despite short-term positive responses, most OvCa specific antibodies have largely failed in clinical trials. This is attributed to limited infiltration of activated immune effector cells into the solid tumor bed. Therefore, it is highly important to generate efficacious therapies that have inbuilt capacity to turn OvCa against itself by exploiting inherent cancer properties. The proposed studies aim to investigate a novel and rationally combined dual-specificity antibody-based approach (called BaCa) that makes use of OvCa enriched surface antigen (FOLR1) and cancer inducible cell-death activator (DR5 or TRAIL-R2). Therapeutic antibodies individually against FOLR1 and DR5 have failed in clinical trials due to lack of efficacy. The BaCa approach combines these two targets in a single agent antibody with combined strength in the activity and selectivity. FOLR1 acts as an anchor to selectivity recruit, retain, and maintain anti-DR5 affinity in the ovarian tumor microenvironment. This results into a high level of DR5 receptor clustering, signaling and activation. As a consequence a highly superior cell death and cytotoxicity is instigated against ovarian tumors. We have already tested the feasibility of BaCa strategy in both ex vivo and in vivo OvCa models. Current application supported with comprehensive preliminary data aims to test the unique ability of BaCa strategy to engage host immune response for long-term immunogenicity against OvCa. If proved accurate and successful in vivo, this path has the inherent “moon-shot” potential to selectively eliminate HGSOC cells, in a similar or improved fashion over FDA approved dual-specificity antibody called blinatumomab. Unlike chemotherapy, proposed biological therapy is safe and will significantly change the landscape of disease progression free survival of OvCa patients. Finally, this strategy has a great potential to be applicable for other solid cancer targeting.

在过去的25年里，癌症的总死亡率下降了约20%，但最近几年仍然保持不变。 阶段卵巢癌（OvCa）患者，使其成为最致命的妇科疾病。癌症免疫疗法 利用基于抗体的方法来激活免疫细胞对抗癌细胞，并已证明 对血癌和黑色素瘤有效尽管短期的积极反应，大多数OvCa特异性 抗体在临床试验中基本上失败了。这归因于激活的免疫细胞的有限浸润。 效应细胞进入实体瘤床。因此，产生有效的疗法是非常重要的， 具有通过利用固有的癌症特性使OvCa对抗自身的内在能力。拟议的研究 目的是研究一种新的、合理组合的基于双特异性抗体的方法（称为巴卡）， 利用富含OvCa的表面抗原（FOLR 1）和癌症诱导性细胞死亡激活剂（DR 5或 TRAIL-R2）。单独针对FOLR 1和DR 5的治疗性抗体在临床试验中失败，原因是缺乏 的功效。巴卡方法将这两种靶点结合在具有组合强度的单剂抗体中 活性和选择性。FOLR 1作为一个锚，选择性募集、保留和维持抗DR 5 卵巢肿瘤微环境中的亲和力。这导致高水平的DR 5受体聚集， 信号和激活。因此，激发了高度上级细胞死亡和细胞毒性， 卵巢肿瘤我们已经在离体和体内OvCa中测试了巴卡策略的可行性 模型目前的应用程序支持全面的初步数据，旨在测试的独特能力， 利用宿主免疫应答的巴卡策略，以获得针对OvCa的长期免疫原性。如果证明 在体内准确和成功，这条路径具有固有的“登月”潜力，选择性地消除 HGSOC细胞，以与FDA批准的双特异性抗体类似或改进的方式， Blinatumomab。与化疗不同，生物疗法是安全的，并将显著改变化疗的效果。 OvCa患者的无疾病进展生存期概况。最后，这一战略有很大的潜力， 也适用于其他实体肿瘤靶向。