A Novel Symbiotic Approach for Ovarian Cancer

在过去的25年里，总体癌症死亡率下降了约20%，但在很晚的时间里保持不变 卵巢癌(OvCa)期患者，使其成为最致命的妇科疾病。癌症免疫治疗 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。尽管短期内反应积极，但大多数OvCa特异性 抗体在临床试验中基本上失败了。这归因于活化免疫的有限渗透。 效应细胞进入实体肿瘤床。因此，产生有效的治疗方法是非常重要的， 具有通过利用固有的癌症特性将卵泡刺激素转化为自身的能力。建议进行的研究 目的研究一种新的、合理组合的基于双特异性抗体的方法(称为BACA)。 利用OvCa富集型表面抗原(FOLR1)和癌症诱导细胞死亡激活剂(DR5或 TRAIL-R2)。分别针对FOLR1和DR5的治疗性抗体因缺乏而在临床试验中失败 效率的问题。BACA方法将这两个靶点结合成具有联合强度的单剂抗体。 在活性和选择性方面。FOLR1充当选择性招募、保留和维护抗DR5的锚 卵巢肿瘤微环境中的亲和力。这导致高水平的DR5受体聚集， 信号和激活。其结果是，高度优越的细胞死亡和细胞毒性被煽动起来反对 卵巢肿瘤。我们已经在体外和体内卵细胞中测试了BACA策略的可行性 模特们。目前的应用程序以全面的初步数据为支持，旨在测试 BACA策略参与宿主免疫反应，以获得针对OvCa的长期免疫原性。如果证明了 在活体内准确和成功，这条路径具有固有的选择性地消除 HGSOC细胞，与FDA批准的称为 Blinatumomab。与化疗不同，拟议的生物疗法是安全的，并将显著改变 卵巢癌患者疾病无进展生存的景观。最后，这一战略有很大的潜力 也适用于其他实体肿瘤靶向。

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.