EMT-6 Syngeneic乳腺肿瘤模型 - 一种强大的免疫肿瘤学研究工具

AUTHOR:

谢Barnes博士|导演,三英洁具tific Development

日期：

2018年5月

乳腺癌是美国女性中最常见的癌症，是癌症死亡的第四个主要原因。在2017年，估计诊断出252,710例新病例（占所有新癌症的15％）和40,610名患者死亡。早期检测举措与改善的治疗方案一起导致5年的整体生存率增加到1975年的75％至超过90％。[1]尽管存在有利的存活统计，转移性疾病仍然是治疗挑战，并且经常导致死亡。因此，需要持续开发乳腺癌新治疗方法。

Advancements in Using Immuno-oncology Combination Therapies for Breast Cancer

While several treatment options are available to fight hormone- or Her2-driven breast cancers, options are somewhat limited for三重阴性乳腺癌不能利用这些有针对性的疗法的患者。添加到这个问题，尽管在治疗黑素瘤和肺癌中的免疫治疗方面取得了成功，但乳腺癌已被证明是特别难以检查点封闭或其他免疫治疗。然而，近年来的重点努力免疫肿瘤学乳腺癌接近，新兴临床数据显示有望，特别是在联合治疗中。[2]为了帮助推动这项研究，Covance已经开发了EMT-6 Syngeenic乳腺肿瘤模型。来自Balb / C小鼠中的移植的增生肺泡结节衍生，[3]该模型利用完整的小鼠免疫系统，并用作免疫肿瘤间空间中的强大工具。

使用EMT-6模型测试组合疗法

In this spotlight, we present data from our initial efficacy study with the EMT-6 model. These data should enable the design of rational combination studies with novel therapeutics while additional studies are performed. Control tumor growth for the EMT-6 model is shown in Figure 1. The median doubling time is 5.5 days on average, allowing for a therapeutic window of at least three weeks with which to elicit anti-tumor activity. The growth rates of untreated tumors and those treated with an isotype control antibody (rat IgG2b) are nearly superimposable. To determine the response of EMT-6 to immunomodulatory therapies, mice bearing EMT-6 tumors were treated with checkpoint blockade (anti-mPD-1 and anti-mPD-L1), and anti-mCD137, a costimulatory molecule. Additionally, as focal radiation is oftentimes used to treat breast cancer, we included modeling of radiation monotherapy and combination therapy.

与对照相比，对检查点封闭的反应是适中的（图2）。虽然动物的子集确实响应，但用抗MPD-1和抗MPD-L1治疗仍然为组合提供改善的空间。此外，Afocal radiationdose of 10Gy, which causes significant tumor growth delay in other syngeneic models, offered only modest activity in EMT-6. Addition of anti-mPD-1 to this regimen offers some additive impact, yet still leaves room for improvement in triple combination. In contrast, treatment with anti-mCD137 monotherapy results in a strong response (4/10 TFS) against EMT-6. Combination with focal radiation offered nominal improvement (5/10 TFS) over anti-mCD137 monotherapy (Figure 3). These data demonstrate the advantage of using the EMT-6 model to investigate dual or triple combination strategies which utilize radiation, checkpoint blockade, and/or costimulatory molecule agonists.

Composition of Infiltrated Immune Cells Within the Tumor

当询问免疫脑神经理目的时，将渗透的免疫细胞的组成变为肿瘤也很重要。为此，检查220-385mm 3之间的肿瘤，用于渗透到T细胞，骨髓细胞表达为CD45 +细胞的百分比（图4）。所有肿瘤上的骨髓隔室均匀地分布在M2巨噬细胞，单核细胞MDSC和粒细胞MDSC上。M1巨噬细胞渗透比其他骨髓衍生细胞相对较低。该组合物提示免疫抑制微环境，这有助于解释测试的大多数免疫疗法方案的有限反应。