PO.IM01.10 · 免疫学
EGFR与检查点抑制剂联合疗法在自发性结肠癌模型中的临床前评估
Preclinical assessment of EGFR and checkpoint inhibitor combination therapy in spontaneous colon cancer model
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
自发性结肠癌模型可密切模拟人类疾病，有助于转化研究和治疗评估。携带APC基因突变的ApcMin/+小鼠是一种成熟的肠道肿瘤模型。近年来，免疫治疗在结直肠癌中显示出前景，但EGFR抑制剂与免疫检查点阻断剂的联合在息肉模型中仍未被充分探索。本研究考察这两种治疗在阻止早期肿瘤方面协同作用的效果，采用实时结肠镜检查观察APC小鼠中肿瘤的生长。在本研究中，我们评估了免疫检查点抑制剂（抗PD-1/CTLA-4）和EGFR抑制剂（如Erlotinib）作为单药以及联合方案在C57BL/6J-Apc Min/J小鼠自发性结肠癌模型中的临床前疗效。四周龄小鼠被随机分组，起始治疗方案为：抗PD1 10mg/kg，即每周两次共8周；抗CTLA-4 10mg/kg，腹腔注射，每周两次共8周；Erlotinib 50mg/kg，口服，每日一次共8周，作为单药以及与Erlotinib联合。每周进行结肠镜检查并采集图像以追踪肿瘤进展。每两周监测体重、临床体征和死亡率。研究结束时，处死小鼠，采集其小肠和结肠，成像并使用ImageJ软件评估息肉负荷。结肠样本被卷制并进行组织学分析处理。在本自发性结肠癌模型中，内镜评估显示，与对照组相比，抗PD-1、CTLA-4和Erlotinib单药治疗显著减少了病灶、肿瘤负荷、炎症和息肉面积。相对于对照组，显著减少了肠道息肉的总面积。小肠（近端、中段和远端）和结肠的息肉面积减少百分比（%）分别为38%、27%和68%。然而，Erlotinib与抗PD-1和抗CTLA-4抗体的联合显示出结肠肿瘤负荷的大幅减少。小肠（近端、中段、远端）和结肠的息肉面积减少百分比（%）分别为88%和74%。组织学显示，联合治疗组的炎症和异型增生较单药治疗更少。总之，联合治疗使ApcMin/+小鼠的小肠息肉数量和大小均显著减少，并具有潜在的生存获益。这些发现表明，双重靶向EGFR信号和免疫检查点可能增强抗肿瘤疗效，为结直肠癌治疗提供了一种有前景的方法。
查看英文原文 English abstract
Spontaneous colon cancer models closely mimic human disease, enabling translational research and therapeutic evaluation. The ApcMin/+ mouse, with a mutation in the APC gene, is a well-established model for intestinal neoplasia. In recent years, immunotherapy has shown promise in colorectal cancer, the combination of EGFR inhibitors and immune checkpoint blockers remains underexplored in polyp models. This research looks at how well these two treatments work together in stopping early tumors, using real time colonoscopy to watch how tumors grow in APC mice. In this study we have evaluated the preclinical efficacy of immune checkpoint inhibitors (anti-PD-1/ CTLA-4) and EGFR inhibitors like Erlotinib and as standalone and in combination regimen in spontaneous colon cancer model of C57BL/6J- Apc Min /J mice. Four-week-old mice were randomized, and treatment was initiated with anti-PD1 10mg/kg, i.e., BIW for 8 weeks, anti-CTLA-4 dosed at 10mg/kg, i.p; BIW for 8 weeks and Erlotinib 50mg/kg, po; QD for 8 weeks, as standalone and combination with Erlotinib. Weekly colonoscopies with image capture tracked tumor progression. Body weight, clinical signs, and mortality were monitored biweekly. At the study end, mice were euthanized, and their small intestines and colons were collected, imaged, and assessed for polyp load using ImageJ software. Colon samples were rolled and processed for histological analysis. In the current spontaneous colon cancer model, endoscopy assessment revealed that the anti-PD-1, CTLA-4, and Erlotinib monotherapies significantly reduced lesions, tumor burden, inflammation, and polyp area compared to controls. Significantly reduced the total area of intestinal polyps relative to the control group. The percentage (%) reduction in polyp area in the small intestine (proximal, middle, and distal) and colon was found to be 38%, 27%, and 68% respectively. However, the combination of Erlotinib with anti-PD-1 and anti-CTLA-4 antibodies showed a substantial reduction in colonic tumor burden. The % reduction in polyp area in the small intestine (proximal, middle, distal) and colon was found to be 88% and 74%, respectively. Histology showed less inflammation and dysplasia in the combination group versus monotherapy. In summary, combination therapy led to a marked decrease in both the number and size of small intestinal polyps in ApcMin/+ mice, with potential survival benefits. These findings indicate that dual targeting of EGFR signalling and immune checkpoints may enhance antitumor efficacy, presenting a promising approach for colorectal cancer treatment
利益披露 Disclosure
B. Ramachandran, None..
S. Rajendiran, None..
G. Joshi, None..
K. Haladasappa, None.