PD-1、VEGFR2抑制剂联合干预结肠癌肝转移的临床研究

Clinical mechanism of PD-1 and VEGFR2 inhibitors combined to interfere with the progression of colon cancer liver metastasis

目的探讨PD-1、VEGFR2抑制剂联合干预结肠癌肝转移的临床研究。方法选取2021年2月至2022年12月在济宁医学院附属医院收治的120例结肠癌肝转移患者为研究对象。根据治疗方案将患者分为对照组(n=60)和观察组(n=60),对照组接受PD-1抑制剂治疗,观察组接受PD-1抑制剂与VEGFR2抑制剂联合治疗。通过动态对比增强磁共振成像(DCE-MRI)评估肿瘤血管密度和渗透性。通过蛋白印记分析PD-1和VEGFR2蛋白表达。通过ELISA检测患者干预前后血清炎症因子IFN-γ、TNF-α、IL-12水平。比较两组的肿瘤控制效果、平均总生存期和平均无进展生存期。结果干预前,观察组与对照组患者比较,血管渗透性和密度的差异无统计学意义(P>0.05);干预6周后,观察组血管渗透性和密度较对照组降低(K^trans:0.12±0.01vs.0.16±0.02;Ve:0.25±0.01vs.0.33±0.03;P<0.05),对照组血管渗透性和密度干预前后无显著变化。干预前,观察组与对照组比较,PD-1和VEGFR2蛋白表达的差异无统计学意义(PD-1:2.04±0.20vs.1.95±0.18;VEGFR2:1.87±0.18vs.1.95±0.19;P>0.05);干预6周后,两组PD-1和VEGFR2蛋白表达较干预前降低,观察组PD-1和VEGFR2蛋白表达较对照组降低(PD-1:1.04±0.02vs.1.30±0.04;VEGFR2:1.12±0.01vs.1.57±0.16;P<0.05)。干预前,观察组与对照组比较,血清IFN-γ、TNF-α、IL-12水平的差异无统计学意义;干预6周后,两组血清IFN-γ、TNF-α、IL-12水平较干预前都升高,但观察组IFN-γ、TNF-α、IL-12升高水平较对照组更明显(IFN-γ:(38.44±3.28)pg/mLvs.(27.55±2.63)pg/mL;TNF-α:(44.62±2.15)pg/mLvs.(30.57±2.09)pg/mL;IL-12:(33.49±2.51)pg/mLvs.(20.75±1.86)pg/mL;P<0.05)。对照组肿瘤部分缓解8例,肿瘤稳定期14例,肿瘤有效控制22例,观察组肿瘤部分缓解17例,肿瘤稳定期24例,肿瘤有效控制41例,观察组PR、SD和DCR较对照组升高,差异有统计学意义(P<0.05)。观察组平均总生存期和平均无进展生存期较对照组延长。结论PD-1和VEGFR2抑制剂联合治疗显著提高了结肠癌肝转移患者的肿瘤控制效果和生存期。通过降低肿瘤血管密度和渗透性、增强免疫应答,减少肿瘤细胞的免疫逃逸,这种联合干预为治疗结肠癌肝转移提供了一种更有效的临床策略。

ObjectiveTo explore the clinical mechanism of PD-1 and VEGFR2 inhibitors combined in intervening the progression of colon cancer liver metastasis.Methods120 patients with colon cancer liver metastasis from Feb.2021 to Dec.2022 were selected as research subjects.According to the treatment plan,patients were divided into control group(n=60)and observation group(n=60).The control group received PD-1 inhibitor treatment,while the observation group received combination of PD-1 inhibitor and VEGFR2 inhibitor treatment.Tumor vascular density and permeability were evaluated by dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI).The expression of PD-1 and VEGFR2 proteins were analyzed through protein blot.The levels of serum inflammatory factors IFN-γ,TNF-α,and IL-12 in patients before and after intervention were detected using ELISA.The tumor control effects between the two groups of patients were compared.The average overall survival and average progression free survival between the two groups of patients were compared.ResultsBefore intervention,there was no statistically significant difference in vascular permeability or density between the observation group and the control group patients;After 6 weeks of intervention,the vascular permeability and density of patients in the observation group decreased compared to the control group.There were no significant changes in vascular permeability or density in the control group before and after intervention.Before intervention,there was no statistically significant difference in the expression of PD-1 or VEGFR2 proteins between the observation group and the control group;P>0.05;After 6 weeks of intervention,the expression of PD-1 and VEGFR2 proteins in both groups of patients decreased compared to that before intervention.The expression of PD-1 and VEGFR2 proteins in the observation group decreased compared to that of the control group(PD-1:1.04±0.02 vs.1.30±0.04;VEGFR2:1.12±0.01 vs.1.57±0.16);P<0.05.Before intervention,there was no statistically significant difference in serum levels of IFN-γ,TNF-α,or IL-12 between the observation group and the control group;After 6 weeks of intervention,the serum levels of IFN-γ,TNF-α,and IL-12 in both groups of patients increased compared to those before intervention.However,the observation group showed a more significant increase in IFN-γ,TNF-α,and IL-12 levels compared to the control group(IFN-γ:38.44±3.28 pg/mL vs.27.55±2.63 pg/mL;TNF-α:44.62±2.15 pg/mL vs.30.57±2.09 pg/mL);IL-12:33.49±2.51 pg/mL vs.20.75±1.86 pg/mL;P<0.05).In the control group,there were 8 cases of partial tumor remission,14 cases of stable tumor phase,and 22 cases of effective tumor control.In the observation group,there were 17 cases of partial tumor remission,24 cases of stable tumor phase,and 41 cases of effective tumor control.PR,SD,and DCR in the observation group were higher than those in the control group,and the difference was statistically significant(P<0.05).The average overall survival and mean progression free survival of the observation group were longer than those of the control group.ConclusionsCombined treatment with PD-1 and VEGFR2 inhibitors significantly improves tumor control and survival in patients with colon cancer liver metastases.By reducing tumor vessel density and permeability,enhancing immune responses,and reducing immune evasion of tumor cells,the combined intervention provides a more effective clinical strategy for the treatment of colon cancer liver metastases.