Enhanced anti-PD-1 therapy in hepatocellular carcinoma by tumor vascular disruption and normalization dependent on combretastatin A4 nanoparticles and DC101.
Enhanced anti-PD-1 therapy in hepatocellular carcinoma by tumor vascular disruption and normalization dependent on combretastatin A4 nanoparticles and DC101.
复制标题
通过依赖考布他汀 A4 纳米粒子和 DC101 的肿瘤血管破坏和正常化增强肝细胞癌的抗 PD-1 治疗
作者：
Bao X;Shen N;Lou Y;Yu H;Wang Y;Liu L;Tang Z;Chen X
抗程序性细胞死亡蛋白1（PD-1）治疗在肝细胞癌（HCC）中显示出有希望的疗效，但其在晚期HCC中的应答率低于20%。其中一个关键原因是CD 8 + T细胞和肿瘤负荷之间的不平衡。在这里，一个新的概念，血管中断和正常化依赖于一个聚合物血管破坏剂（VDA）聚（L-谷氨酸）-接枝-甲氧基聚（乙二醇）/考布他汀A4（CA 4-NPs）+血管内皮生长因子（VEGF）/VEGF受体2（VEGFR 2）抑制剂DC 101用于改善抗PD-1治疗，其中CA 4-NP降低肿瘤负荷，并且DC 101同时增加肿瘤内CD 8 + T细胞的数量，成功地调节了H22肿瘤模型中的上述失衡。研究方法：评价血管密度、肿瘤细胞增殖和坏死以揭示CA 4-NP治疗对降低肿瘤负荷的作用。检查血管的周细胞覆盖、肿瘤血管灌注、肿瘤缺氧和肿瘤内免疫细胞，以验证它们在DC 101的血管正常化和免疫细胞归巢中的作用。此外，研究了CA 4-NPs + DC 101对降低肿瘤负荷和增加免疫细胞数量的作用。最后，验证了肿瘤抑制、肿瘤内CD 8 + T细胞活化以及抗PD-1与CA 4-NPs + DC 101组合的协同作用。结果如下：抗PD-1抗体联合CA 4-NPs + DC 101的抑瘤率达到86.4%，显著高于单用抗PD-1的抑瘤率（16.8%）。重要的是，反映CA 4-NP + DC 101和抗PD-1之间协同作用的Q值为1.24，表明强协同作用。此外，CA 4-NP + DC 101通过增加瘤内CD 8 + T细胞的数量来改善抗PD-1治疗（抗PD-1，0.31% vs三药联合，1.18%）。结论：这些结果揭示了在HCC中使用VDAs + VEGF/VEGFR 2抑制剂增强抗PD-1治疗的新方法。
Anti-programmed cell death protein 1 (PD-1) therapy has shown promising efficacy in hepatocellular carcinoma (HCC), but its response rates in advanced HCC are lower than 20%. A critical reason for this is the imbalance between CD8+ T cells and tumor burden. Here, a novel concept of vascular disruption and normalization dependent on a polymeric vascular disrupting agent (VDA) poly (L-glutamic acid)-graft-methoxy poly (ethylene glycol)/combretastatin A4 (CA4-NPs) + a vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) inhibitor DC101 is applied to improve anti-PD-1 therapy, wherein CA4-NPs reduce tumor burden and DC101 simultaneously increases the number of intratumoral CD8+ T cells, successfully regulating the abovementioned imbalance in an H22 tumor model. Methods: Blood vessel density, tumor cell proliferation, and necrosis were evaluated to reveal the effects on reducing tumor burden by CA4-NP treatment. Pericyte coverage of blood vessels, tumor blood vessel perfusion, tumor hypoxia, and intratumoral immune cells were examined to verify their role in vascular normalization and immune cell homing of DC101. Furthermore, the effects of CA4-NPs + DC101 on reducing tumor burden and increasing the number of immune cells were studied. Finally, tumor suppression, intratumoral CD8+ T cell activation, and the synergistic effects of anti-PD-1 combined with CA4-NPs + DC101 were verified. Results: The tumor inhibition rate of anti-PD-1 antibody combined with CA4-NPs + DC101 reached 86.4%, which was significantly higher than that of anti-PD-1 (16.8%) alone. Importantly, the Q value reflecting the synergy between CA4-NPs + DC101 and anti-PD-1 was 1.24, demonstrating a strong synergistic effect. Furthermore, CA4-NPs + DC101 improved anti-PD-1 therapy by increasing the number of intratumoral CD8+ T cells (anti-PD-1, 0.31% vs triple drug combination, 1.18%). Conclusion: These results reveal a novel approach to enhance anti-PD-1 therapy with VDAs + VEGF/VEGFR2 inhibitors in HCC.