中国海王可激活抗乳腺癌免疫记忆
维迪西妥单抗（爱地希）是中国原创的人类表皮生长因子受体HER2单克隆抗体迪西妥单抗与3～4个小分子细胞微管蛋白聚合抑制剂维多汀的缀合物，不仅可以增强动物模型抗肿瘤免疫力，还可以改善胃癌、尿路上皮癌、HER2低表达乳腺癌等患者的临床结局。由于此类药物部分依赖于有效的抗肿瘤免疫反应，如果联合免疫细胞程序性死亡受体PD-1及其配体PD-L1等免疫检查点抑制剂，例如帕博利珠单抗（可瑞达，俗称K药）或阿替利珠单抗（泰圣奇，俗称T药），可能有助于克服耐药并带来长期获益。
前情提要
2021年10月16日，施普林格自然旗下《乳腺癌研究与治疗》在线发表同济大学生命科学与技术学院顾华、房健民等学者的研究报告，首次探讨了维迪西妥单抗联合免疫检查点抑制剂对HER2阳性乳腺癌的治疗效果。
该临床前动物研究首先将表达人类HER2的小鼠乳腺癌细胞注入人类PD-1转基因小鼠体内，随后分别给予磷酸盐缓冲液、维迪西妥单抗、帕博利珠单抗、阿替利珠单抗、维迪西妥单抗＋帕博利珠单抗、维迪西妥单抗＋阿替利珠单抗进行比较。
结果发现，维迪西妥单抗可显著增强帕博利珠单抗或阿替利珠单抗的肿瘤抑制作用和抗肿瘤免疫，并且伴随大量T淋巴细胞浸润和免疫标志激活。此外，联合治疗可促进免疫记忆形成，防止肿瘤复发。
因此，该临床前动物研究结果表明，维迪西妥单抗可显著提高免疫检查点抑制剂对人类HER2阳性乳腺癌小鼠的效果，并且引发持久的免疫记忆。该研究深入剖析了维迪西妥单抗治疗活性的有效机制，并为维迪西妥单抗联合免疫治疗奠定了基础，故有必要进一步开展人类临床研究进行验证。
Breast Cancer Res Treat. 2021 Oct 16. Online ahead of print.
A HER2 target antibody drug conjugate combined with anti-PD-(L)1 treatment eliminates hHER2+ tumors in hPD-1 transgenic mouse model and contributes immune memory formation.
Lei Huang, Ruiqin Wang, Kun Xie, Jingming Zhang, Fei Tao, Chenyu Pi, Yan Feng, Hua Gu, Jianmin Fang.
School of Life Sciences and Technology, Tongji University, Shanghai, China; Tongji Hospital, Tongji University, Shanghai, China; Tongji University Suzhou Institute, Suzhou, Jiangsu, China.
PURPOSE: Disitamab vedotin (RC48) is an HER2-directed antibody-drug conjugate, emerging as an effective strategy for cancer therapy, which not only enhances antitumor immunity in previous animal models but also improves clinical outcomes for patients such as with gastric cancer, urothelium carcinoma, and HER2 low-expressing breast cancer. Here, we explore the combination therapeutic efficacy of this novel HER2-targeting ADC with immune checkpoint inhibitors in a human HER2-expressing syngeneic breast cancer model.
METHODS: The human HER2+ cancer cell line is constructed by stable transfection and individual clones were isolated by single-cell sorting. Flow cytometry was performed to determine its binding activity. Cytotoxic effect was determined using an MTT assay with the supplement of RC48. Human PD-1 transgenic mice were used to analyze the in vivo antitumor effects of the ADC and its combination therapy with PD-1/PD-L1 antibody.
RESULTS: The combination of RC48 and PD-1/PD-L1 immune checkpoint inhibition significantly enhanced tumor suppression and antitumor immunity. Tumor rejection in the synergistic groups was accompanied by massive T cell infiltration and immune marker activation. Furthermore, the combination therapy promoted immunological memory formation in the tumor eradication animals, protecting them from tumor rechallenge.
CONCLUSION: A novel HER2-targeting ADC combined with immune checkpoint inhibitors can achieve remarkable effects in mice and elicit long-lasting immune protection in a hHER2+ murine breast cancer model. This study provides insights into the efficacy of RC48 therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.
KEYWORDS: Antibody-drug conjugates, HER2-positive breast cancer, Checkpoint inhibitor combination therapy
DOI: 10.1007/s10549-021-06384-4