Capitao Marisa, Perrin Justine, Simon Sylvain, Gouard Sébastien, Chouin Nicolas, Bruchertseifer Frank, Morgenstern Alfred, Rbah-Vidal Latifa, Chérel Michel, Scotet Emmanuel, Labarrière Nathalie, Guilloux Yannick, Gaschet Joëlle
Université de Nantes, CNRS, Inserm, CRCINA, F-44000 Nantes, France.
Université de Nantes, CNRS, Inserm, Oniris, CRCINA, F-44000 Nantes, France.
Cancers (Basel). 2021 Mar 12;13(6):1256. doi: 10.3390/cancers13061256.
PD-L1 (programmed death-ligand 1, B7-H1, CD274), the ligand for PD-1 inhibitory receptor, is expressed on various tumors, and its expression is correlated with a poor prognosis in melanoma. Anti-PD-L1 mAbs have been developed along with anti-CTLA-4 and anti-PD-1 antibodies for immune checkpoint inhibitor (ICI) therapy, and anti-PD-1 mAbs are now used as first line treatment in melanoma. However, many patients do not respond to ICI therapies, and therefore new treatment alternatives should be developed. Because of its expression on the tumor cells and on immunosuppressive cells within the tumor microenvironment, PD-L1 represents an interesting target for targeted alpha-particle therapy (TAT). We developed a TAT approach in a human melanoma xenograft model that stably expresses PD-L1 using a Bi-anti-human-PD-L1 mAb. Unlike treatment with unlabeled anti-human-PD-L1 mAb, TAT targeting PD-L1 significantly delayed melanoma tumor growth and improved animal survival. A slight decrease in platelets was observed, but no toxicity on red blood cells, bone marrow, liver or kidney was induced. Anti-tumor efficacy was associated with specific tumor targeting since no therapeutic effect was observed in animals bearing PD-L1 negative melanoma tumors. This study demonstrates that anti-PD-L1 antibodies may be used efficiently for TAT treatment in melanoma.
程序性死亡配体1（PD-L1，B7-H1，CD274）是PD-1抑制性受体的配体，在多种肿瘤上表达，其表达与黑色素瘤的不良预后相关。抗PD-L1单克隆抗体已与抗CTLA-4和抗PD-1抗体一起开发用于免疫检查点抑制剂（ICI）治疗，抗PD-1单克隆抗体现在被用作黑色素瘤的一线治疗药物。然而，许多患者对ICI治疗无反应，因此应开发新的治疗方案。由于PD-L1在肿瘤细胞和肿瘤微环境中的免疫抑制细胞上表达，它是靶向α粒子治疗（TAT）的一个有吸引力的靶点。我们在人黑色素瘤异种移植模型中开发了一种TAT方法，该模型使用双抗人PD-L1单克隆抗体稳定表达PD-L1。与未标记的抗人PD-L1单克隆抗体治疗不同，靶向PD-L1的TAT显著延迟了黑色素瘤肿瘤的生长并提高了动物存活率。观察到血小板略有减少，但未诱导对红细胞、骨髓、肝脏或肾脏的毒性。抗肿瘤疗效与特异性肿瘤靶向有关，因为在携带PD-L1阴性黑色素瘤肿瘤的动物中未观察到治疗效果。这项研究表明，抗PD-L1抗体可有效地用于黑色素瘤的TAT治疗。
