Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
Front Immunol. 2021 Oct 26;12:728750. doi: 10.3389/fimmu.2021.728750. eCollection 2021.
Owing to broad and notable clinical anti-tumor activity, anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) antibodies have been indicated for almost all types of cancer, and form a part of the current standard of care. However, a large proportion of patients do not respond to anti-PD-1/PD-L1 therapy (primary resistance), and responders often develop progressive disease (acquired resistance). The mechanisms of resistance are complex and largely unknown; therefore, overcoming resistance remains clinically challenging, and data on reversing anti-PD-1 resistance are scarce. Herein, we report the case of a 58-year-old woman with renal cell carcinoma associated with Xp11.2 translocation/transcription factor E3 gene fusion, who had already showed resistance to both anti-PD-1 monotherapy and standard-dose axitinib. However, she finally achieved a partial response with a continuous combination therapy comprising low-dose axitinib and anti-PD-1. We speculate that axitinib played a key role in reversing the primary resistance to anti-PD-1 therapy. Interestingly, we observed that the number of peripheral regulatory T cells increased after the standard-dose axitinib therapy, with accompanied tumor enlargement; however, after the dose was reduced, the number of regulatory T cells decreased gradually, and the tumor regressed. We also reviewed relevant literature, which supported the fact that low-dose axitinib might be more beneficial than standard-dose axitinib in assisting immunotherapy. Given that this is a single-case report, the immunomodulatory effect of axitinib requires further investigation.
由于广泛而显著的抗肿瘤临床活性，抗程序性细胞死亡-1（PD-1）/抗程序性细胞死亡配体 1（PD-L1）抗体已被用于几乎所有类型的癌症，并成为当前治疗标准的一部分。然而，很大一部分患者对抗 PD-1/PD-L1 治疗没有反应（原发性耐药），而应答者通常会出现进行性疾病（获得性耐药）。耐药机制复杂，很大程度上尚不清楚；因此，克服耐药性仍然具有临床挑战性，关于逆转抗 PD-1 耐药性的数据也很少。在此，我们报告了一例 58 岁女性肾细胞癌伴 Xp11.2 易位/转录因子 E3 基因融合，她已对抗 PD-1 单药治疗和标准剂量阿昔替尼均产生耐药。然而，她最终通过低剂量阿昔替尼和抗 PD-1 的连续联合治疗实现了部分缓解。我们推测阿昔替尼在逆转抗 PD-1 治疗的原发性耐药中发挥了关键作用。有趣的是，我们观察到标准剂量阿昔替尼治疗后外周调节性 T 细胞数量增加伴随肿瘤增大；然而，当剂量降低时，调节性 T 细胞的数量逐渐减少，肿瘤消退。我们还回顾了相关文献，支持低剂量阿昔替尼可能比标准剂量阿昔替尼更有利于免疫治疗的事实。鉴于这是一个单病例报告，阿昔替尼的免疫调节作用需要进一步研究。
