泌尿系统恶性肿瘤免疫检查点阻断治疗的进展

Advances in Immune Checkpoint Blockade Therapy for Urinary System Cancer

在肿瘤微环境中,免疫检查点分子过表达会抑制肿瘤特异性T细胞的免疫活性,促进肿瘤的进展。靶向检查点的抗体通过阻断受体—配体相互作用,可以恢复T细胞的抗肿瘤免疫活性。对内分泌治疗抵抗的前列腺癌,CTLA-4抗体易普利姆玛(ipilimumab)单药的Ⅲ期试验中,总体结果为阴性。然而,在预后特征良好的亚组患者,可显著改善总体生存率。在2015~2016年,FDA批准纳武单抗(nivolumab)治疗抗血管治疗后的晚期RCC患者;阿特朱单抗(atezolizumab)治疗转移性尿路上皮癌患者。而且也报道了avelumab(PD-L1抑制剂)和派姆单抗(pembrolizumab)治疗泌尿系统癌症的数据。尽管存在一些差异,在转移性尿路上皮癌铂类治疗后,反应率均优于历史上的细胞毒化疗。此外,PD-L1高表达的肿瘤患者反应率接近30%,而且比化疗有更好的耐受性,3或4度毒性发生率小于15%。也有研究结果鼓励新的免疫疗法联合,与传统的抗癌药物联合治疗的临床试验。然而,也不是在每一个癌症患者都有反应。因此,根据免疫检查点阻断生物机制的科学认识,需要预计单药治疗和联合治疗的生物标志物,并提供早期治疗反应指标。

Over-expression of immune checkpoint molecules in tumor microenvironment inhibits the activity of tumor-specific T cells and promotes tumor progression. Checkpoints-targeted antibodies can restore the antitumor activity of T cells by blocking the receptor-ligand interactions.The clinical trial of CTLA-4 antibody ipilimumab monotherapy showed negative results for endocrinotherapy-resistant prostate cancer;however,for subgroups of prostate cancer with good prognostic features it can significantly improve overall survival. US FDA approved nivolumab for advanced renal cell carcinoma（RCC） patients after anti-angiogenic therapy and atezolizumab（PD-L1inhibitor） for metastatic urothelial cancer in 2015~2016. It is also reported data about PD-L1 inhibitors avelumab and pembrolizumab for urinary system cancer;although there are some discrepancies,their response rates seem to be superior to cytotoxic chemotherapy for metastatic urothelial cancer after platinum-based therapy. In addition,the response rate in patients with positive expression of PD-L1 is nearly 30% with better tolerance. The results in clinical trials are encouraged for new immune therapy combined with conventional anti-cancer drugs. Based on the biological mechanisms of immune checkpoint block,it is important to find biomarkers for monotherapy or combination therapy and to provide early indicators of therapeutic response.