PD‐1/PD‐L1 inhibitors‐based treatment for advanced renal cell carcinoma: Mechanisms affecting efficacy and combination therapies

• Published in: Cancer medicine (Malden, MA) MA), 2021-09, Vol.10 (18), p.6384-6401
• Main Authors: Ding, Lei, Dong, Hui yu, Zhou, Tian ren, Wang, Yu hao, Yan, Tao, Li, Jun chen, Wang, Zhong yuan, Li, Jie, Liang, Chao
• Format: Article
• Language: English
• Subjects: advanced renal cell carcinoma; Antigens; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Cancer Biology; Cancer therapies; Carcinoma, Renal Cell - diagnosis; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - mortality; Cell Line, Tumor; Cell-mediated immunity; cellular immunity; Chemotherapy; Clinical trials; combination therapy; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - immunology; Drug Screening Assays, Antitumor; Epigenesis, Genetic; fundamental mechanisms; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Kidney cancer; Kidney Neoplasms - diagnosis; Kidney Neoplasms - drug therapy; Kidney Neoplasms - immunology; Kidney Neoplasms - mortality; Ligands; Lymphocytes; Medical research; Metabolism; Monoclonal antibodies; Mutation; Patients; PD-L1 protein; PD‐1; PD‐L1 inhibitor; Pembrolizumab; Phosphorylation; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Progression-Free Survival; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Radiation therapy; Renal cell carcinoma; Review; Transcription factors; Tumors
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.4190

With the widespread use of PD‐1/PD‐L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD‐1/PD‐L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD‐L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD‐1/PD‐L1 mAb in the treatment of aRCC, and CTLA‐4 mAb has been shown to have a non‐redundant effect with PD‐1/PD‐L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD‐1/PD‐L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians’ select treatment options for patients with refractory kidney cancer. PD‐1/PD‐L1 inhibitors have been gradually applied in the treatment of advanced renal cell carcinoma, but the efficacy is limited. Alternations in PD‐L1 expression and cellular immunity can directly or indirectly affect the efficacy of PD‐L1 inhibitors. Antiangiogenic drugs and CTLA‐4 inhibitors have been shown to significantly improve the efficacy of PD‐1/PD‐L1 inhibitors.