Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

• Published in: Molecular cancer Vol. 21; no. 1; pp. 28 - 27
• Main Authors: Yi, Ming, Zheng, Xiaoli, Niu, Mengke, Zhu, Shuangli, Ge, Hong, Wu, Kongming
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21-01-2022; BioMed Central; BMC
• Subjects: Agonists; Angiogenesis; Angiogenesis inhibitor; Angiogenesis inhibitors; Antibodies; Antigen presentation; Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; Biological response modifiers; Biomarkers, Tumor; Bispecific antibodies; Cancer; Cancer therapies; Cell cycle; Cell death; Chemotherapy; Clinical Studies as Topic; Clinical trials; Combination therapy; Combined Modality Therapy; Cytokines; Disease Management; Disease Susceptibility; Drug dosages; Epigenetics; FDA approval; Fecal microflora; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - administration & dosage; Immune response; Immunomodulation; Immunotherapy; Interferon; Lymphocytes; Lymphocytes T; Medical research; Medicine, Experimental; Microbiota; Molecular Targeted Therapy; Monoclonal antibodies; Neoplasms - diagnosis; Neoplasms - drug therapy; Neoplasms - etiology; Neoplasms - mortality; Patients; PD-1; PD-1 protein; PD-L1; PD-L1 protein; Pembrolizumab; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Radiation therapy; Radiotherapy; Review; STING; T cell receptors; T cells; Transplantation; Treatment Outcome; Tumor microenvironment; Tumors; Viral antibodies; United States > US; China; Gut microbiota; PD-L1; STING; Bispecific antibody; Combination therapy; Radiotherapy; PD-1; Angiogenesis inhibitor
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-021-01489-2

Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.