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

Abstract

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.

• Authors: Ming Yi, Xiaoli Zheng, Mengke Niu, Shuangli Zhu, Hong Ge, Kongming Wu
• Journal: Molecular cancer (Mol Cancer) Vol. 21 Issue 1 Pg. 28 (01 21 2022) ISSN: 1476-4598 [Electronic] England
• PMID: 35062949 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2022. The Author(s).

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• B7-H1 Antigen (antagonists & inhibitors)
• Biomarkers, Tumor
• Clinical Studies as Topic
• Combined Modality Therapy
• Disease Management
• Disease Susceptibility
• Humans
• Immune Checkpoint Inhibitors (administration & dosage)
• Molecular Targeted Therapy
• Neoplasms (diagnosis, drug therapy, etiology, mortality)
• Prognosis
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Treatment Outcome