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.

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

“…Therefore, it may be difficult to achieve promising results by simply blocking PD-1/PD-L1 signaling alone. Combination of PD-1/PD-L1 inhibitor with other ICIs has been suggested [ 76 , 164 – 167 ]. Other immune checkpoints (Fig.…”

Emerging strategies to overcome resistance to third-generation EGFR inhibitors

“…For most patients, the PD-1/PD-L1 pathway is not the sole rate-limiting factor for antitumor immunity, and blocking the PD-1/PD-L1 axis is insufficient to activate an effective antitumor immune response [ 211 ]. Strategies that lead to acquired EGFR-TKI resistance, such as HGF, MET amplification, and EGFR T790M, also promote immune escape in lung cancer by upregulating the expression of PD-L1.…”

The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma

“…Th17 cells and MCs in ESCC TME have been shown to secrete IL-17 to promote ESCC cells to release CXCL9/10, CXCL2/3, and CCL2/20, which could facilitate NK cell infiltration and activity ( 66 ). PD-1, a member of the CD28 family, is mainly expressed on activated T cells ( 135 ). When PD-1 is combined with its ligand (PD-L1 or PD-L2), which can be expressed by tumor cells, immune cells (i.e., macrophages), and endothelial cells, then T-cell activation will be inhibited ( 136 , 137 ).…”