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.

Keywords: Angiogenesis inhibitor; Bispecific antibody; Combination therapy; Gut microbiota; PD-1; PD-L1; Radiotherapy; STING.

Fig. 1

The synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with chemotherapy, radiotherapy, or angiogenesis inhibitor. a Chemotherapy synergizes with α-PD-1/PD-L1. Some cytotoxic chemotherapeutic drugs could induce immunogenic cell death and stimulate antitumor immune response. Immunogenic cell death is featured with some upregulated damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), ATP, and high-mobility group box 1 (HMGB1). The ATP-P2RX7, CRT-CD91, and HMGB1-TLR4 pathways facilitate the antigen capture and presentation of DC, ultimately motivating adaptive antitumor immune response. Apart from immunogenic cell death, low-dose chemotherapy depletes regulatory T cells (Tregs) and promotes the repolarization of tumor-associated macrophage (TAM) from M2-like to M1-like phenotype. b Radiotherapy synergizes with α-PD-1/PD-L1. Firstly, radiotherapy could induce immunogenic cell death, enhance antitumor immune response, promote T cell infiltration, expand T-cell receptor (TCR) repertoire in the TME. Secondly, radiotherapy upregulates the expression of PD-L1 on tumor cells, which might be utilized by additional α-PD-1/PD-L1. Thirdly, radiotherapy increases the MHC-I on tumor cells and relieves resistance to α-PD-1/PD-L1. c Angiogenesis inhibitor synergizes with α-PD-1/PD-L1. Angiogenesis inhibitor blocks proangiogenic pathways, promotes vessel normalization, improves tumor perfusion and oxygenation, restores the hypoxic TME, and enhances drug delivery. Also, angiogenesis inhibitor reshapes the TME: promoting T cell infiltration and DC maturation, enhancing the differentiation towards M1-like macrophage, decreasing the ratio of Treg and MDSC, and alleviating hypoxia-induced PD-L1

Fig. 2

The synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other novel therapies. a The co-inhibitory and co-stimulatory pathways regulating the activities of T cells or NK cells. The green circle refers to co-stimulatory pathway, and the red circle refers to co-inhibitory pathway. b Targeted therapy synergizes with α-PD-1/PD-L1. Oncogenic pathways such as MAPK and PI3K-AKT promote PD-L1 transcription. Targeted therapies including EGFR-TKI, ALK-TKI, and RAS inhibitor not only directly retard tumor growth, but also decrease intrinsic PD-L1 expression. Moreover, STING agonist enhances DC function by activating STING-IFN-I pathway. c The bifunctional and bispecific antibody containing α-PD-L1 moiety. The structures of M7824 and YM101. d The effect of gut microbiota on antitumor immunity. Gut microbiota regulates DC function, Th1-skweing immunity, Th17 polarization, Treg differentiation, and cytokines secretion. Altered gut mucosa immunity could influence the effect of systemic anticancer immunotherapy. Abbreviations: EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor; ALK, anaplastic lymphoma kinase; PARP, Poly (ADP-ribose) polymerase; DSB, double-strand break; STING, stimulator of interferon genes

Fig. 3

Therapies regulating the cancer-immunity cycle. The cancer-immunity cycle starts with cancer antigen release and ends with cancer cell-killing by immune cells. Each step in the cycle is regulated by various factors. The stimulatory factors (shown in green) enhance antitumor immunity, while the inhibitory factors (shown in red) undermine antitumor immunity. These factors provide potential therapeutic targets to promote antitumor immunity. The figure presents some of therapies regulating the cancer-immunity cycle. Abbreviations: CAF, cancer-associated fibroblasts; PARP, Poly (ADP-ribose) polymerase; DSB, double-strand break; STING, stimulator of interferon genes; A2AR, adenosine 2A receptor