Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials

Zhao, Bin; Zhao, Hong; Zhao, Jiaxin

doi:10.1177/1758835920937612

Cited by 113 publications

(79 citation statements)

References 198 publications

(184 reference statements)

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“…Anti-PD(L)1 immune checkpoint inhibitors (ICI) singly or in combination with anti-CTLA-4 or other agents are approved across multiple indications in sixteen separate diseases including a histology-agnostic indication in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. 1,2 The hallmark of ICI therapy is the durability of responses in a subset of patients as evidenced by progression-free survival (PFS) rates of 21-29% in melanoma and 22% in non-small cell lung cancer (NSCLC) with anti-PD(L)1 singly; [3][4][5][6][7] and up to 36% with anti-PD-1/anti-CTLA-4 dual ICI in melanoma. 8 However, the majority of patients do relapse and the question of how to improve outcomes in these patients remains a vexing problem for the field.…”

Section: Introductionmentioning

confidence: 99%

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Karapetyan

Luke

Davar

2020

OTT

100

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Toll-like receptor 9 (TLR9) is a pattern recognition receptor that is predominantly located intracellularly in immune cells, including dendritic cells, macrophages, natural killer cells, and other antigen-presenting cells (APC). The primary ligands for TLR9 receptors are unmethylated cytidine phosphate guanosine (CpG) oligodinucleotides (ODN). TLR9 agonists induce inflammatory processes that result in the enhanced uptake and killing of microorganisms and cancer cells as well as the generation of adaptive immune responses. Preclinical studies of TLR9 agonists suggested efficacy both as monotherapy and in combination with several agents, which led to clinical trials in patients with advanced cancer. In these studies, intravenous, intratumoral, and subcutaneous routes of administration have been tested; with anti-tumor responses in both treated and untreated metastatic sites. TLR9 agonist monotherapy is safe, although efficacy is minimal in advanced cancer patients; conversely, combinations appear to be more promising. Several ongoing phase I and II clinical trials are evaluating TLR9 agonists in combination with a variety of agents including chemotherapy, radiotherapy, targeted therapy, and immunotherapy agents. In this review article, we describe the distribution, structure and signaling of TLR9; discuss the results of preclinical studies of TLR9 agonists; and review ongoing clinical trials of TLR9 agonists singly and in combination in patients with advanced solid tumors.

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Section: Introductionmentioning

confidence: 99%

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Karapetyan

Luke

Davar

2020

OTT

100

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“…Recent meta-analyses of the efficacy of antibodies targeting PDCD1/CD274 as monotherapy [ 7 , 8 ] found that this treatment is associated with more tumor responses and increased overall survival (OS) compared to conventional therapy. Although there are some patients who show long-term complete responses [ 9 , 10 ], the average response rate is 20% with significant differences across different tumor types [ 8 ]. It is of significant interest to identify the minority of patients who will benefit from immune checkpoint blockade to better direct this therapy and avoid the (often immune-mediated) adverse events [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of PD-1 and PD-L1 Activity on a Pan-Cancer Basis: A Bioinformatic Exploratory Study

Kannan

O’Connor

Bakker

2021

IJMS

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Immune checkpoint blockade targeting PD-1 (PDCD1)/PD-L1 (CD274) is increasingly used for multiple cancers. However, efficacy and adverse-related events vary significantly. This bioinformatic study interrogated molecular differences pertaining to PDCD1/CD274 and their correlated genes on a pan-cancer basis to identify differences between cancer types. Patient RNA-seq data from fifteen cancer types were accessed on cBioPortal to determine the role of PDCD1/CD274 in patient survival and to identify positively and negatively correlated genes, which were also assessed for clinical relevance. Genes correlating with PDCD1/CD274 across multiple cancers were taken forward for drug repurposing via DRUGSURV and microRNA analysis using miRDB and miRabel. MicroRNAs were also screened for clinical relevance using OncomiR. Forty genes were consistently correlated with PDCD1/CD274 across multiple cancers, with the cancers themselves exhibiting a differential role for the correlated genes in terms of patient survival. Esophageal and renal cancers in particular stood out in this regard as having a unique survival profile. Forty-nine putative microRNAs were identified as being linked to the PDCD1/CD274 network, which were taken forward and further assessed for clinical relevance using OncomiR and previously published literature. One hundred and thirty significant survival associations for 46 microRNAs across fourteen groups of cancers were identified. Finally, a total of 23 putative repurposed drugs targeting multiple components of the PDCD1/CD274 network were identified, which may represent immunotherapeutic adjuvants. Taken together, these results shed light on the varying PDCD1/CD274 networks between individual cancers and signpost a need for more cancer-specific investigations and treatments.

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“…Immune checkpoint blockade of PD-1/PD-L1 is being widely tested against different cancer types, with various levels of success [ 39 ]. Despite the presence of immune infiltrates in patients with ovarian cancer, PD-1/PD-L1 blockade has shown limited effectiveness in clinical trials with only a modest 9–15% response rate [ 15 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Associations between DNA Damage and PD-L1 Expression in Ovarian Cancer, a Potential Biomarker for Clinical Response

Mann

Lee

Chen

et al. 2021

Biology

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Programmed death ligand-1 (PD-L1) inhibitors are currently under investigation as a potential treatment option for ovarian cancer. Although this therapy has shown promise, its efficacy is highly variable among patients. Evidence suggests that genomic instability influences the expression of PD-L1, but little is known about this relationship in ovarian cancer. To examine the relationship between PD-L1 expression and genomic instability, we measured DNA damage using Repair Assisted Damage Detection (RADD). We then correlated the presence of persistent DNA damage in the ovarian tumor with protein expression of PD-L1 using immunohistochemistry. Ovarian tumors showed a high prevalence of oxidative DNA damage. As the level of oxidative DNA damage increased, we saw a significant correlation with PD-L1 expression. The highest correlation between DNA damage and PD-L1 expression was observed for mucinous ovarian tumors (r = 0.82), but a strong correlation was also observed for high grade serous and endometrioid tumors (r = 0.67 and 0.69, respectively). These findings link genomic instability to PD-L1 protein expression in ovarian cancer and suggest that persistent DNA damage can be used as a potential biomarker for patient selection for immunotherapy treatment.

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Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials

Cited by 113 publications

References 198 publications

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Molecular Mechanisms of PD-1 and PD-L1 Activity on a Pan-Cancer Basis: A Bioinformatic Exploratory Study

Associations between DNA Damage and PD-L1 Expression in Ovarian Cancer, a Potential Biomarker for Clinical Response

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