High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab

Bao, Halin; Bai, Tuya; Takata, K.; Yokobori, Takehiko; Ohnaga, Takashi; Hisada, Takeshi; Maeno, Toshitaka; Bao, Pinjie; Yoshida, Tatsushi; Kumakura, Yuji; Honjo, Hiroaki; Sakai, Makoto; Sohda, Makoto; Fukuchi, Minoru; Altan, Bolag; Handa, Tadashi; Ide, Munenori; Miyazaki, Tatsuya; Ogata, Kenichi; Oyama, Tetsunari; Shimizu, Kimihiro; Mogi, Akira; Asao, Takayuki; Shirabe, Ken; Kuwano, Hiroyuki; Kaira, Kyoichi

doi:10.3892/ol.2017.7671

Cited by 15 publications

(14 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, previous studies are mostly limited to observation of PD-L1 expression on CTCs, lacking comparison with paired TTs, or the detection method of PD-L1 in TTs is inconsistent with that in CTCs, so it is difficult to judge the actual consistency. 32,33 In this study, for the first time, we tried to isolate CTCs from peripheral blood of NSCLC patients based on pore size, further used 28-8 antibody to evaluate PD-L1 expression, and analyzed the correlation between PD-L1 expression in CLCs and that in paired TTs and its relationship with clinicopathological features.…”

Section: Discussionmentioning

confidence: 99%

<p>Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer</p>

Cheng¹,

Wang²,

Lv³

et al. 2020

CMAR

View full text Add to dashboard Cite

Background: The expression of programmed cell death ligand 1(PD-L1) is related to the efficacy of immune checkpoint inhibitors on patients with non-small cell lung cancer (NSCLC), but tumor tissue (TT) samples are difficult to obtain, and initial TT samples are difficult to reflect the spatial-temporal heterogeneity. Therefore, we explored the feasibility of separating circulating tumor cells (CTCs) and detecting PD-L1 expression on CTCs. Patients and Methods: Peripheral blood specimens were sampled from 66 NSCLC patients, and CTCs were separated by membrane filtration based on size. For 59 patients with paired TT specimens, the expression of PD-L1 in their CTCs and TTs was determined using the immunohistochemistry and immunocytochemistry based on 28-8 antibody, respectively. The PD-L1 expression in TTs was set as a gold standard for calculation of sensitivity, specificity, consistency, positive predictive value (PPV), and negative predictive value (NPV), and the Cohen kappa coefficient for CTCs and paired TTs was calculated. In addition, the T-test, Chi-square test, and Mann-Whitney U-test were adopted to analyze the correlation of clinical pathological features and prognosis with PD-L1 expression. Results: Sensitivity, specificity, concordance, PPV and NPV of detecting PD-L1 in CTCs of the 41 initial treated patients were 88.89%, 73.91%, 80%, 72.73% and 89.47%, respectively, and the Cohen kappa coefficient of CTC and paired TTs was 0.613. The univariate analysis of survival showed that the progression-free survival time of initial treated patients with positive PD-L1 expression was shorter than that of those with negative PD-L1 expression in CTCs or TTs (P>0.05), and the positive PD-L1 expression in CTCs or TTs had nothing to do with age, sex, smoking status, histological type, and stage (P > 0.05). Conclusion: The study confirms the feasibility of CTC PD-L1 detection in peripheral blood and lays a foundation for exploring real-time and individualized immunotherapy molecular biomarkers.

show abstract

Section: Discussionmentioning

confidence: 99%

<p>Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer</p>

Cheng¹,

Wang²,

Lv³

et al. 2020

CMAR

View full text Add to dashboard Cite

show abstract

“…The heterogeneity of melanoma CTCs and the significance of CTC subsets (e.g., receptor activator of NF-κβ (RANK) expressing CTCs) as biomarkers has been found to affect targeted treatment; this was not, however, observed for ICI ( 65 ). For NSCLC, high expression of carcinoembryonic antigen and telomerase reverse transcriptase was linked to non-response to nivolumab ( 95 ). For urothelial carcinoma, CTCs with high PD-L1 expression were associated with worse OS ( 96 ), and for chemotherapeutically treated SCCHN, high levels of CTCs with PD-L1 expression were linked to poor PFS and OS ( 97 ).…”

Section: Blood Biomarkersmentioning

confidence: 99%

Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment—A Review From the Melanoma Perspective and Beyond

2018

View full text Add to dashboard Cite

BackgroundImmune checkpoint inhibition (ICI) with anti-CTLA-4 and/or anti-PD-1 antibodies is standard treatment for metastatic melanoma. Anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for treatment of several other advanced malignancies, including non-small-cell lung cancer (NSCLC); renal cell, and urothelial carcinoma; head and neck cancer; gastric, hepatocellular, and Merkel-cell carcinoma; and classical Hodgkin lymphoma. In some of these malignancies approval was based on the detection of biomarkers such as PD-L1 expression or high microsatellite instability.MethodsWe review the current status of prognostic and predictive biomarkers used in ICI for melanoma and other malignancies. We include clinical, tissue, blood, and stool biomarkers, as well as imaging biomarkers.ResultsSeveral biomarkers have been studied in ICI for metastatic melanoma. In clinical practice, pre-treatment tumor burden measured by means of imaging and serum lactate dehydrogenase level is already being used to estimate the likelihood of effective ICI treatment. In peripheral blood, the number of different immune cell types, such as lymphocytes, neutrophils, and eosinophils, as well as different soluble factors, have been correlated with clinical outcome. For intra-tumoral biomarkers, expression of the PD-1 ligand PD-L1 has been found to be of some predictive value for anti-PD-1-directed therapy for NSCLC and melanoma. A high mutational load, particularly when accompanied by neoantigens, seems to facilitate immune response and correlates with patient survival for all entities treated by use of ICI. Tumor microenvironment also seems to be of major importance. Interestingly, even the gut microbiome has been found to correlate with response to ICI, most likely through immuno-stimulatory effects of distinct bacteria. New imaging biomarkers, e.g., for PET, and magnetic resonance imaging are also being investigated, and results suggest they will make early prediction of patient response possible.ConclusionSeveral promising results are available regarding possible biomarkers for response to ICI, which need to be validated in large clinical trials. A better understanding of how ICI works will enable the development of biomarkers that can predict the response of individual patients.

show abstract

“…However, one has to be aware that inconsistency might be also caused by various types of therapy since patients in this study were treated with mainly radio- and/or chemotherapy before blood collection, followed by a first- to fifth- line of therapy with ICIs. On the same line, Bao and colleagues [24] also focused on the development and optimization of a CTC-sorting system—in this case a size-based chip—which could give the chance to investigate the PD-L1 expression, achieved through a RT-qPCR approach. However, the lack of CTC + patients (~7% based on CK19 mRNA expression) did not allow for drawing any significant conclusion about the clinical utility of PD-L1 [24].…”

Section: Clinical Significance Of Pd-l1-positive Ctcs In Nsclcmentioning

confidence: 99%

“…On the same line, Bao and colleagues [24] also focused on the development and optimization of a CTC-sorting system—in this case a size-based chip—which could give the chance to investigate the PD-L1 expression, achieved through a RT-qPCR approach. However, the lack of CTC + patients (~7% based on CK19 mRNA expression) did not allow for drawing any significant conclusion about the clinical utility of PD-L1 [24].…”

Section: Clinical Significance Of Pd-l1-positive Ctcs In Nsclcmentioning

confidence: 99%

Circulating Tumor Cell PD-L1 Expression as Biomarker for Therapeutic Efficacy of Immune Checkpoint Inhibition in NSCLC

Kloten

Lampignano

Krahn

et al. 2019

Cells

View full text Add to dashboard Cite

Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients. PD-L1 tumor expression, along with tumor mutational burden, is currently being explored as a predictive biomarker for responses to immune checkpoint inhibitors (ICIs). However, lung cancer patients may have insufficient tumor tissue samples and the high bleeding risk often prevents additional biopsies and, as a consequence, immunohistological evaluation of PD-L1 expression. In addition, PD-L1 shows a dynamic expression profile and can be influenced by intratumoral heterogeneity as well as the immune cell infiltrate in the tumor and its microenvironment, influencing the response rate to PD-1/PD-L1 axis ICIs. Therefore, to identify subgroups of patients with advanced NSCLC that will most likely benefit from ICI therapies, molecular characterization of PD-L1 expression in circulating tumor cells (CTCs) might be supportive. In this review, we highlight the use of CTCs as a complementary diagnostic tool for PD-L1 expression analysis in advanced NSCLC patients. In addition, we examine technical issues of PD-L1 measurement in tissue as well as in CTCs.

show abstract

High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab

Cited by 15 publications

References 30 publications

<p>Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer</p>

<p>Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer</p>

Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment—A Review From the Melanoma Perspective and Beyond

Circulating Tumor Cell PD-L1 Expression as Biomarker for Therapeutic Efficacy of Immune Checkpoint Inhibition in NSCLC

Contact Info

Product

Resources

About