scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

Poor performance status and front-line pembrolizumab in advanced non-small-cell lung cancer (NSCLC) patients with PD-L1>50%.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21651-e21651
Author(s):  
Alfredo Addeo ◽  
Giulio Metro ◽  
Diego Signorelli ◽  
Panagiota Economopoulou ◽  
Fausto Roila ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Performance Status ◽  
Small Cell ◽  
Front Line ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

e21651 Background: We retrospectively analysed real-world clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) harbouring high PD-L1 expression ( > 50%) and treated with first-line pembrolizumab, following the Keynote 024 regimen. In the recent PePS2 trial and Checkmate 817, we see that some patients with PS2 could benefit from a durable response to checkpoint inhibitors. However, current data does not suggest an improvement in median OS compared to historical data on chemotherapy in this setting. Methods: Data was collected by 16 participating centers. The trial was approved by local ethics committees and patients included signed a general consent form. All patients with NSCLC with PD-L1 expression ≥50%, treated with first-line pembrolizumab were included, from the introduction of first-line pembrolizumab to the present. We collected medical data from patient files, pathology reports and laboratory reports for all patients. Patient characteristics, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and tumor characteristics were reported. Overall survival (OS) was calculated from the date of the first cycle of pembrolizumab to death and estimated through the Kaplan-Meier method. Results: 302 patients were identified, of which 247 with a PS of 0-1, 52 with a PS of 2. Patients (3) with PS3 were excluded. The median age was 69 with a range from 19 to 87 years. There were 193 males and 106 females, 90% were active or former smokers, 19% had brain lesions at diagnosis. Only 14% received brain radiotherapy. Median OS was 7.2 months among patients with PS2, while not reached for those with PS0-1 (HR 3.80, 95% confidence interval 2.49-5.78). Conclusions: Patients with a PS of 2 had significantly worse survival than those with PS0-1. The retrospective nature of our trial and lack of a control arm treated with chemotherapy do not allow us to postulate as to whether PS is predictive or prognostic. Our data suggests worse survival among NSCLC patients with PS2 treated with front-line pembrolizumab. A prospective randomized trial comparing immunotherapy to chemotherapy or chemo-immunotherapy in this population would be welcome.

scholarly journals Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non-Small Cell Lung Cancer

2018 ◽  
Vol 47 (6) ◽  
pp. 2407-2419 ◽  
Author(s):  
Hong-Min Wang ◽  
Xiao-Hong Zhang ◽  
Ming-Ming Feng ◽  
Yan-Jun Qiao ◽  
Li-Qun Ye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

Background/Aims: Interleukin (IL)-35 has immunosuppressive functions in autoimmune diseases, infectious diseases, and certain cancers. However, few studies have focused on its immunoregulatory activity in non-small cell lung cancer (NSCLC). Thus, we investigated the role of IL-35 in the pathogenesis of this disease. Methods: A total of 66 NSCLC patients and 21 healthy individuals were enrolled. IL-35 expression in peripheral blood and bronchoalveolar lavage fluid (BALF) was measured. The modulatory functions of IL-35 on purified CD4+ and CD8+ T cells from NSCLC patients were investigated in direct and indirect coculture systems with NSCLC cell lines. Results: IL-35 expression was significantly increased in BALF from the tumor site, but not in the peripheral blood of NSCLC patients. IL-35 did not affect the bioactivity including proliferation, cytokine production, cell cycle, and cellular invasion of NSCLC cells. It suppressed responses from type 1 T helper (Th1) and Th17 cells but elevated the regulatory T cell response in cultured CD4+ T cells from NSCLC patients, and reduced cytokine-mediated CD4+ T cells cytotoxicity to NSCLC cells. Moreover, IL-35 also inhibited cytotoxic gene expression in CD8+ T cells from NSCLC, reducing their cytolytic and noncytolytic functions. Conclusion: The results of this study suggest that IL-35 contributes to the dysfunction/exhaustion of T cells and limited antitumor immune responses in NSCLC.

scholarly journals Prognostic significance of peripheral CD8+CD28+ and CD8+CD28− T cells in advanced non-small cell lung cancer patients treated with chemo(radio)therapy

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Chao Liu ◽  
Wang Jing ◽  
Ning An ◽  
Aijie Li ◽  
Weiwei Yan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Natural Killer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Radio Therapy ◽  
Nsclc Patients

Abstract Background Noninvasive prognostic biomarkers are needed for advanced non-small cell lung cancer (NSCLC) patients with different histological types to identify cases with poor survival. Here, we investigated the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28− T cells in advanced NSCLC patients treated with chemo(radio)therapy and the impact of histological type on them. Methods Of 232 registered advanced NSCLC patients, 101 treatment-naïve individuals were eligible and included in our study. Flow cytometry was used to evaluate CD8+CD28+ T cells, CD8+CD28− T cells, CD4+ CD25hi T cells, B cells, natural killer cells, γδT cells, and natural killer T cells in patients’ peripheral blood. Results The median follow-up time was 13.6 months. Fifty-nine (58.4%) patients died by the end of our study. Fifty-three of the 101 advanced NSCLC cases selected for our study were adenocarcinomas (ADs), and 48 were squamous cell carcinomas (SCCs). Multivariate analyses showed that increased levels of CD8+CD28+ T cells independently predicted favorable overall survival (OS) [hazard ratio (HR): 0.51, 95% confidence interval (CI) 0.30–0.89, P = 0.021] and progression-free survival (PFS) (HR: 0.66, 95% CI 0.37–0.93, P = 0.038) in ADs, but the prediction in SCCs was not statistically significant. In contrast, high levels of CD8+CD28− T cells independently predicted unfavorable OS (HR: 1.41, 95% CI 1.17–3.06, P = 0.035) and PFS (HR: 2.01, 95% CI 1.06–3.85, P = 0.029) in SCCs, but the prediction in ADs was not statistically significant. ADs had higher levels of CD4+CD25hi T cells and CD8+CD28− T cells and lower NK cells (all P < 0.05) than SCCs. Conclusions Our findings uncovered the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28− T cells in advanced NSCLC patients treated with chemo(radio)therapy, which could help to identify patients with poor outcomes and refine treatment strategies.

scholarly journals TCF-1+ PD-1+ CD8+T Cells Are Associated With The Response To PD-1 Blockade In Non-Small Cell Lung Cancer Patients

2021 ◽  
Author(s):  
Xia Fang ◽  
Gang Wu ◽  
Jing Hua ◽  
Pei Zhao ◽  
Mengtian Shan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
High Frequency ◽  
Cell Subset ◽  
Small Cell ◽  
Smoking History ◽  
Small Cell Lung ◽  
Nsclc Patients

Abstract Purpose: To determine whether TCF-1+ PD-1+ CD8+T cells are associated with the response to PD-1 blockade in non-small cell lung cancer (NSCLC) patients. Methods: We investigated the expression of TCF-1+ PD-1+ CD8+T cells and elucidated their predictive role in NSCLC patients. Pretreatment specimens from fifteen advanced NSCLC patients who underwent PD-1 immunotherapy or combined with chemotherapies were analyzed. The frequency of TCF-1+ cells in PD-1+ CD8+T cells were determined in these biospecimens by using multi-label immunofluorescence staining and multi-spectral acquisition technology. The clinical role of TCF-1+PD-1+CD8+T cells were evaluated via analyzing our patients’ clinic parameters and public NSCLC database. Results: A high frequency of TCF-1+ PD-1+ CD8+T cells were identified in responders compared with non-responders (p=0.0427), and the patients with high expression of this cell subset had durable clinical benefit of anti-PD-1 therapy. There were no significant association between the expression of TCF-1+ PD-1+ CD8+T cells and patients’ age, gender, smoking history, pathologic type and genetic status. In univariate logistic regression analysis, high frequency of TCF-1+ PD-1+ CD8+T cells were significantly correlated with patients’ benefit of PD-1 blockade (p=0.035). Conclusion: Our study indicated that TCF-1+ PD-1+ CD8+T cells are associated with the response to PD-1 blockade, and may be a predictor of anti-PD-1 therapy.

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