scholarly journals Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Junyu Long ◽  
Dongxu Wang ◽  
Xu Yang ◽  
Anqiang Wang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bladder Cancer ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Esophagogastric Cancer ◽  
Clinical Benefits

Abstract Background Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy. Methods We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data. Results We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets. Conclusions Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

scholarly journals Soluble PD-L1 is a predictive and prognostic biomarker in advanced cancer patients who receive immune checkpoint blockade treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
So Yeon Oh ◽  
Soyeon Kim ◽  
Bhumsuk Keam ◽  
Tae Min Kim ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Prognostic Factor ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Progressive Disease ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Checkpoint Inhibitor Therapy

AbstractCirculating soluble programmed death-1 ligand (sPD-L1) is measurable in the serum of cancer patients. This study aimed to investigate the significance of sPD-L1 in cancer patients receiving immune checkpoint inhibitor therapy. Blood samples were obtained before and after immune checkpoint inhibitor therapy (January 2015 to January 2019). The study cohort consisted of 128 patients who were diagnosed with non-small cell lung cancer (n = 50), melanoma (n = 31), small cell lung cancer (n = 14), urothelial carcinoma (n = 13), and other cancers (n = 20). Patients with a high level (> 11.0 pg/μL) of sPD-L1 were more likely to exhibit progressive disease compared with those with a low level (41.8% versus 20.7%, p = 0.013). High sPD-L1 was also associated with worse prognosis; the median PFS was 2.9 (95% confidence interval [CI] 2.1–3.7) months versus 6.3 (95% CI 3.0–9.6) months (p = 0.023), and the median OS was 7.4 (95% CI 6.3–8.5) months versus 13.3 (95% CI 9.2–17.4) months (p = 0.005). In the multivariate analyses, high sPD-L1 was an independent prognostic factor for both decreased PFS (HR 1.928, p = 0.038) and OS (HR 1.788, p = 0.004). sPD-L1 levels did not correlate with tissue PD-L1 expression. However, sPD-L1 levels were positively correlated with neutrophil to lymphocyte ratios and negatively correlated with both the proportion and the total number of lymphocytes. We found that high pretreatment sPD-L1 levels were associated with progressive disease and were an independent prognostic factor predicting lower PFS and OS in these patients.

scholarly journals Major Durable Response of Pembrolizumab in Chemotherapy Refractory Small Cell Bladder Cancer: A Case Report

2020 ◽  
Vol 13 (3) ◽  
pp. 1059-1066
Author(s):  
Olav Toai Duc Nguyen ◽  
Stein Harald Sundstrøm ◽  
Ganna Surzhykova Westvik ◽  
Ane Karoline Stræte Røttereng ◽  
Mona Røli Melhus ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bladder Cancer ◽  
Case Report ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Durable Response ◽  
Cell Bladder Cancer

Small cell carcinoma of the urinary bladder is a rare subtype (incidence of 1–9/1,000,000), characterized by an aggressive behavior with early metastasis and poor prognosis. Chemotherapy, radiation, and surgery are the usual treatment options, but to date, no accepted standard treatment exists. Since small cell bladder cancer shares similar clinicopathological features with small cell lung cancer, the same type of chemotherapy has been used. Recently, immune checkpoint inhibitors have shown effect in small cell lung cancer, but data regarding small cell bladder cancer is insufficient. Here we present a case where a 73-year-old male with chemorefractory metastatic small cell bladder cancer received a successful treatment with immune checkpoint inhibitor pembrolizumab resulting in a major durable response and no side effects. To our knowledge, this is the second case report on successful treatment of the rare subtype of small cell bladder cancer with an immune checkpoint inhibitor, supporting the use of pembrolizumab as a therapeutic option for small cell bladder cancer. Serum neuron-specific enolase was a useful biomarker both for chemo- and immunotherapy response.

scholarly journals Effectiveness of corticosteroids on immune checkpoint inhibitor-induced interstitial pneumonia among patients with a history of interstitial pneumonia: A case series

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110313
Author(s):  
Takenori Ichimura ◽  
Miwa Hinata ◽  
Daisuke Ichikura ◽  
Shinya Suzuki
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Interstitial Pneumonia ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients ◽  
History Of

There are few reports on the effectiveness of corticosteroids for immune checkpoint inhibitor-induced interstitial pneumonia in patients with a history of interstitial pneumonia. We report on 10 non-small cell lung cancer patients with a history of interstitial pneumonia who experienced immune checkpoint inhibitor-induced interstitial pneumonia. The immune checkpoint inhibitor-induced interstitial pneumonia lasted for a median duration of 41.5 days (range = 22–127 days). Eight of the ten patients responded to corticosteroid monotherapy; one patient responded to corticosteroids and the immunosuppressant, tacrolimus; and one patient did not improve after corticosteroid treatment. In non-small cell lung cancer patients with a history of interstitial pneumonia, immune checkpoint inhibitor-induced interstitial pneumonia was generally responds to corticosteroids.

Immune checkpoint inhibitor efficacy and safety in elderly non-small cell lung cancer patients.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e21034-e21034
Author(s):  
Hiromi Watanabe ◽  
Toshio Kubo ◽  
Kiichiro Ninomiya ◽  
Daisuke Minami ◽  
Kenichiro Kudo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Efficacy And Safety ◽  
Small Cell Lung ◽  
Lung Cancer Patients
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