Systemic immunotherapy of superficial mouse bladder cancer with Avelumab (MSB0010718C), an anti-PD-L1 immune checkpoint inhibitor

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.

Download Full-text

Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer

Medicina ◽

10.3390/medicina57080769 ◽

2021 ◽

Vol 57 (8) ◽

pp. 769

Author(s):

Arthur Peyrottes ◽

Idir Ouzaid ◽

Gianluigi Califano ◽

Jean-Francois Hermieu ◽

Evanguelos Xylinas

Keyword(s):

Bladder Cancer ◽

Clinical Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Response Rate ◽

Checkpoint Inhibitor ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Neoadjuvant Immunotherapy ◽

Muscle Invasive

Background and Objectives: Facing neoadjuvant chemotherapy followed by surgery, neoadjuvant immunotherapy is an innovative concept in localized muscle-invasive bladder cancer. Herein, we performed a review of the available and ongoing evidence supporting immune checkpoint inhibitor (ICI) administration in the early stages of bladder cancer treatment. Materials and Methods: A literature search was performed on Medline and clinical trials databases, using the terms: “bladder cancer” OR “urothelial carcinoma”, AND “neoadjuvant immunotherapy” OR “preoperative immunotherapy”. We restricted our investigations to prospective clinical trials evaluating anti-PD-(L)1 and anti-CTLA-4 monoclonal antibodies. Data on efficacy, toxicity and potential biomarkers of response were retrieved. Results: The search identified 6 ICIs that were tested in the neoadjuvant setting for localized bladder cancer—4 anti-PD-(L)1 inhibitors (Pembrolizumab, Atezolizumab, Nivolumab and Durvalumab) and 2 anti-CTLA-4 inhibitors (Ipilimumab and Tremelimumab). Most of the existing literature was based on single-arm phase 2 clinical trials that included from 23 to 143 patients. The pathological complete response rate (pCR) and pathological response rate (pRR) ranged from 31% to 46% and from 55.9% to 66%, respectively. Survival data were immature at this time. The safety profile was acceptable, with severe treatment-related adverse events ranging from 6% to 41%. Conclusions: The results of early phase trials are encouraging, and more investigations are needed to strengthen the rationale for immune checkpoint inhibitor administration in localized muscle-invasive bladder cancer.

Download Full-text

Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.672158 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xingyu Chen ◽

Haotian Chen ◽

Dong He ◽

Yaxin Cheng ◽

Yuxing Zhu ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Immune Cell ◽

Cox Regression ◽

Prognostic Biomarker ◽

Checkpoint Inhibitor ◽

Clinical Prognosis

The tumor microenvironment (TME) plays a crucial role in cancer progression and recent evidence has clarified its clinical significance in predicting outcomes and efficacy. However, there are no studies on the systematic analysis of TME characteristics in bladder cancer. In this study, we comprehensively evaluated the TME invasion pattern of bladder cancer in 1,889 patients, defined three different TME phenotypes, and found that different subtypes were associated with the clinical prognosis and pathological characteristics of bladder cancer. We further explored the signaling pathways, cancer-immunity cycle, copy number, and somatic mutation differences among the different subtypes and used the principal component analysis algorithm to calculate the immune cell (IC) score, a tool for comprehensive evaluation of TME. Univariate and multivariate Cox regression analyses showed that ICscore is a reliable and independent prognostic biomarker. In addition, the use of anti-programmed death-ligand (PD-L1) treatment cohort, receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), Subnetwork Mappings in Alignment of Pathways (SubMAP), and other algorithms confirmed that ICscore is a reliable prognostic biomarker for immune checkpoint inhibitor response. Patients with higher ICscore showed a significant therapeutic advantage in immunotherapy. In conclusion, this study improves our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance for more effective personalized immunotherapy strategies.

Download Full-text

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

Case Reports in Oncology ◽

10.1159/000509747 ◽

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.

Download Full-text

Re: Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients with Advanced Urothelial Bladder Cancer

The Journal of Urology ◽

10.1016/j.juro.2017.11.024 ◽

2018 ◽

Vol 199 (2) ◽

pp. 341-342 ◽

Cited By ~ 2

Author(s):

Sam S. Chang

Keyword(s):

Bladder Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Urothelial Bladder Cancer ◽

Safety And Efficacy ◽

Urothelial Bladder

Download Full-text

Transcriptional signatures associate with the clinical outcomes of immune checkpoint inhibitor treatment in advanced bladder cancer

10.21203/rs.3.rs-889171/v2 ◽

2021 ◽

Author(s):

Xiaofeng Xu ◽

Dian Fu ◽

Hai Zhao ◽

Jie Huang ◽

Zuheng Wang ◽

...

Keyword(s):

Bladder Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Treatment Protocol ◽

Outcome Data ◽

Transcriptional Signature ◽

Metastatic Urothelial Cancer ◽

Platinum Based Chemotherapy ◽

Inhibitor Treatment

Abstract Background Urothelial bladder cancer (UBC) is one of the most lethal cancers worldwide, the 5-year survival rate remain poor with platinum-based chemotherapy regimens as the standard of cancer treatment protocol. Recent FDA approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in advanced UBC patients is changing the therapeutic landscape. Although the response to anti-PD-L1 is correlated to PD-L1 expression and tumor mutation burden, the molecule determinants of responsiveness or non-responsiveness to immune checkpoint inhibitor (ICI) is largely unknown. Result A published immunotherapy cohort with whole exome sequencing, RNAseq and clinic outcome data for 29 metastatic urothelial cancer patients was used, paralleled with The Cancer Genome Altas Bladder Cancer cohort for validation. Genomic mutational profiling, mutational signature, a panel genes in antigen presentation and interferon signaling in bladder cancer were delineated with little correlation with durable clinic benefit (DCB) or non-DCB of PD-L1 inhibitor treatment. Whereas, characterized immune-responsive or resistant associated genes showed differentially expressed between DCB group and non-DCB group. Further more, transcriptional signature and transcriptional regulators between DCB and non-DCB were identified from transcripome data. Conclusion Our exploratory analyses provided multidimension view of complexity of determinants of immune-responsiveness and suggest the influences of transcriptional reprogram in immune checkpoint blockage therapy.

Download Full-text

Immune checkpoint inhibitor shows activity against bladder cancer

The Pharmaceutical Journal ◽

10.1211/pj.2014.20067327 ◽

2014 ◽

Keyword(s):

Bladder Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor

Download Full-text

Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.643282 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yi-Hui Pan ◽

Jia-Xing Zhang ◽

Xu Chen ◽

Fei Liu ◽

Jia-Zheng Cao ◽

...

Keyword(s):

Bladder Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Risk Group ◽

Checkpoint Inhibitor ◽

High Risk Group ◽

Inhibitor Therapy ◽

Mutation Burden ◽

Checkpoint Inhibitor Therapy ◽

Validation Set

BackgroundOnly a proportion of patients with bladder cancer may benefit from durable response to immune checkpoint inhibitor (ICI) therapy. More precise indicators of response to immunotherapy are warranted. Our study aimed to construct a more precise classifier for predicting the benefit of immune checkpoint inhibitor therapy.MethodsThis multi-cohort study examined the top 20 frequently mutated genes in five cohorts of patients with bladder cancer and developed the TP53/PIK3CA/ATM mutation classifier based on the MSKCC ICI cohort. The classifier was then validated in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. The molecular profile and immune infiltration characteristics in each subgroup as defined by this classifier were explored.ResultsAmong all 881 patients with bladder cancer, the mutation frequency of TP53, PIK3CA, and ATM ranked in the top 20 mutated genes. The TP53/PIK3CA/ATM mutation classifier was constructed based on the Memorial Sloan Kettering Cancer Center (MSKCC) ICI cohort and only showed predictive value for patients with bladder cancer who received ICI therapy (median overall survival: low-risk group, not reached; moderate-risk group, 13.0 months; high-risk group, 8.0 months; P<0.0001). Similar results were found in subgroups of MSKCC ICI cohort defined by tumor mutation burden. Multivariate Cox analysis revealed that the risk group defined by the classifier served as an independent prognostic factor for overall survival in patients with bladder cancer. Efficacy of the classifier was verified in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. Lower expression of PD-1/PD-L1 and less tumor immune infiltration were observed in the high-risk group than the other two groups of the TCGA cohort and the IMvigor210 cohort.ConclusionOur study constructed a TP53/PIK3CA/ATM mutation classifier to predict the benefit of immune checkpoint inhibitor therapy for patients with bladder cancer. This classifier can potentially complement the tumor mutation burden and guide clinical ICI treatment decisions according to distinct risk levels.

Download Full-text