Abstract A5: Genome-wide methylation pattern predicts clinical benefit of immune checkpoint blockade therapy in NSCLC patients

2020 ◽  
Author(s):  
Jeongyeon Kim ◽  
Hyeon Gu Kang ◽  
Jae Soon Park
Keyword(s):  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Immune Checkpoint Blockade ◽  
Methylation Pattern ◽  
Checkpoint Blockade ◽  
Genome Wide ◽  
Nsclc Patients

scholarly journals Mutations Associated with No Durable Clinical Benefit to Immune Checkpoint Blockade in Non-S-Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1397
Author(s):  
Guangsheng Zhu ◽  
Dian Ren ◽  
Xi Lei ◽  
Ruifeng Shi ◽  
Shuai Zhu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Gene Mutations ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Related Gene ◽  
Nsclc Patients

(1) Background: The immune checkpoint blockade (ICB) has shown promising efficacy in non-small-cell lung cancer (NSCLC) patients with significant clinical benefits and durable responses, but the overall response rate to ICBs is only 20%. The lack of responsiveness to ICBs is currently a central problem in cancer immunotherapy. (2) Methods: Four public cohorts comprising 2986 patients with NSCLC were included in the study. We screened 158 patients with NSCLC with no durable clinical benefit (NDB) to ICBs in the Rizvi cohort and identified NDB-related gene mutations in these patients using univariate and multivariate Cox regression analyses. Programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), neoantigen load, tumor-infiltrating lymphocytes, and immune-related gene expression were analyzed for identifying gene mutations. A comprehensive predictive classifier model was also built to evaluate the efficacy of ICB therapy. (3) Results: Mutations in FAT1 and KEAP1 were found to correlate with NDB in patients with NSCLC to ICBs; however, the analysis suggested that only mutation in FAT1 was valuable in predicting the efficacy of ICB therapy, and that mutation in KEAP1 acted as a prognostic but not a predictive biomarker for NSCLC. Mutations in FAT1 were associated with a higher TMB and lower multiple lymphocyte infiltration, including CD8 (T-Cell Surface Glycoprotein CD8)+ T cells. We established a prognostic model according to PD-L1 expression, TMB, smoking status, treatment regimen, treatment type, and FAT1 mutation, which indicated good accuracy by receiver operating characteristic (ROC) analysis (area under the curve (AUC) for 6-months survival: 0.763; AUC for 12-months survival: 0.871). (4) Conclusions: Mutation in FAT1 may be a predictive biomarker in patients with NSCLC who exhibit NDB to ICBs. We proposed an FAT1 mutation-based model for screening more suitable NSCLC patients to receive ICBs that may contribute to individualized immunotherapy.

scholarly journals Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e000374 ◽  
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Shuang Li ◽  
Jifang Gong ◽  
Jian Li ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Copy Number ◽  
Validation Cohort ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Copy Number Alterations ◽  
Gi Cancer

BackgroundDespite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer.MethodsThis study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort.ResultsIn the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well.ConclusionsOur results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.

scholarly journals Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients

2018 ◽  
Vol 10 ◽  
pp. 175883401774974 ◽  
Author(s):  
Niki Karachaliou ◽  
Maria Gonzalez-Cao ◽  
Guillermo Crespo ◽  
Ana Drozdowskyj ◽  
Erika Aldeguer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Free Survival ◽  
Melanoma Patients ◽  
Ifn Γ ◽  
Nsclc Patients ◽  
Important Marker

Background: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated. Results: A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. Conclusions: IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.

scholarly journals Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma

2020 ◽  
Vol 27 (1) ◽  
pp. 276-287
Author(s):  
J. Bryan Iorgulescu ◽  
Prafulla C. Gokhale ◽  
Maria C. Speranza ◽  
Benjamin K. Eschle ◽  
Michael J. Poitras ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Evaluation of Prognostic Utility of Tumor Mutation Burden for NSCLC response to Immune Checkpoint Blockade Therapy: A Single Institute Study

2019 ◽  
Author(s):  
Jean R. Clemenceau ◽  
Sung Hak Lee ◽  
Peter Bazeley ◽  
Alex Millinovich ◽  
Jian Jin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Cleveland Clinic ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Status ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Prognostic Utility ◽  
Nsclc Patients

IMPORTANCEThe role of Tumor Mutation Burden (TMB) as a prognostic and/or predictive biomarker for Immune Checkpoint Blockade (ICB) therapy in a real-world clinical setting is still unclear.OBJECTIVETo assess whether TMB status provided by a clinically and commercially available tumor genomic profiling (TGP) assay is associated with overall survival of Non-Small Cell Lung Cancer (NSCLC) patients treated with ICB from a single institute.DESIGN, SETTING, AND PARTICIPANTSOutcomes and genetic testing data were collected for 188 NSCLC patients treated within the Cleveland Clinic system between August 2012 and July 2017.MAIN OUTCOMES AND MEASURESOverall survival (OS) from time receiving ICB therapy.RESULTSAmong 188 patients with NSCLC (median age, 62 years; 49.5% female), 86 (45.7%) received ICB therapy. Patients were grouped into three categories based on the status of TMB (in mutations/Mb): high (>= 20/Mb), intermediate (>=5 to <= 20/Mb), and low (<5/Mb). In patients treated with ICB, TMB high status was not significantly associated with improved OS from therapy initiation (HR: 0.90 [95% CI, 0.52-2.49, P>0.8], median OS difference: 9.7 months).CONCLUSIONS AND RELEVANCEAmong patients with NSCLC from a single institute in a longitudinal database of clinical data including TGP results, exploratory analyses do not show statistical significance for the prognostic utility of TMB. These findings indicate that there is a need for more prospective data on the use of TMB status as a guide for ICB therapy in a routine care setting.

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