Analysis of over 100,000 patients with cancer for CD274 (PD-L1) amplification: Implications for treatment with immune checkpoint blockade.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 47-47 ◽  
Author(s):  
Aaron Goodman ◽  
David Eric Piccioni ◽  
Shumei Kato ◽  
Amelie Boichard ◽  
Vighnesh Walavalkar ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Response Rate ◽  
Immune Checkpoint Blockade ◽  
Refractory Disease ◽  
Copy Number Alterations ◽  
Patients With Cancer ◽  
Systemic Therapies

47 Background: The majority of patients with Hodgkin lymphoma have copy number alterations in the genes CD274 (PD-L1), PDCD1LG2 ( PD-L2) and JAK2 (chromosome 9p24.1) resulting in high response rates to PD-1/PD-L1 blockade, even in refractory disease. The prevalence and importance of this biomarker as a predictor of response to PD-1 blockade is unknown across all solid tumors. Methods: We analyzed > 100,000 de-identified patient samples from the Foundation Medicine database and 2,039 clinically annotated patients from UCSD. CD274 amplification was called for copy number alterations (CNAs) ≥ 6. PFS was calculated by KM analysis. Results: Altogether, 0.7% of all tumors types had ≥ 6 CNAs in CD274 (Table). CD274 CNAs were identified in 121 tumor histologies. 13 patients at UCSD were found to have CD274 amplification of which nine were treated with PD-1/PD-L1 blockade (either alone or in combination with another immunotherapeutic or targeted therapy) after a median of four prior systemic therapies. The response rate to PD-1/PD-L1 blockade was 67% (6 of 9 patients); median PFS = 15.1 (range, 1.6-21.8+) months (includes 3 objective responses ongoing for 15+ months as well as a glioblastoma with a PR for 4.4+ months). Conclusions: CD274 amplification is rare in most malignancies; however, testing for this alteration is warranted given the frequent and durable responses to PD-1/PD-L1 blockade. [Table: see text]

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.

Burden of copy number alterations predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14068-e14068
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Shuang Li ◽  
Xi Jiao ◽  
Lihong Wu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Copy Number ◽  
Objective Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Copy Number Alterations ◽  
Sequencing Platform ◽  
Gi Cancer ◽  
Ffpe Tumor ◽  
Gi Cancers

e14068 Background: Despite the great achievements made in immune checkpoint blockade (ICB) in cancer therapy, how to identify patients who may benefit from ICB still remains one of the central questions, especially in gastrointestinal (GI) cancer. Methods: To address this, we analyzed FFPE tumor specimens from 73 patients with metastatic GI cancers who were treated with ICB. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Overall, tumor mutation burden (TMB) and copy number alterations (CNAs) were determined by using the whole-exome sequencing platform. FFPE samples of 65 patients were analyzed via a multiplex RNA immune oncology sequencing panel. Results: Here we show that lower burden of copy number alteration (CNA) was observed in responders to immunotherapy in both discovery and validation cohorts. More importantly, lower burden of CNA in GI cancers were associated with improved objective response, clinical benefit and overall survival. Efficacy also correlated with the higher TMB. Of note, a combinatorial biomarker of TMB and burden of CNA may better stratify responders from patients received immunotherapy. In addition, patients with lower burden of CNA revealed increased IFNγ and expanded immune signatures in our GI patient cohort and TCGA cohorts as well. Conclusions: Our results suggest that burden of CNA may expand the predictive and prognostic value of genomic determinants in identifying potential responders with GI cancer to immune checkpoint blockade therapy.

scholarly journals Impact of Treatment Beyond Progression with Immune Checkpoint Blockade in Hodgkin Lymphoma

2020 ◽  
Vol 25 (6) ◽  
Author(s):  
Reid W. Merryman ◽  
Nicole A. Carreau ◽  
Ranjana H. Advani ◽  
Michael A. Spinner ◽  
Alex F. Herrera ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Treatment Beyond Progression

scholarly journals Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Simona Camorani ◽  
Margherita Passariello ◽  
Lisa Agnello ◽  
Silvia Esposito ◽  
Francesca Collina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors

2020 ◽  
Vol 38 (27) ◽  
pp. 3088-3094 ◽  
Author(s):  
Anita Gul ◽  
Tyler F. Stewart ◽  
Charlene M. Mantia ◽  
Neil J. Shah ◽  
Emily Stern Gatof ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Metastatic Rcc

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

scholarly journals Recent Findings in the Posttranslational Modifications of PD-L1

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Shu-Man Li ◽  
Jie Zhou ◽  
Yun Wang ◽  
Run-Cong Nie ◽  
Jie-Wei Chen ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Immune Checkpoint ◽  
Protein Modification ◽  
Immune Cell ◽  
Response Rate ◽  
Malignant Tumors ◽  
Objective Response ◽  
Cell Activity ◽  
Patients With Cancer ◽  
L1 Protein

Immune checkpoint therapy, such as the reactivation of T-cell activity by targeting programmed cell death 1 (PD-1) and its ligand PD-L1 (also called B7-H1 and CD274) has been found pivotal in changing the historically dim prognoses of malignant tumors by causing durable objective responses. However, the response rate of immune checkpoint therapy required huge improvements. It has been shown that the expression of PD-L1 on cancer cells and immune cell membranes is correlated with a more durable objective response rate to PD-L1 antibodies, which highlights the importance of deeply understanding how this protein is regulated. Posttranslational modifications such as phosphorylation, N-glycosylation, and ubiquitination of PD-L1 have emerged as important regulatory mechanisms that modulate immunosuppression in patients with cancer. In this review, we summarized the latest findings of PD-L1 protein modification and their clinical applications.

scholarly journals Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 310-316 ◽  
Author(s):  
W. Robert Liu ◽  
Margaret A. Shipp
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Evasion ◽  
Copy Number ◽  
Genetic Basis ◽  
Immune Cell ◽  
Classical Hodgkin Lymphoma ◽  
Copy Number Alterations ◽  
Cell Infiltrate ◽  
Immune Cell Infiltrate ◽  
Survival And Growth

Abstract Classical Hodgkin lymphoma (cHL) is an unusual B-cell–derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number–dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor–positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade.

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