scholarly journals P3.04-14 TMB and Immune Checkpoint Inhibitor Gene Expression are Unrelated in NSCLC Patients

2018 ◽  
Vol 13 (10) ◽  
pp. S927
Author(s):  
C. Szeto ◽  
R. Parulkar ◽  
C. Garner ◽  
S. Reddy
2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A495-A495
Author(s):  
David Saltman ◽  
Nicole Croteau ◽  
Heather Lockyer ◽  
Rob Seitz ◽  
Frank McMahon ◽  
...  

BackgroundLung cancer is the leading cause of cancer-related deaths worldwide. The advent of ICIs specifically targeting programmed cell death protein-1 (PD-1), or its ligand (PD-L1) represents a major therapeutic advance that is now included in standard of care regimens for non-small-cell-lung cancer (NSCLC). PD-L1 expression measured by immunohistochemistry (IHC) staining is the current gold standard predictive biomarker for immune checkpoint inhibitor (ICI) therapy in NSCLC, however many factors beyond PD-L1 expression alone affect the outcome of ICI therapy. Evaluation of other factors to better inform clinical practice will reduce both the potential for adverse immune-related toxicities and expenditure on ineffective costly therapies while potentially identifying patients otherwise missed by PD-L1 staining. The 27-gene IO assay is a RT-qPCR based gene expression panel1 that was developed to classify the tumor immune microenvironment (TIME). It has been shown to be associated with response to ICI therapy in multiple tumor types including triple negative breast cancer, metastatic urothelial carcinoma, and NSCLC where the association was independent of PD-L1 status in patients treated either with monotherapy or combination therapy.2 Currently, BC Cancer measures PD-L1 status by IHC using the PD-L1 22C3 PharmDx assay and reports the tumor proportional score (TPS) to inform clinical decision. Patients with a TPS ≥ 50% may be eligible for first-line treatment with ICI monotherapy and those with < 50% TPS are eligible for second line or later ICI monotherapy. We established this retrospective study of ICI monotherapy treated NSCLC patients to assess the 27-gene IO assay as an informative biomarker for NSCLC ICI treatment decisions.MethodsThis retrospective study is utilizing the BC Cancer Study Database to select approximately 150 patients with stage IIIB or IV NSCLC treated with single-agent ICI therapy across four BC Cancer centers from 2017 forward (figure 1). Patients are selected based on availability of adequate biopsy specimens (FFPE with at least 20% tumor content), availability of PD-L1 IHC results or sufficient tissue to conduct staining, and for whom outcome data is available via chart review. RNA from patient samples is isolated from FFPE biopsies (either primary or metastatic sites) and those that yield ≥50ng RNA will be analyzed by the 27-gene IO assay 1 to derive IO scores (IO positive or IO negative) based on previously defined thresholds.3 The association between patient outcomes on ICI monotherapy and IO scores and PD-L1 IHC will be reported and compared.Abstract 466 Figure 1Schematic representation of patient workflow forReferencesSaltman, A, et al. Prostate cancer biomarkers and multiparametric MRI: is there a role for both in prostate cancer management? Ther Adv Urol 2021;13: 1756287221997186.Ranganath HJA, Smith JR, et al. One-year progression-free survival in lung cancer patients treated with immune checkpoint inhibitors is significantly associated with a novel immunomodulatory signature but not PD-L1 staining. in SITC. Journal Immunotherapy Cancer. 2019.Nielsen, TJ, et al. A novel immuno-oncology algorithm measuring tumor microenvironment to predict response to immunotherapies. Heliyon 2021;7(3):e06438.Ethics ApprovalThe University of British Columba BC Cancer Research Ethics Board Chair, Vice-Chair or second Vice-Chair, has reviewed the above described research project, including associated documentation, and finds the research project acceptable on ethical grounds for research involving human subjects. All participants have provided informed consent before taking part in the study. REB Number H20-02635.


2020 ◽  
Author(s):  
Laetitia Douguet ◽  
Serena Janho dit Hreich ◽  
Jonathan Benzaquen ◽  
Laetitia Seguin ◽  
Thierry Juhel ◽  
...  

ABSTRACTOnly a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop new therapeutic strategies to improve patient outcome. We developed a new chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7 expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a promising novel strategy that may be active against NSCLC.


Author(s):  
Benjamin Adam ◽  
Naoka Murakami ◽  
Graeme Reid ◽  
Katie Du ◽  
Ruqaya Jasim ◽  
...  

Background and objectives: Immune checkpoint inhibitors are increasingly used to treat various malignancies but their application in kidney transplant patients is complicated by high allograft rejection rates. Immune checkpoint inhibitor-associated rejection is a novel, poorly understood entity demonstrating overlapping histopathological features with immune checkpoint inhibitor-associated acute interstitial nephritis, which poses a challenge for diagnosis and clinical management. We sought to improve the understanding of these entities through biopsy-based gene expression analysis. Design, setting, participants, and measurements: NanoString was used to measure and compare the expression of 725 immune-related genes in 75 archival kidney biopsies, including a 25-sample discovery cohort comprising pure T-cell mediated rejection (TCMR) and immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN), and an independent 50-sample validation cohort comprising ICI-AIN, immune checkpoint inhibitor-associated T-cell mediated rejection (ICI-TCMR), immune checkpoint inhibitor-associated crescentic glomerulonephritis, drug-induced acute interstitial nephritis (Drug-AIN), BK virus nephropathy, and normal biopsies. Results: Significant molecular overlap was observed between ICI-AIN and TCMR. Nevertheless, IFI27, an interferon-alpha induced transcript, was identified and validated as a novel biomarker for differentiating ICI-TCMR from ICI-AIN (validation cohort: P<0.001, AUC=100%, accuracy=86%). Principal component analysis revealed heterogeneity in inflammatory gene expression patterns within sample groups; however, ICI-TCMR and ICI-AIN both demonstrated relatively more molecular overlap with Drug-AIN than TCMR, suggesting potential dominance of hypersensitivity mechanisms in these entities. Conclusions: These results indicate that, although there is significant molecular similarity between immune checkpoint inhibitor-associated rejection and AIN, biopsy-based measurement of IFI27 gene expression represents a potential biomarker for differentiating these entities.


2017 ◽  
Vol 142 (6) ◽  
pp. 1277-1284 ◽  
Author(s):  
Francesco Passiglia ◽  
Antonio Galvano ◽  
Sergio Rizzo ◽  
Lorena Incorvaia ◽  
Angela Listì ◽  
...  

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