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S. Olugbile



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    MA15 - Immunotherapy Prediction (ID 400)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA15.07 - Molecular Determinants of Lack of Tumor Immune Infiltration in NSCLC (ID 5191)

      14:20 - 15:50  |  Author(s): S. Olugbile

      • Abstract
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) make up the majority of all lung cancer cases and is associated with very poor prognosis. Immune checkpoint blockers have now been shown to induce unprecedented durable response in a fraction of NSCLC patients with pre-existing T cell infiltration within their tumor. However in order to improve their efficacies beyond this subset of patients, a detailed molecular characterization to identify factors associated with lack of T cell infiltration is needed. A recent analysis in metastatic melanoma identified Wnt/B-catenin pathway activation as a mechanism for lack of T cell infiltration. We pursued similar analyses of immunologic gene signatures and molecular associations in squamous cell lung cancer (SCC) and lung adenocarcinoma (LA).

      Methods:
      We analyzed RNAseq data from two lung cancer datasets of The Cancer Genome Atlas (TCGA) (N = 499 for SCC and N = 514 for LA). Samples were categorized into non-T cell inflamed and T cell-inflamed groups using unsupervised consensus clustering based on the expression of 160 immune-related genes. Ingenuity pathway analysis was utilized to identify molecular pathways activated in non-T cell-inflamed tumors.

      Results:
      A similar proportion of non-T cell-inflamed tumors were identified in the two cohorts (SCC: 34%; LA: 31%). 47% of the SCC tumors were identified as T cell-inflamed, as compared to 37% in LA. A positive correlation was observed between CD8A and PD-L1, IDO1, LAG3 and TIM3 (p<0.00001). Total of 1,216 genes are significantly up-regulated in non-T cell-inflamed SCC tumors and 596 in LA with at least 1.5-fold change and FDR-adjusted p<0.05. Among these, a total of 194 genes are up-regulated in both SCC and LA, with the rest being specific for each subtype (SCC: 84%; LA: 67%). Pathway analysis suggested 35 upstream regulators were activated in SCC and 32 in LA (activation z-scoreā‰„2.0). Among these, 10 upstream regulators are activated in both datasets (ATF4, CTNNB1, KAT6A, KLF4, MYC, NFE2L2, PI3K, SCAP, SP1, SREBF2). Finally, we performed the same gene expression analysis on RNAseq data from matched normal tissues (N = 51 for SCC and N = 59 for LA) and confirmed that the T-cell inflamed gene signature is a property of the tumor rather than normal lung tissue.

      Conclusion:
      Our analyses successfully identified genes and associated pathways that are enriched in NSCLC subtypes with no immune infiltration. Rational strategies to improve the efficacy of immune checkpoint blockers beyond the current subset of responders should be based on targeting these pathways.

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    OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      OA13.05 - Somatic Genetic Alterations and Immune Microenvironment in Malignant Pleural Mesothelioma (ID 5087)

      14:20 - 15:50  |  Author(s): S. Olugbile

      • Abstract
      • Presentation
      • Slides

      Background:
      The genomic landscape of malignant pleural mesothelioma (MPM) is not well understood. Advanced high-throughput sequencing technologies allow comprehensive characterization of genetic alterations. Knowledge of the somatic mutations and the immune microenvironment in patients with MPM will help to develop effective targeted therapies.

      Methods:
      We examined biopsy specimens from 12 MPM patients (8 epithelioid and 4 biphasic) that were removed during maximal cyto-reductive surgery. Specimens from 3 different sites (anterior, posterior and diaphragm, a total of 36 tissue samples) were studied through whole exome sequencing, T cell receptor (TCR) repertoire analysis of tumor-infiltrating T cells (TILs), and expression levels of immune-related genes. We also performed in silico prediction of potent neoantigens derived from non-synonymous somatic mutations in each specimen. For the comparison of tumor tissues from 3 different sites, we performed hierarchical clustering to assess the tumor heterogeneity and differences in immune environment.

      Results:
      High mutation/neoantigen load was significantly correlated with higher clonal expansion of TILs (R=0.46) and high expression levels of immune-associated cytolytic factors, granzyme A (R=0.25) and perforin 1 (R=0.48), in tumor tissues. In the clustering analysis, heterogeneous MPM cases revealed unique neoantigens and clonotypes of TILs that were restricted to each of tumor site, suggesting infiltration of the neoantigen-specific T cells. Further sub-analysis according to histologic types showed that biphasic tumors had higher mutation/neoantigen load and stronger oligo-clonal T cell expansion (p=0.01) than epithelioid tumors.

      Conclusion:
      Our analysis demonstrated a significant correlation between somatic mutation/neoantigen load, clonality of TILs, and the immune-related tumor microenvironment in MPM. Our findings suggest that high mutation/neoantigen load in tumor cells might promote effective expansion and infiltration of functional (tumorocidal) T cells into the tumor bed. These findings provide a rationale for selecting MPM patients who can benefit from treatment with immune checkpoint blockades. This may accelerate development of the neoantigen targeting TCR-engineered T cell therapy for MPM.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-058 - In-Depth Molecular Characterization of T Cell Clonal Expansion Induced by Anti-PD1 Therapy in NSCLC (ID 5183)

      14:30 - 15:45  |  Author(s): S. Olugbile

      • Abstract

      Background:
      Inhibitors of PD1/PD-L1 checkpoint have been shown to be active among a broad range of cancers including NSCLC. They induce proliferation of T cells within the tumor microenvironment (as revealed by IHC) leading to tumor eradication. There is however lack of detailed molecular characterization of these proliferating T cells including the dynamics of their clonalilty during treatment and its correlation with response, their antigen specificity and the molecular changes induced in the expanded clones at single cell level. Such understanding will serve as a biomarker to detect early response after one dose of therapy, ascertain efficacy (especially when radiological assessments are equivocal) and guide determination of optimal duration of therapy. Furthermore, insight into molecular changes in the proliferating T cell clones induced by these agents at single-cell level will identify the baseline unique characteristics of T cells clones that undergo rapid expansion upon exposure to anti-PD1 therapy, define the molecular mediators of tumor eradication in responders and serve as a foundation for the development of novel treatment strategies for non-responders.

      Methods:
      We performed next-generation T cell receptor alpha/beta chain sequencing on serially obtained tumor and PBMC samples from 54 NSCLC patients undergoing anti-PD1 therapy. We compared the dynamics of the T cell repertoire in responders versus non-responders within unsorted PBMC and in CD8 positive/negative T cells. We also assessed the expression of key mediators of cytotoxicity and T cell activation/dysfunction in these expanded CD8 T cell clones at single cell level among responders and non-responders.

      Results:
      We identified concordant early clonal T cell expansion after 1-4 doses of anti-PD1 therapy within the tumor and PBMC of responders. We confirmed these expanded T cell clones to be CD8 positive subgroup of CD3+ T cells in responders and CD8 negative subgroup of CD3+ T cells in non-responders. Furthermore, among responders we found that persistence of the expanded T cell clones for several months while on treatment is associated with durable response. Additional results on antigen specificity and gene expression of the expanded T cell clones in responders versus non-responders will be presented.

      Conclusion:
      Our results showed that early concordant clonal expansion of a defined population of CD8+ T cells detected both within the tumor and PBMC correlate with response to therapy. We also confirmed that the persistence of these unique T cell clones several months after their initial expansion correlates with durable response.