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E. Parra

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    MS 21 - Immunotherapy Predictive Biomarkers (ID 39)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MS21.03 - Assessment of Immune Cells in Tumor Biopsies as a Biomarker (ID 1943)

      14:15 - 15:45  |  Author(s): E. Parra

      • Abstract
      • Presentation

      Multiple genetic and epigenetic changes in several cancer types cause resistance to immune attack of tumors by inducing specific T cells tolerance and by expressing ligands that engage inhibitory receptors and block T cells activation, all resulting on T-cells anergy or exhaustion within the tumor microenvironment (1). In this process, programmed death 1 (PD-1) protein, a T-cell co-inhibitory receptor, and one of its ligands, PD-L1 (B7-H1 or CD274), play a pivotal role in the ability of tumor cells to evade the host’s immune system. Antibody-mediated blockade PD-1/PD-L1 induced durable tumor regression and prolonged disease stabilization in non-small cell carcinoma (NSCLC) (2). Although these studies have reported correlations between PD-L1 immunohistochemical (IHC) expression levels on NSCLC tumor cells and clinical responses to PD-1 and PD-L1 inhibitors, there are patients with negative PD-L1 expression tumors who have showed similar responses than patients with positive expression. Recently, it has been shown that across multiple cancer types, including NSCLC, responses to anti-PD-L1 therapy were observed in patients with tumors expressing high levels of PD-L1, especially when PD-L1 was expressed by tumor-associated infiltrating cells (TAICs). Altogether, these findings suggest that there are other factors in the tumor microenvironment, including tumor infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) that may drive responses to anti-PD-1/PD-L1 therapies, and be involved in lung cancer pathogenesis and progression. A number of studies have characterized the PD-L1 protein expression by immunohistochemistry (IHC) or immunofluorescence (IF) in all NSCLC stages using formalin-fixed and paraffin-embedded (FFPE) tumor tissues, and correlated those findings with patient’s outcome, and in a limited number of cases with response to immunotherapy (3, 4). Those studies differ on the type of specimens (whole histology sections vs. tissue microarrays [TMAs]), the protein expression analysis (IHC vs. IF), and the quantification assessment (image analysis vs. microscope observation). Only few studies have attempted to correlate the expression of PD-L1 and TAICs, particularly TILs, using a limited number of IHC markers (e.g., CD8, CD45) (5). Up to date, there is no published study in which a comprehensive panel of immune markers, including PD-L1, has been performed attempting to develop a clinical relevant immuno-score system in surgically resected NSCLCs and explore their role as predictive markers of response to immunotherapy. We will present data on the characterization of TAICs in lung cancer tumor specimens using a large panel of markers (PD-L1, PD-1, CD3, CD4, CD8, CD45RO, CD57, Granzyme B, FOXP3, OX-40, and CD68) examined by both uniplex IHC and multiple immunofluorescence (IF) methodologies, and quantitated using image analysis systems (Aperio, Vectra and MultiOmyx). In surgically resected NSCLC tumor tissues the analysis was performed at both peri-tumoral and intra-tumoral compartments, and those data provided interesting data on the spatial distribution of TAICs and the expression of immune checkpoints in lung tumors. Our approach allowed us to devise an immuno-score system for lung cancer tissue specimens using both surgically resected and small diagnostic biopsies (core needle biopsies, CNBs) that correlated with clinical, pathological and molecular features of tumors. References: 1. Mellman I, Coukos G, Dranoff G: Cancer immunotherapy comes of age. Nature 2011, 480:480-9. 2. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of medicine 2012, 366:2443-54. 3. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014, 515:563-7. 4. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA: Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti-PD-1 Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2014, 20:5064-74. 5. Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, Herbst RS, Rimm DL. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst. 2015 Feb 3;107(3).

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