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N. Mani

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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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      MA15.06 - Predictive Value of Measuring Somatic Mutations and Tumor Infiltrating Lymphocytes for PD-1 Axis Therapy in Non-Small Cell Lung Cancer (NSCLC) (ID 6255)

      14:20 - 15:50  |  Author(s): N. Mani

      • Abstract
      • Slides

      Diverse factors have been associated with clinical benefit to PD-1 axis blockers in NSCLC including PD-L1 protein expression by immunohistochemistry and increased mutation load/predicted class-I neoantigens. However, the association and predictive value of the tumor genomic landscape, composition of the tumor immune microenvironment and T-cell function remain unclear.

      We performed whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) for T-cells in pre-treatment FFPE samples from 45 NSCLC patients treated with PD-1 axis blockers (alone or in combination) in our institution. Genomic analysis was used to evaluate the mutational load and predicted class-I neoantigens. Multiplexed QIF-based immunoprofiling was used to measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3+ cells) and T-cell activation (Granzyme-B in CD3+ cells). We studied the association between the tumor somatic mutations, predicted neoantigens, T-cell infiltration/function and clinical benefit /survival.

      Increased mutational load was positively associated with predicted class-I neoantigens, variants in DNA-repair genes, smoking and absence of activating mutations in EGFR; but not associated with the level of CD3+ T-cells, T-cell proliferation (Ki-67 in CD3+ cells) and function (Granzyme-B in CD3+ cells). Increased mutations and candidate class-I neoantigens were significantly associated with response to therapy (P=0.02 and 0.03, respectively), but not with overall survival at 3-years (median cut-point, log rank P=0.92 and 0.80, respectively). Higher CD3 positivity was not associated with response to therapy (P=0.17), but was significantly associated with overall survival (median cut-point, log rank P=0.03). Regardless of the mutational load and candidate neoantigen content, elevated CD3 with low Ki-67/Granzyme-B in CD3 predicted longer survival after PD-1 axis blockade than high CD3/high Ki-67/Granzyme-B in CD3, or low T-lymphocyte infiltration.

      Increased somatic mutations are associated with smoking and response to PD-1 agents, but not with tumor T-cell infiltration/activation and overall survival. Regardless of the mutational load, increased T-cell infiltration using QIF is significantly associated with longer survival after PD-1 axis blockade in NSCLC. The subgroup of NSCLC with the highest potential of benefit to immune reinvigoration using PD-1 axis blockade comprise tumors with elevated lymphocyte infiltration but low in situ activation/proliferation.

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