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Licia Rivoltini



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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.06 - PD-1 Blockade Promotes Hyperprogressive Disease in NSCLC Through Macrophages Activation via Antibody-Fc/FcR Interaction (ID 12334)

      14:05 - 14:10  |  Author(s): Licia Rivoltini

      • Abstract
      • Presentation
      • Slides

      Background

      In a subset of patients, named hyperprogressors (HPs), immunotherapy seems to paradoxically boost tumor growth. However, neither pathological and clinical features nor the underlying biological mechanism have been identified. We dissected the role of tumor-myeloid cells crosstalk as possible players.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      HPs were defined on the basis of clinical and radiological features. Baseline histological samples from patients treated with immune checkpoints inhibitors (ICI) were evaluated by immunohistochemistry for myeloid and lymphoid markers. We tested the effect on tumor growth of murine and human ICI in T-cell deficient mice injected with human lung cancer cell lines and PDXs bearing different genotypes (EGFR+, KRAS+, STK11+ and wt). Innate immune microenvironment was evaluated by FACS analysis and immunohistochemistry. In vitro studies of ICI binding functional modulation were performed in human myeloid cells from patients and healthy donors.

      4c3880bb027f159e801041b1021e88e8 Result

      In a clinical series of 187 patients treated with ICI, hyperprogression was observed in 40 (26.3%) cases. All available HP pre-treatment tissue samples (11 cases) showed CD163+CD33+PD-L1+Arginase-A1+ clustered epithelioid macrophages infiltrating the tumor foci also expressing FcRs including CD32b. No differences in T cell compartment were observed. Murine and human PD1 blocking mAbs induced a boost of tumor growth in H460 xenografs in imunocompromised mice. A similar effect was observed in EGFR+ but not in KRAS+ and wt PDXs treated with human anti-PD1. Notably, no hyperprogression was observed after treatment with murine and human anti PD-1 F(ab)2. Hyperprogressive tumors were enriched in arginase+ myeloid-macrophage cells and fibrotic features. ICI bind in vitro to human macrophages and monocytes via Fc/FcR interactions, likely involving CD32b (FcgRIIb) and triggering functional polarization.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results provide evidence that FcR triggering on macrophages by ICI delivers a signaling cascade promoting a functional reprogramming of these cells toward a more aggressive pro-tumorigenic behavior eventually inducing hyperprogression in a subset of patients with distinctive immune and genetic profile. A validation prospective study in ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-11 - An IL-8/IFN-gammma/NLR Plasma Score to Predict Nivolumab Efficacy in Patients with NSCLC (ID 14139)

      16:45 - 18:00  |  Author(s): Licia Rivoltini

      • Abstract
      • Slides

      Background

      In the present study we investigated whether baseline plasma cytokines as well as neutrophil to lymphocyte ratio (NLR) could predict resistance to nivolumab in pre-treated patients with advanced non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From September 2015 to January 2018, 42 NSCLC patients receiving i.v. nivolumab 3 mg/kg every two weeks were included within a translational study. All the patients underwent CT-scan every 6 cycles and responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Peripheral blood samples were obtained from the patients at baseline. A panel of cytokines and chemokines (IL-6, IL-8, CXCL10, CX3CL1, CCL2, VEGF, and IFN- gamma) were quantified in plasma by Cytokine Bead Array and their association with OS and TTP was assessed by Adaptive Index Modeling multivariable analysis. NLR in blood cell counts was also assessed for potential association with clinical outcomes.

      4c3880bb027f159e801041b1021e88e8 Result

      An Index Score was identified clustering patients into 4 groups with progressively worsening TTP and OS. The score was composed by higher IL-8 and NLR (above the cut-offs of 10.76 pg/ml and 5.4, respectively) and lower IFN-gamma level (below cut-off of 11 pg/ml). Patients with score 0-1 (i.e. with none or 1 altered parameter; n= 17) displayed a median TTP of 11 months (95% IC= 5-NA) and median OS of 16 months (95% IC= 12-NA); in contrast, patients with score 2-3 (2 or 3 altered parameters; n=23) showed a median TTP of 3 months (95% IC= 2-5) and median OS of 5 months (95% IC= 2-8). The divergences among both TTP and OS Kaplan Meyers curves were statistically significant (P<0.0001). NLR alone showed instead either a borderline association with OS (p=0.048) and no ability to predict TTP (p=0.23).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Baseline plasma levels of IL-8 and IFN-gamma potentiate the ability of NLR to predict resistance to nivolumab in pre-treated patients with advanced NSCLC. These data suggest that the systemic balance between neutrophil-related inflammation and lymphocyte anti-tumor immunity may condition response to immunotherapy in lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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