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Kazuto Nishio



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    MS 25 - Novel Molecular Targets (KRAS/MET/Novel Fusions): Druggable or Not? (ID 547)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      MS 25.04 - FGFR-Related Novel Molecular Targets (ID 7762)

      14:30 - 16:15  |  Presenting Author(s): Kazuto Nishio

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Aberrant activation of fibroblast growth factor (FGF) signaling due to up-regulation of FGF receptor gene (FGFR) expression, alternative splicing of FGFR transcripts, FGFR mutations or translocations, or increased availability of FGF has been found to contribute to prognosis in several types of tumors(1, 2). Our previous evidence suggest that these gene alterations increase the sensitivity to multi-kinase inhibitors (3, 4, 5). FGFR gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in preclinical and clinical studies for non-small cell lung cancer and other solid tumors (6,7,8). We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy. 1) Mizukami T, et al. Mol Carcinog. 2017;56(1):106-117. 2) Matsumoto K, et al. Br J Cancer. 2012;106(4):727-32. 3) Arao T, et al. Hepatology. 2013;57(4):1407-15. 4) Sakai K, et al. Oncotarget. 2015;6(25):21636-44. 5) Kaibori M, et al. Oncotarget. 2016; 7(31):49091-49098. 6) Kudo K, et al. Clin Cancer Res. 2011; 17(6):1373-81. 7) Okamoto I, et al. Mol Cancer Ther. 2010; 9(10):2825-33. 8) M. Takeda K. et al. Ann Oncol. 2016; 27(4): 748–750.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-021 - A Checkpoint Molecule B7-H3 as a Novel Immune Therapy Target for Non-Small Cell Lung Cancer (NSCLC) (ID 8598)

      09:30 - 16:00  |  Author(s): Kazuto Nishio

      • Abstract
      • Slides

      Background:
      Anti-PD-1 immune therapy improved survival in NSCLC, whereas some patients were not responding to this treatment, indicating the requirement of alternative strategies for these patients. B7-H3, an immune checkpoint molecule, has known to be expressed in some cancer cells including NSCLC. In this study, we examined the therapeutic potential of targeting B7-H3 using a mouse model, also elucidated the expression levels of B7-H3 on NSCLC tumor cells.

      Method:
      Pan02 murine cancer cells were inoculated in syngeneic mice, and anti-tumor efficacy of anti-B7-H3, anti-PD-L1 antibodies were evaluated. T-cell expression of IFN gamma was evaluated in the spleen and tumor infiltrating lymphocytes using flow-cytometer. B7-H3 expression on tumor cells in patients with NSCLC (n=69) was evaluated by immunohistochemistry.

      Result:
      In the mouse model study, the treatment with anti-B7-H3 antibody significantly prevented the tumor-growth as compared to isotype antibody. The numbers of CD4+ and CD8+ T-cells infiltrated in the tumor significantly increased following treatment with anti-B7-H3 antibody. Importantly, depletion of CD8+ T-cells cancelled the anti-tumor effect of anti-B7-H3 antibody treatment, indicating that the blockade of B7-H3 potentiates anti-tumor CD8+ T-cell responses. In fact, CD8+ T-cell expressions of IFN gamma in response to tumor cells were improved when mice were treated with anti-B7-H3 antibody. Furthermore, combination with anti-B7-H3 and anti-PD-L1 antibody treatment showed synergic effect in inhibiting tumor-growth. The expressions of B7-H3 were evident on NSCLC tumors, which consists 62% of NSCLC patients.

      Conclusion:
      Anti-B7-H3 antibody exhibited CD8+ T-cell-mediated anti-tumor effects in the mouse model study. B7-H3 was aberrantly expressed in NSCLC tumor cells. Anti-B7-H3 antibody or its combination with anti-PD-1 antibody is suggested to be effective for patients with NSCLC. Figure 1



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