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Yoshinori Hasegawa



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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-45 - Cisplatin Plus Gemcitabine Therapy Followed by Maintenance Gemcitabine for Advanced Squamous Cell Lung Cancer (KTORG1302) (Now Available) (ID 514)

      08:00 - 18:00  |  Author(s): Yoshinori Hasegawa

      • Abstract
      • Slides

      Background

      One of the standard treatments in chemo-naïve patients with advanced non-small cell lung cancer (NSCLC) is platinum-containing doublet chemotherapy. Moreover non-squamous NSCLC, patients benefit from pemetrexed maintenance therapy following induction therapy with cisplatin (CDDP) plus pemetrexed. However, no large-scale trial showing the efficacy of maintenance therapy has been reported in squamous cell lung cancer. We evaluated the efficacy and the safety of continuation maintenance therapy with gemcitabine (GEM) after induction chemotherapy with CDDP plus GEM in advanced squamous cell lung cancer.

      Method

      This study was a single-arm, multicenter and phase II trial. Main eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, and the aged of 20 to 74 years old. Patients received an induction phase which consisted of 4 cycles of CDDP (80mg/m2, day 1, q3w) plus GEM (1000mg/m2, day 1, 8, q3w). Patients who did not progress after completion of 4 cycles of induction received continuation maintenance therapy with GEM (1000mg/m2, day 1, 8, q3w) until disease progression. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population.

      Result

      Between June 2013 and October 2018, 26 patients were enrolled in this study. Although the scheduled numbers were 60, this study was ended early for poor accrual.

      The mean age was 65.7 years (range, 47 – 74 years). 18 patients (69.2%) completed 4 cycles of CDDP plus GEM, and 16 patients (61.5%) received continuation maintenance therapy with GEM. At the cutoff date of December 31, 2018, overall response rate was 46.2%, median PFS from induction therapy was 5.3 months (95% confidence interval [CI]: 2.9-7.3), and median PFS from continuation maintenance therapy was 3.8 months (95% CI: 2.3-5.2). Median overall survival from induction therapy was 11.9 months (95% CI: 7.5-26.5). The most common grade 4 adverse events were neutropenia (16%) and thrombocytopenia (12%). Pneumonitis ware seen in 3 cases (grade 1: 1, grade 2: 1, grade 3: 1 case). Adverse events except for hematotoxicity were generally well tolerated. There were no treatment-related deaths.

      Conclusion

      This study terminated early because of poor accrual and did not meet its primary endpoint. However, this study indicated continuation maintenance therapy with GEM can be well-tolerated treatment option for patients with advanced squamous NSCLC.

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    P1.06 - Mesothelioma (ID 169)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.06-07 - Targeting Photo-Therapy for Malignant Pleural Mesothelioma; Near Infrared Photoimmunotherapy Targeting Podoplanin (ID 883)

      09:45 - 18:00  |  Author(s): Yoshinori Hasegawa

      • Abstract

      Background

      mosikizu2.pngMalignant pleural mesothelioma (MPM) has a poor prognosis, and the number of patients is thought to increase in the future over the world. However, the therapy for MPM is very limited with few regimens. Thus, development of new therapies for unresectable MPM is highly desirable.

      Podoplanin is a transmembrane glycoprotein that has been reported to be specifically up-regulated in MPM, and the antibody(D2-40) has been used as a marker to decide MPM in pathological diagnosis. This time, we successfully established a new anti-podoplanin antibody, NZ-1.

      Near infrared photoimmunotherapy (NIR-PIT) is a recent-developed cancer therapy that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. It is now in international Phase III clinical trial against locoregional, recurrent head and neck squamous cell cancer (LUZERA-301), and expected to be clinically licensed in near future.

      In this preclinical study, we develop new photo-targeting therapy against MPM, with the combination of NIR-PIT and NZ-1.

      Method

      An antibody-photosensitizer conjugate consisting of NZ-1 and a phthalocyanine dye, IRDye-700DX, was synthesized and evaluated its specificity. In vitro and in vivo experiments were conducted with a podoplanin, luciferase expressing mesothelioma cell line(MSTO-211H/PDPN-luc-GFP). In vitro NIR-PIT cytotoxicity was assessed with dead staining and luciferase activity. In vivo NIR-PIT was examined in mice with tumors implanted in the flank or in the thoracic cavity, by in vivo real-time imaging with luciferase activities.

      Result

      In vitro NIR-PIT-induced cytotoxicity was in a light dose dependent. In vivo NIR-PIT led significant reductions in both tumor volume (p<0.05 vs. APC) and luciferase activity (p<0.05 vs. APC) in a flank model. Bioluminescence indicated that NIR-PIT lead to reduction in pleural dissemination mice model.

      Conclusion

      This study suggested that podoplanin-targeting-NIR-PIT with NZ-1 could be a new promising treatment for MPM.

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    P1.12 - Small Cell Lung Cancer/NET (ID 179)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.12-07 - Near Infrared Photoimmunotherapy Targeting DLL3 Against Small Cell Lung Cancer (ID 331)

      09:45 - 18:00  |  Author(s): Yoshinori Hasegawa

      • Abstract

      Background

      Small cell lung cancer (SCLC) has poor prognosis, and its treatment options are limited. Delta-like protein 3 (DLL3) is a promising treatment target for SCLC, and Rovalpituzumab tesirine (Rova-T) is the first antibody drug conjugate targeting DLL3, which is currently in clinical trials. Although DLL3 is ideal target for SCLC, the result of clinical studies has not reached its primary object. Thus, new approaches are still needed.

      Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumor with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. This new therapy is now in international Phase III clinical trial against locoregional, recurrent head and neck squamous cell cancer (LUZERA-301).

      Herein, we exploited NIR-PIT to develop new therapy for SCLC with DLL3 antibody. We preclinically evaluates the efficacy of DLL3-targeted-NIR-PIT.

      dll3研究概要.png

      Method

      In vitro and in vivo experiments were conducted with DLL3, GFP, and luciferase-expressing SCLC cell line and/or mouse fibroblast cell line (SBC5-DLL3-luc-GFP and 3T3-DLL3-luc-GFP). An antibody-photosensitizer conjugate consisting of rovalpituzumab (anti-DLL3 humanized monoclonal antibody) and a phthalocyanine dye, IRDye-700DX, was synthesized (rova-IR700) and cells or tumors were exposed to NIR-light. Serial fluorescence microscopic observation was done before and after NIR-PIT. In vitro NIR-PIT cytotoxicity was assessed with dead cell staining by flow cytometry and luciferase activity. In vivo NIR-PIT was performed in mice with tumors implanted in the flank and these were assessed by tumor volume, bioluminescence and overall survival.

      Result

      After exposure to NIR-light, cellular swelling, bleb formation, rupture of the lysosome and dead cell staining were observed in fluorescence microscope. In vitro cytotoxicity of NIR-PIT was light dose dependent. In vivo the antitumor effects of NIR-PIT were confirmed by significant reductions in tumor volume (p < 0.05), luciferase activity (p < 0.01) and overall survival (p = 0.023).

      Conclusion

      These results suggest that DLL3-targeting-NIR-PIT could be a new promising treatment for SCLC.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-91 - Exosomal Analysis of ALK Rearrangements by Spin Column with Porous Glass Filter (ID 2206)

      10:15 - 18:15  |  Author(s): Yoshinori Hasegawa

      • Abstract

      Background

      ALK rearrangements account for about 3-5% of non-small cell lung cancer (NSCLC). ALK-tyrosin kinase inhibitors (TKI) demonstrated robust efficacy compared with cytotoxic chemotherapy in patients with ALK alterations detected in the tumor tissues. Identifying ALK rearrangement was performed using tissue samples, which are not always available. The spin column with porous glass filter has been developed by Nagoya university and AGC Inc, resulting in highly efficient and easy to use exosome isolation. The exosomes contain various molecules of their cell of origin, including proteins and RNA. The purpose of this study was to explore the spin column to capture exosome and detect ALK alterations in exosomal RNA from blood.

      Method

      The supernatant of cell culture medium (H3122, H2228) and plasma samples from 3 patients with ALK-positive NSCLC were passed through the filter using a conventional centrifugation. Exosome captured in the filter was lysed with reagent for RNA extraction. The total RNA was retrotranscripted by random primers. The ALK rearrangement in the exosome were determined by RT-qPCR and DNA sequencing.

      Result

      EML4-ALK variant 1 and 3 were detected in exosome from 500μL of culture supernatant of H3122 and H2228, respectively. In the analysis of exosome in plasma from patients with EML4-ALK determined by fluorescence in situ hybridization and immunohistochemistry, EML4-ALK variant 1 was successfully detected in all cases.

      Conclusion

      Exosome remains relatively stable in the blood, making it an attractive target for liquid biopsy. Our preliminary results showed potential capability in the detection of ALK alteration in exosomes from blood. These findings require confirmation in further studies with a larger number of patients with ALK-positive NSCLC.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-23 - UHRF1 as a Potential Therapeutic Target for KRAS Mutated Non-Small Cell Lung Cancer (ID 687)

      10:15 - 18:15  |  Author(s): Yoshinori Hasegawa

      • Abstract

      Background

      KRAS mutation occurring in approximately 20% of non-small cell lung cancer (NSCLC) functions as a driver oncogene and it serves as a potential therapeutic target. However, development of KRAS-targeted drugs has not been successful primarily because of difficulty in pharmacologically inhibiting a constitutively activated KRAS signaling. Activation of several driver oncogenes including mutant KRAS in normal cells causes cellular senescence, leading to permanent cell cycle arrest, which is termed oncogene-induced senescence (OIS). Thus, KRAS mutated cancers are thought to acquire additional alterations that allow bypassing OIS and such alterations could be good targets for them. With this background, we designed the present study to identify therapeutic targets whose inhibition cause growth suppression in KRAS mutated NSCLC through inducing OIS.

      Method

      We established cdk4/hTERT-immortalized normal human bronchial epithelial cell (HBEC) that expresses mutant KRAS upon tetracycline treatment (designated HBEC-RIN). A semi-genome wide shRNA library (DECIPHER) targeting 5,000 genes was transduced in HBEC- RIN. Each shRNA vector is barcoded with unique sequence for quantification. Two weeks after culturing the cells, we extracted genomic DNA from cells at two points: before (point#1) and after (point #2) tetracycline treatment. The barcodes of DNA were sequenced with NGS at a depth of 20 million reads. The effects of senescence-bypass were determined by dividing the normalized barcode abundance at point #2 by that of point#1. The significance of change of each gene was determined by performing t-test to compare replicates of shRNA with a given gene with those of luciferase. Senescence was evaluated by senescence associated b-gal staining. Three KRAS mutated lung cancer cell lines (A549, H2009, and H460) were used to examine effects of silencing candidates of OIS-bypassing genes. Association between prognosis and expression of candidate genes in NSCLC patients was analyzed with several online datasets.

      Result

      We drew a volcano plot from results of a shRNA screen. We selected genes based on significant average suppressive effects. In the present study, we focused on Ubiquitin-like, containing PHD and RING finger domains, 1 (UHRF1) because we were able to confirm OIS-bypassing ability of this gene in HBEC-RIN by its transient silencing with synthetic siRNA. Colorimetric growth and colony formation assays showed that UHRF1 knockdown suppresses cell growth and colony formation in H2009 but not in A549 or H460. Importantly, we found that expression of UHRF1 mRNA correlated with worse prognosis in patients with NSCLC in multiple independent datasets, suggesting its potential as a prognostic marker.

      Conclusion

      These results suggest that UHRF1 is a potential therapeutic target for KRAS mutated NSCLC and that it is a prognostic marker for NSCLC.

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    P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.18-18 - Impact of Combined Evaluation Using Tumor Volume and Metastatic Nodal Extent in Stage III NSCLC Treated with CRT (ID 310)

      10:15 - 18:15  |  Author(s): Yoshinori Hasegawa

      • Abstract
      • Slides

      Background

      Chemoradiotherapy (CRT) is the standard treatment for patients with unresectable stage III non-small cell lung cancer (NSCLC). In those, gross tumor volume (GTV) and number of metastatic nodal stations were proposed as possible prognostic factors, while TNM stage classification (stage IIIA vs. stage IIIB/IIIC) did not show significant prognostic impact. However, these evidences remain controversial. The aim of this study was to investigate the prognostic impact of GTV and metastatic nodal extent.

      Method

      We retrospectively reviewed stage III NSCLC patients treated with CRT at our institution between October 2005 and December 2018. Simplified GTV (sGTV) was calculated by oval volume formula. We confirmed statistically significant association between sGTV and standard GTV as previous preparation. Metastatic nodal extent was divided into limited nodal extent (≤ND2a) (defined as "LN") or extensive nodal extent (>ND2a)(defined as "EN"). Prognostic impact of sGTV and metastatic nodal extent was evaluated by univariate and multivariate analysis.

      Result

      58 patients were enrolled in this study. Median progression-free survival (PFS) of all patients were 9.0 months. In univariate analysis, patients with sGTV>90cm3 had shorter PFS compared to those with sGTV≤90cm3 (median PFS: 6.7 vs. 11.7, p=0.03). Further, patients with sGTV>90cm3 and EN showed poorer PFS (HR 3.3; 95% CI,1.40-7.87; p<0.01) and OS (HR 3.3, 95% CI: 1.18-9.32, p<0.01) in univariate analysis. Multivariate analysis also showed an independent poor prognosis in patients with sGTV>90cm3 and EN (adjusted HR of PFS: 3.6, 95% CI: 1.49-8.71, p<0.01, adjusted HR of OS 4.1, 95% CI: 1.37-12.6, p=0.01).

      Conclusion

      Combined evaluation using sGTV and metastatic nodal extent can be a useful stratified factor for clinical trial in patients with stage III NSCLC.

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