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Hirotoshi Yasui



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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): Hirotoshi Yasui

      • 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): Hirotoshi Yasui

      • 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.