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Mikihiro Kohno

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    OA 02 - Mesothelioma: Challenges For New Treatment (ID 653)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Mesothelioma
    • Presentations: 1
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      OA 02.06 - Radioimmunotherapy Combining CTLA-4 Blockade or Low-Dose Cyclophosphamide with Local Radiation in Murine Malignant Mesothelioma (ID 8843)

      11:00 - 12:30  |  Presenting Author(s): Mikihiro Kohno

      • Abstract
      • Presentation
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      Our group has developed a new approach focusing on Surgery for Mesothelioma After Radiation Therapy (SMART), with encouraging results in a phase I/II clinical trial. The impact on the immune system of high-dose hypofractionated radiation therapy is expected to open the door for new combination therapy of immunotherapy and radiation to optimize their synergism on the immune system. The aim of this study is to investigate the antitumor effect of non-ablative hypofractionated radiation combined with anti-CTLA-4 antibody (a-CTLA-4) or low-dose cyclophosphamide (LD-CTX) in murine malignant mesothelioma model.

      Balb/c mice were subcutaneously injected with murine mesothelioma AB12 cells into the left flank on day 0 (primary tumor) and into the right flank on day 7 (secondary tumor). Local radiotherapy (LRT) 5 Gy was delivered to primary tumor once daily for 3 consecutive days (total dose: 15 Gy). Mice were randomized into six groups: (1) No treatment, (2) LRT, (3) a-CTLA-4, (4) LRT+a-CTLA-4, (5) LD-CTX, (6) LRT+LD-CTX. We assessed local and abscopal effects by measuring primary and secondary tumor growth. Furthermore, CD4+ and CD8+ T cell proportion in tumor, spleen and peripheral blood were determined by flow cytometry.

      Mice treated with LRT+a-CTLA-4 and LRT+LD-CTX showed the most significant deceleration in primary tumor growth compared to the other 4 groups. Both combination groups showed similar antitumor effects on the primary tumor. The secondary tumor growth tested the abscopal effect tended to be decreased in mice treated with LRT and LRT+a-CTLA-4 or LRT+LD-CTX compared to untreated mice, but the difference was not significant. Quantification of tumor-infiltrating T cells by flow cytometry showed that the percentages of total T cells, and CD4+ and CD8+ T cells in the primary tumor were increased in the combination groups.

      Combination of LRT and immunotherapy showed synergistic antitumor effects in controlling irradiated-tumor growth. CTLA-4 blockade and LD-CTX might be good candidates in combination with radiotherapy.

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