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Minoru Fukuda



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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-015 - The Relationship between the UGT1A1*27 and UGT1A1*7 Genetic Polymorphisms and Irinotecan-Related Toxicities in Patients with Lung Cancer (ID 7500)

      09:30 - 16:00  |  Presenting Author(s): Minoru Fukuda

      • Abstract

      Background:
      Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1), UGT1A7, and UGT1A9 genes are associated with interindividual differences in irinotecan toxicities. Purpose: To evaluate the effects of gene polymorphisms, including UGT1A1*7, *27, and *29, on the safety of irinotecan therapy.

      Method:
      The eligibility criteria were as follows: lung cancer patients who were scheduled to undergo irinotecan therapy, aged ≥20 years, and had a performance status of 0-2. After informed consent had been obtained, patients were enrolled, and their blood was collected and used to examine the frequency of the UGT1A1*6, *7, *27, *28, and *29 polymorphisms and the drug concentrations of irinotecan, SN-38, and SN-38G after irinotecan therapy.

      Result:
      Thirty-one patients were enrolled. The patients’ characteristics were as follows: male/female = 25/6, median age (range) = 71 (55-84), stage IIB/IIIA/IIIB/IV = 2/6/11/12, and Ad/Sq/Sm/Oth = 14/10/3/4. The -/-, *6/-, *7/-, *27/-, *28/-, and *29/- UGT1A1 gene polymorphisms were observed in 10 (32%), 10 (32%), 2 (6%), 2 (6%), 7 (23%), and 0 (0%) cases, respectively. There were no homozygous or complex heterozygous polymorphisms. The UGT1A1*27 polymorphism occurred separately from the UGT1A1*28 polymorphism. The lowest leukocyte counts of the patients with the UGT1A1*27 and UGT1A1*6 gene polymorphisms were lower than those seen in the wild-type patients. SN-38 tended to remain in the blood for a prolonged period after the infusion of irinotecan in patients with the UGT1A1*27 or UGT1A1*28 polymorphism. No severe myelotoxicity was seen in the patients with UGT1A1*7.

      Conclusion:
      UGT1A1*27 and UGT1A1*7 are both rare gene polymorphisms. UGT1A1*27 can occur separately from UGT1A1*28 in some circumstances and is related to leukopenia during irinotecan treatment. UGT1A1*7 is less relevant to irinotecan-induced toxicities, and UGT1A1*29 seems to have little clinical impact.

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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: 2
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      P2.07-018 - Correlation of Clinical Response and XAGE1 Immunity in Lung Adenocarcinoma (ID 8446)

      09:30 - 16:00  |  Author(s): Minoru Fukuda

      • Abstract
      • Slides

      Background:
      Cancer/testis (CT) antigen is a class of antigens that express predominantly in the testes and various tumor types. Some CT antigens have been shown to be highly immunogenic and are considered to be attractive targets for cancer immunotherapy.　We identified XAGE1 as a dominant CT antigen in lung adenocarcinoma (LAD). In this study, we investigated the correlation of clinical response and XAGE1 immunity in LAD.

      Method:
      XAGE1 antigen expression and immune checkpoint molecules were determined with tumor tissues by immunohistochemistry. The XAGE1 antibody and T-cell immune responses, as well as immune cell phenotypes, were analyzed with blood samples.　The overall survival (OS) of the XAGE1 antigen-positive and -negative, and XAGE1antibody-positive and -negative patients were investigated.

      Result:
      The XAGE1 antigen is expressed in 30 to 40% of LAD. In pStage I-IIIA LAD, expression of the XAGE1 antigen was correlated with shortened OS in both Hokkaido (n=77) and Kawasaki (n=120) cohort, suggesting its relation to malignancy. Based on the expression profiles of XAGE1, and immune checkpoint molecules of PD-L1 and Galectin-9 on tumor cells, we developed a discriminant function capable of efficiently predicting OS in pStage I-IIIA LAD. The XAGE1 antibody response was observed 6% (9/155) in pStage I-IIIA, and 20% (34/167) in cStage IIIB-IV LAD, respectively, suggesting a higher antibody response rate in more advanced stage patients. In the antibody-positive patients, CD4 and CD8 T-cell responses were frequently elicited, and phenotypic and functional analyses of T cells indicated immune activation. Furthermore, we revealed that the OS of antibody-positive patients was prolonged significantly compared with that of antibody-negative patients with either XAGE1 antigen-positive EGFRwt (31.5 vs. 15.6 months, P = 0.05) or EGFRmt (34.7 vs. 11.1 months, P = 0.001) LAD. Multivariate analysis showed that XAGE1 antigen expression was a worse predictor in patients with EGFRmt tumors (HR: 5.23). On the other hand, the presence of the XAGE1 antibody was a strong predictor for prolonged OS in patients with XAGE1 antigen positive tumors (HR: 0.18) and in patients with either EGFRwt or EGFRmt tumors.

      Conclusion:
      Frequent antibody and T cell responses indicate the strong immunogenicity of the XAGE1 antigen. The findings suggest that production of XAGE1 antibody predicts good prognosis of lung adenocarcinoma patients as an immune biomarker and sheds light on the role of the protective effect of this naturally occurring immune response supporting the concept of immunotherapy.　

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      P2.07-045 - A Retrospective Analysis of Nivolumab-Related Pneumonitis in Non-Small Cell Lung Cancer Patients (ID 10051)

      09:30 - 16:00  |  Author(s): Minoru Fukuda

      • Abstract

      Background:
      Nivolumab is a human IgG4 monoclonal antibody that targets programmed cell death-1 (PD-1). In advanced non-small-cell lung cancer patients, nivolumab has been well tolerated. However, some patients develop nivolumab-related pneumonitis.

      Method:
      We retrospectively analyzed the clinical features and prognosis of nivolumab-related pneumonitis in non-small cell lung cancer patients in the institutions of the Nagasaki Thoracic Oncology Group.

      Result:
      From January 1, 2016 to May 31, 2017, 101 non-small cell lung cancer patients were treated with nivolumab monotherapy and 8 patients (7.9%) developed nivolumab-related pneumonitis. 7 were male, and 1 was female, with a median age of 70 years. The histological subtype was squamous cell carcinoma in 3 patients, non-squamous cell carcinoma in 5 patients. 6 patients were stage III or IV. 2 patients were postoperative recurrence. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 6 patients and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The median time from nivolumab treatment initiation to development of pneumonitis was 8.5 weeks (range, 1-16). 2 patients of AIP/ARDS pattern developed pneumonitis within 2 weeks. Bronchoalveolar lavage conducted in 4 patients and bronchoalveolar lavage fluid revealed elevation of lymphocyte in all patients. All patients received corticosteroids. 6 patients of COP pattern had clinical and radiographic improvement. 2 patients of AIP/ARDS pattern worsened clinically and died during the course of pneumonitis treatment. One of patient experienced recurrent pneumonitis in the course of corticosteroid taper.

      Conclusion:
      We retrospectively analyzed the clinical features and prognosis of nivolumab-related pneumonitis in non-small cell lung cancer patients. Nivolumab-related pneumonitis showed variable onset and radiographic patterns. COP pattern was most common. Most patients were successfully treated with corticosteroids, but AIP/ARDS pattern was risk of poor prognosis.