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M. Isobe
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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
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-015 - Reviving Chemotherapy Sensitivity after Anti-CCR4 mAb (Mogamulizumab) Treatment in Lung Cancer Patients (ID 8240)
09:30 - 09:30 | Author(s): M. Isobe
- Abstract
Background:
Patients with advanced lung cancer have poor survival, although they have received multidisciplinary therapy. Therefore, the novel effective therapy is needed. In various malignancies, tumor cells escape the host immune defenses, in which regulatory T cells (Tregs) play an important role. Tregs, maintaining self-tolerance and homeostasis in the immune system, suppress antitumor immune responses in cancer patients. Thus, Tregs are crucial in controlling antitumor immune responses. Several clinical studies show that a number of Tregs at tumor site was correlated with poor prognosis and Tregs suppress the antigen-specific T-cell induction in immunotherapy. Therefore, controlling Treg functions is probably promising immunotherapy. The study of adult T-cell leukemia-lymphoma (ATL) revealed that Tregs strongly express CCR4 molecule of a CC chemokine receptor on their surface. The humanized anti-human-CCR4 monoclonal antibody (mogamulizumab) recognizes CCR4 molecule and shows a robust ADCC activity against CCR4-positive cells such as Tregs. Thus, Tregs depletion by mogamulizumab probably enhances the host immune response against the tumor. We recently finished the clinical trial of mogamulizumab treatment in advanced solid cancer, and the monitoring of Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used.
Method:
In this study, we analyzed the response against chemotherapy before and after mogamulizumab treatment in 6 advanced lung cancer patients who were enrolled in the clinical trial. In 3 of those patients, we analyzed the number of immune cells (CD3 T cells and CCR4[+/-] FoxP3[+]Tregs) and expression of PD-L1 (SP142) on tumor cells in lung cancer tissues by immunohistochemistry at diagnosis and after mogamulizumab treatment.
Result:
Although the patients finished standard chemotherapy and therefore were to be refractory, 4 of 6 patients showed the partial response (PR) in chemotherapy after mogamulizumab treatment. While 2 of 6 patients showed PR in chemotherapy before mogamulizumab. In 3 of those patients, we observed efficient depletion of CCR4[+]FoxP3[+]Tregs after mogamulizumab treatment in all patients, while CCR4[-]FoxP3[+]Tregs were detected in lung cancer tissues. In 2 PR patients in chemotherapy after mogamulizumab treatment, we observed increased number of CD3 and PD-1[+]cells. In one patient, increased PD-L1 expression on tumor cells was observed. On the other hand, in one SD patient in chemotherapy after mogamulizumab, the number of CD3, PD-1[+] cells, and expression of PD-L1 on tumor cells were decreased.
Conclusion:
Treg depletion by mogamulizumab may induce inflamed tumor microenvironment in some lung cancer patients, and result in reviving chemotherapy sensitivity.
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P2.07-018 - Correlation of Clinical Response and XAGE1 Immunity in Lung Adenocarcinoma (ID 8446)
09:30 - 09:30 | Author(s): M. Isobe
- Abstract
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.
