Virtual Library
Start Your Search
K. Yamamoto
Author of
-
+
P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.02-051 - Bevacizumab Prevents Growth of Established Non-Small Cell Lung Cancer Brain Metastases in Hematogenous Brain Metastasis Model (ID 8165)
09:30 - 09:30 | Author(s): K. Yamamoto
- Abstract
Background:
Patients with non-small cell lung cancer are at high risk of developing brain metastases. The mainstay treatment for patients with brain metastasis is surgical excision, whereas radiation is used for multiple brain metastases. Regardless of the treatment, brain metastasis is associated with poor prognosis and the diminished quality of life. Here, we established experimental brain metastasis model allowed interrogation of the brain-specific requirements for cancer cell metastasis and evaluated antitumor efficacy of bevacizumab (BEV), a humanized monoclonal antibody targeting VEGF.
Method:
To produce brain metastases model, we transfected secreted NanoLuc (Nluc) genetic reporter vectors into NCI-H1915 cell line, which was established from a brain metastasis derived from a primary human lung carcinoma and injected into internal carotid artery of SCID mice with external carotid clamped with microclamp. Mice whose Nluc activities in plasma (Relative Light Unit; RLU/5μl) were detected 16 days after inoculation of NCI-H1915 cells were randomly allocated to control and BEV treatment groups (n=9). HuIgG or BEV (5 mg/kg) was intraperitoneally administered once a week (Day 1, 8, 15). Antitumor activity was evaluated by measuring Nluc activity (RLU/whole brain) in supernatant of brain parenchyma homogenized with cell lysis buffer on Day 22. Statistical analysis was performed using the Wilcoxon test.
Result:
Large metastatic nodules were macroscopically observed in brain on Day 22 in 6/9 mice in the control group, whereas those were not observed in any mice treated with BEV. Nluc activity in brain parenchyma homogenate (RLU, mean ± SD) in the BEV group (3.12E+9 ± 3.04E+9) was significantly lower than that in the control group (1.88E+10 ± 2.03E+10, p<0.05). Meanwhile, the weight of parenchyma (mg, mean ± SD) on Day 22 of control and BEV, was 417 ± 27.5 and 398 ± 15.6, respectively and there was no significant difference between them (p>0.05).
Conclusion:
In the secNluc-transfected H1915 hematogeneous metastasis model, BEV showed remarkable activity in reducing Nluc activity in brain parenchyma as well as emergence of visible legion. These results suggested BEV has efficacy against established hematogenous lung cancer brain metastasis lesions in the xenograft model and it may be one of the treatments for brain metastases from lung cancer.
-
+
P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P2.07-006 - Irinotecan Augmented Anti-Tumor Activity of Anti-PD-L1 through Enhancing CD8 Proliferation Regardless of Its Hematotoxicity (ID 7963)
09:30 - 09:30 | Author(s): K. Yamamoto
- Abstract
Background:
PD-L1 binds PD-1 and B7.1 on effector T cells to induce anergy and blockade of this interaction unleashes antitumor T-cell activity. Irinotecan, a topoisomerase 1 inhibitor, has been widely used for cancer treatment. Although there are numerous clinical studies evaluating combination of standard chemotherapeutic agents and PD-L1/PD-1 inhibitors, irinotecan has not yet been investigated so that there is little information about its compatibility. In this study, we investigated the efficacy of an anti-PD-L1 antibody in combination with irinotecan using mouse models and analyzed the mode of action.
Method:
Mice were inoculated with the syngeneic breast cancer cell line FM3A and anti-mouse PD-L1 antibody (10 mg/kg, anti-PD-L1) was intraperitoneally (i.p.) administered three times a week, and irinotecan (250 mg/kg) was i.p. administered once on the day of treatment initiation (day 1). The number and activation status of immune cells were analyzed by flow cytometry; the CD8+ cell localization in tumor tissue was assessed by immunohistochemistry. Tumor draining lymph nodes were assessed for tumor-specific immunity by an IFN-gamma release assay.
Result:
Despite a transient decrease of lymphocytes in peripheral blood on day 8, irinotecan augmented antitumor activity of anti-PD-L1 on day 19 (Tumor volume [mean ± SD]: Control = 2226 ± 829 mm[3]; anti-PD-L1 = 1265 ± 878 mm[3]; irinotecan = 1514 ± 775 mm[3] and Combination = 593 ± 558 mm[3]). On day 19, in the combination group tumors, a pathologically confirmed significant increase of CD8+ cells was observed vs each monotherapy group. Tumor cell-stimulated IFN-gamma release by lymph node cells was increased in the combination group and anti-PD-L1 group vs control group. Frequency of Ki67+ CD8+ cells in the combination group significantly increased vs each monotherapy group in both tumors and lymph nodes on day 8. Irinotecan was found to increase MHC I and PD-L1 expression on tumor cells and decrease Treg in both tumors and lymph nodes on day 4.
Conclusion:
The anti-tumor activity of anti-PD-L1 plus irinotecan was significantly higher than each agent alone regardless of initial hematotoxicity. Enhanced proliferation of CD8+ cells in both tumors and lymph nodes was considered to be one of the mechanisms of increased tumor specific CD8+ cells. In addition to direct cytotoxic effects on tumor cells, irinotecan increased MHC I and PD-L1 expression and decreased Tregs, which may contribute to combination effects with anti-PD-L1. The present study may provide a rationale to conduct clinical studies of anti-PD-L1 in combination with chemotherapy, especially irinotecan.
