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Toshiki Iwai
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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: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-006 - Irinotecan Augmented Anti-Tumor Activity of Anti-PD-L1 through Enhancing CD8 Proliferation Regardless of Its Hematotoxicity (ID 7963)
09:30 - 16:00 | Presenting Author(s): Toshiki Iwai
- 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.
