Abstract 563: Combined treatment with PD-L1 blockade and a TLR7/8 agonist dramatically enhances antitumor immunity

Abstract

Abstract [Aim] Toll like receptor (TLRs) are expressed in many types of immune cells and function as a key sensor of microbial products. Ligand binding to TLRs leads to activation of signaling pathways in innate immune cells, particularly dendritic cells and subsequent induction of adaptive immune responses. TLR7/8 agonists have been shown to enhance antiviral and antitumor immune responses via multiple cytokine production such as IFN-α, IL-1β, IL-6 and TNFα. Resiquimod (R-848) is a synthetic imidazoquinoline-like molecule that binds to TLR7 and TLR8. Presently, resiquimod has been used as a topical drug for skin cancer and viral infection, because of severe side effects of systemic administration. Thus far, the clinical results of anti-PD-1 or anti-PD-L1 therapy have showed great benefits by inducing tumor regression and improving survival. However, the patients obtained the benefits of this treatment are around one third. An additional approach is required to enhance the efficacy of PD-1 blockade therapy. In this study, we examined the effects of combined treatment with anti-PD-L1 antibody and a low dose of resiquimod administration in two murine tumor models (a squamous cell carcinoma cell line, SCCVII and a colon carcinoma cell line, Colon26). [Methods] Anti-PD-L1 mAb (MIH5, 200 μg/mouse) and/or resiquimod (1.73 μg/mouse) were intraperitonealy administrated at three times a week and tumor growth was evaluated. [Results and Discussion] In a Colon26 model, either anti-PD-L1 (MIH5) mAb or resiquimod treatment alone slightly decreased tumor growth, but the combined treatment dramatically reduced the tumor growth and completely eradicated the tumor in some of mice. In a SCCVII model, monotherapy with resiquimod markedly reduced the tumor growth and completely eradicated the tumor in some of mice. The combined treatment further enhanced the efficacy. The delayed combined treatment at day 7 also showed the reduction of tumor size. Functional analyses at 3-4 wks after the tumor inoculation revealed that monotherapy with resiquimod in the SCCVII model and the combined treatment in both models significantly enhanced the percentages of IFN-γ+-expressing CD8+ T cells, but did not clearly affect the percentages of Foxp3+ regulatory T cells. Our results suggest that TLR7/8 agonist administration alone markedly enhanced antitumor responses in a selected tumor model and the combined treatment with PD-L1 blockade and a TLR7/8 agonist further amplify their effects. Citation Format: Naoto Nishii, Yuta Kondo, Lixin Li, Walter Lau, Hiroyuki Harada, Miyuki Azuma. Combined treatment with PD-L1 blockade and a TLR7/8 agonist dramatically enhances antitumor immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 563.