Abstract 4130: Anti-cancer efficacy of systemic and Intratumoral YS-ON-001 as monotherapy or in combination with checkpoint inhibitor in syngeneic cancer models
Authors: Zhongkai Shi, Yuan Liu, Yi Zhang
Journal: Cancer Research (2019)

Abstract Background: YS-ON-001 is a complex containing synthetic double-strand RNA, a toll-like receptor 3 (TLR3) agonist. TLR3 agonist stimulates antigen-presenting cells, increases T, NK, NKT cells and decreases regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), reprogrames macrophages from protumorigenic to anti-tumor. YS-ON-001 is being evaluated for systemic and intratumoral use alone or combined with checkpoint inhibitor to treat cancer. Method: The anti-tumor efficacy of systemically or intratumorally (it) injected YS-ON-001 alone or in combination with PD-1 antagonist was assessed in several syngeneic tumor models including pancreatic cancer, hepatocellular carcinoma. Tumors were implanted into left and/or right flanks while only one tumor was injected with YS-ON-001. YS-ON-001 was administered by IM injection every other day or it injection twice a week. Murine PD-1 antibody was infused intraperitoneally (ip) once a week. In addition to body weight, tumor volume was monitored on both flanks. Surviving mice with unnoticeable tumor were rechallenged. Flow cytometry was used to analyze immune cells from the tumors including T, NK, NKT cells, macrophages 1 and 2, Tregs, and MDSCs. Results: Within tumor microenvironment YS-ON-001 IM monotherapy resulted in increased infiltration of CD4+ T cells and CD8+ T cells, NK cells and NKT cells, reduced Tregs and MDSCs, and increased the M1/M2 ratio, leading to significant tumor growth inhibition in more than 10 cancer models. Combination of YS-ON-001 im with anti-PD1 ip resulted in greater anti-tumor efficacy compared to anti-PD1 monotherapy in both 4T1 breast cancer and LLC2 lung cancer models. Rejecting tumor rechallenge in surviving mice from the initial challenge treated with IM YS-ON-001suggested long-term anti-tumor immunity. Monotherapy of YS-ON-001 it or anti-PD-1 ip significantly suppresses tumor growth not only at the primary injection site, but also at uninjected site (p&amp;lt;0.05). Combination of YS-ON-001 it with anti-PD-1 ip significantly enhanced suppressive effect of anti-PD1 at both primary injected and distant uninjected sites. Conclusions: these experiments demonstrated systemic or intratumoral delivery of YS-ON-001 can modulates immune responses in tumor microenvironment by increasing anti-tumor cells in T, NK, NKt cells and decreasing pro-tumor cells in Treg, MDSC, leading to significant tumor growth inhibition. Combination of YS-on-001, IM or It with PD-1 antibodies significantly enhanced the anti-tumor efficacy of PD-1 antibodies. These results provide a strong rationale and support clinical development as standalone therapy or in combination with other modalities such checkpoint inhibitors. Citation Format: Zhongkai Shi, Yuan Liu, Yi Zhang. Anti-cancer efficacy of systemic and Intratumoral YS-ON-001 as monotherapy or in combination with checkpoint inhibitor in syngeneic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4130.