Abstract A136: AST-008, a novel TLR9 agonist SNA, induces abscopal antitumor effects in mouse tumor models

Abstract

Spherical nucleic acids (SNA) are a novel class of therapeutic agents in which oligonucleotides are densely packed and radially arranged on the surface of liposomal nanoparticles providing a 3D-architecture. This architecture provides increased cellular uptake and nuclease stability compared to linear oligonucleotides that are not in SNA format. AST-008 is an SNA configuration of a Toll-like receptor 9 (TLR9) agonist that induces potent Th1-type immune responses in vitro, and in mice and nonhuman primates. Subcutaneous (SC), intratumoral (IT) and intravenous (IV) administration of AST-008 has shown potent antitumor activity as a monotherapy and enhanced checkpoint inhibitor (CPI) activity in a number of mouse tumor models. Our previous studies have shown that AST-008 induces potent innate and adaptive immune responses and increases tumor infiltrating lymphocytes, interferon-inducible gene expression, and activation and expansion of CD8+ T-cells with reduced T-regulatory cells in the tumor microenvironment facilitating increased effectiveness of CPI. In the present studies, we have evaluated i) sequence-specific antitumor effects of AST-008 following SC delivery in an EMT-6 breast tumor model, ii) abscopal antitumor effects of a murine version of the TLR9 agonist SNA following SC delivery in a two-flank EMT-6 tumor model, and iii) abscopal antitumor effects of AST-008 following SC and IT administrations in an MC38 colon cancer model. Treatment of EMT-6 breast tumors in mice with SC administration of AST-008 showed dose-dependent tumor growth inhibition that was statistically significant compared with vehicle-treated tumor-bearing mice. A control oligonucleotide-SNA had no effect on tumor growth compared with the vehicle group. In a two-flank EMT-6 breast tumor model, SC administration of TLR9 agonist SNA showed about 59% and 37% tumor growth inhibition at the injected and distant tumors, respectively, compared to the vehicle-treated mice. The tumor growth inhibition was statistically significant at both the injected and uninjected tumors compared to vehicle-treated tumor-bearing mice. In a two-flank MC38 colon cancer model, either SC or IT administration of AST-008 resulted in 69% and 68% tumor growth inhibition, respectively, at the injected tumor. In this study, distant tumor that was not treated with AST-008 showed 59% and 46% tumor growth inhibition for SC and IT routes of administration, respectively. The tumor growth inhibition at both the treated and untreated tumors was statistically significant compared to the vehicle-treated tumors. These data demonstrate sequence-specific antitumor activity of AST-008 and that SC or IT administration at one tumor lesion leads to systemic antitumor activity at distant uninjected tumors. The current results, together with our previous studies in combination with CPI in several tumor models, support the potential utility of the TLR9-mediated innate immune stimulator AST-008 in combination with CPI in cancer patients. AST-008 is currently in clinical development. Citation Format: Ekambar R. Kandimalla, SubbaRao Nallagatla, Bart R. Anderson, Richard Kang. AST-008, a novel TLR9 agonist SNA, induces abscopal antitumor effects in mouse tumor models [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A136.