Stimulator of interferon genes (STING) is a critical component of an innate immune pathway that activates robust antiviral and antitumor responses in mouse models. Activation of the STING pathway by intratumoral (IT) injection of synthetic cyclic dinucleotides (CDNs) is being explored as a cancer therapy and has shown potent antitumor activity in preclinical models. Here we assessed the benefit of combining immune checkpoint blockade with ADU-S100 (MIW815), a CDN under clinical evaluation, in different syngeneic mouse tumor models. In mice bearing dual flank 4T1 mammary carcinoma tumors resistant to anti-PD-1 treatment, adding a single dose of ADU-S100 with anti-PD-1 induced eradication of both injected and noninjected tumors, leading to near-complete responses, demonstrating that ADU-S100 potentiates the activity of checkpoint blockade. Tumor control was CD8+ T cell-dependent and correlated with an enhanced CD8+ T-cell effector profile in both the periphery and in noninjected tumors. Combining a single injection of ADU-S100 with anti-PD-1 also elicited enhanced tumor control in the dual flank MC-38 colon carcinoma model compared to ADU-S100 or anti-PD-1 treatment alone. Those mice cured by combination treatment were also protected from tumor rechallenge. Moreover, in the poorly immunogenic B16.F10 model, adding ADU-S100 to the ineffective combination therapy of anti-PD-1 and anti-CTLA-4 induced tumor-specific CD8+ T-cell responses and tumor control, leading to multiple complete responses and durable immunity in surviving animals. Together, these results highlight the immune correlates of STING-mediated antitumor efficacy and illustrate the potential of combining ADU-S100 with checkpoint inhibitors for the treatment of human cancer. Clinical trials of ADU-S100 in combination with anti-PD-1 or with anti-CTLA-4 are ongoing and could further elucidate the immunologic mechanism of action and therapeutic effect in humans.

This abstract is also being presented as Poster B47.

Citation Format: Weiwen Deng, Anthony L. Desbien, Kelsey Sivick Gauthier, Gabrielle Reiner, Leticia Corrales, Tamara Schroeder, Laura Hix Glickman, Natalie H. Surh, Brian Francica, Justin J. Leong, Ken Metchette, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, Steven L. Bender, Chudi Ndubaku, Meredith L. Leong, Andrea van Elsas, Sarah M. McWhirter. ADU-S100 (MIW815) synergizes with checkpoint blockade to elicit an antitumor CD8+ T-cell response to control distal tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR09.