Combination of Immune Checkpoint Therapy with STING Targeted Therapy

Stimulator of interferon genes (STING), a transmembrane protein, is an essential DNA sensor and also an adaptor for other DNA sensors. Emerging evidence reported the roles of STING in tumorigenesis as well as tumor migration and metastasis. The activation of STING signaling provides an important immunosurveillance against tumor cells. STING is a novel and promising target for the development of targeted therapy for cancer. Several STING-targeted agents have been approved for clinical trials to assess their safety and efficacy in cancer therapy in humans.

Immune checkpoint inhibitors (ICIs) such as anti-CTLA-4 blockade and anti-PD-1/PD-L1 blockade are effective immunotherapy-based drugs for multiple types of cancer, which activate cancer-killing against cancer cells. Interestingly, several studies have reported that the combination of ICIs and targeted therapy could have a synergistic effect for cancer, with a long-lasting response and high response rate. Treatments with ICIs can counteract the upregulation of immune checkpoints induced by STING, enhance the efficacy of STING targeted tumor immunotherapy, and eventually lead to complete tumor regression and long-term immune memory of immunotherapy-resistant tumors.

Fig.1 Effect of STING agonist (S) and anti-PD-1 (P) or anti-CTLA-4 (C) on tumor microenvironment and anti-tumor immunity. (Yang, 2019)

Applications in Cancer Therapy

Although Lewis lung carcinoma (LLC) tumors were completely resistant to monotherapy with ICIs (anti-PD-1 or anti-CTLA-4), the combination of STING agonist with anti-PD-1 or anti-CTLA-4 showed improved anti-tumor efficacy compared with monotherapy, with a complete response rate >35%. Furthermore, LLC tumor cells treated with triple combination immunotherapy of STING agonist, ICI (anti-PD-1 or anti-CTLA-4), and anti-VEGFR2 on antitumor responses also showed a comparable synergistic anticancer effect, with complete tumor regression and improved overall survival.

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Reference

Yang, H.; et al. STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade. J Clin Invest. 2019, 129(10):4350-4364.

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