Buzz Continues Over STING Agonists

Pharmaceutical companies around the world are beginning clinical trials with STING (stimulator of interferon genes) agonists. The goal is to come up with orally bioavailable, non-nucleotide modulators of the STING pathway in order to combat cancer in a whole new way. Several companies have phase I and II studies planned for 2018 and others are developing various compounds and even STING agonist cancer vaccines.

It is believed that this approach can help T cells thrive and work synergistically with other cancer therapies. Testing is underway to see if these agents can be used in conjunction with checkpoint inhibitors to boost the number of cancer patients who respond.  

In 2013, Zhijian “James” Chen, MD, who is a professor of molecular biology and a Howard Hughes Medical Institute investigator at the University of Texas (UT) Southwestern Medical Center in Dallas, Texas, and colleagues identified a new sensor of innate immunity (the enzyme cyclic GMP-AMP synthase (cGAS)).  They discovered that cGAS sounds a cellular alarm when it encounters DNA in the cytoplasm. After the enzyme detects and binds to the DNA, it catalyzes the formation of a compound called cyclic GMP-AMP (cGAMP), which functions as a second messenger that binds to an adaptor protein called STING.

Since that report, significant advances have occurred. Trials are underway and STING agonist vaccine trials are in the planning stage. It is theorized that STING agonists can activate interferon genes, allowing an individual to produce additional interferon alpha and beta. Investigators are looking at whether antibody-based checkpoint inhibitors, such as pembrolizumab and nivolumab, may be combined with a STING agonist to improve outcomes in significantly more patients than currently respond to checkpoint-inhibitor therapy. Dr. Chen said that in mouse tumor models, activation of the cGAS-STING pathway has been shown to have significant antitumor effects, especially when combined with immune checkpoint blockade. “This approach has the potential to turn ‘cold’ tumors into ‘hot’ tumors, allowing some patients that are refractory to immune checkpoint inhibitors to respond to these treatments,” Dr. Chen told Cancer Network.

He said STING agonists may be helpful with many different tumor types. However, he said the final answer to the types of tumors that are most responsive to targeting the STING pathway awaits clinical testing. It is hoped that oral STING modulators will not only treat cancers but infectious diseases as well. Dr. Chen and his team currently are working with physicians at UT Southwestern to explore clinical testing of STING-activating nanovaccines for a variety of cancer indications.

“I think this is a promising approach. How well it will work in the clinics depends on the therapeutic window, the balance between efficacy and safety. Activating the STING pathway will certainly enhance antitumor immunity, but it can also have side effects by activating inflammatory responses and potentially autoimmunity,” cautioned Dr. Chen.