PET Measures Effects of STING-Activating Drugs
A study led by UCLA researchers suggest that PET imaging could provide a widely accessible approach to measure the pharmacodynamic effects of using stimulator of interferon genes, or STING, activating drugs. STING helps regulate immune activation and drugs that activate STING are being tested as a form of cancer immunotherapy and for treating certain infections. Findings from the study published in the Journal of Nuclear Medicine reveal previously unknown functional links between STING signaling and immunometabolism.
Oral and IV administration of STING-activating drugs stimulate potent anti-tumor responses in mouse models of cancer, suggesting this as a possible strategy for human therapy. Until now, however, researchers have not had a way to determine the magnitude, duration and location of immune activation. This research, led by UCLA Jonsson Comprehensive Cancer Center investigators, investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging.
Lab mice were treated with systemic STING agonists and later imaged with PET scans using standard ﬂuorodeoxyglucose (FDG) radiotracing. Immune cells from the spleen were analyzed by RNA sequencing and ﬂow cytometry. The amount of tracer in B and T lymphocytes was measured. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on tracer uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated.
Systemic delivery of STING-activating drugs in mice signiﬁcantly increased PET tracer uptake in the spleen. Analyses of immune cells indicated an increase of tracer in both T and B lymphocytes correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration signiﬁcantly delayed tumor growth and increased radiotracer uptake in secondary lymphoid glands. In addition to identifying previously unknown functional links between STING signaling and immunometabolism, the study suggests that readily available PET scanning could enable a whole-body analysis of the effects of systemic STING-activating therapy in humans. This could potentially provide a diagnostic tool guiding clinical development of this treatment approach.
“A new generation of STING agonists have broadened the available routes of administration to include systemic immune activation and are thus moving quickly in the clinical setting of cancer immunotherapy,” said co-ﬁrst co-author Hailey Lee, a graduate student in the laboratory of Dr Caius Radu, MD, a professor in the Molecular and Medical Pharmacology and Surgery Departments at UCLA and a member of the UCLA Jonsson Comprehensive Cancer Center.
Dr Radu, the article’s senior author, said, “Given that overstimulation of the immune system could lead to potential toxic side effects for STING agonists, signiﬁcant questions remain in regard to optimizing the correct dose and treatment schedule for individual patients. Our recent investigation into the identiﬁcation of a clinically applicable biomarker highlights PET as a readout for measuring STING agonist-induced immune activation in both the preclinical and clinical settings.”
Co-ﬁrst author Thuc Le, PhD, an adjunct professor of molecular and medical pharmacology at UCLA, added, “Such imaging tools can guide the dosing and scheduling of STING agonists to minimize the risk of immune overstimulation while still retaining therapeutic efﬁcacy. We hope our ﬁndings will impact the clinical application of STING agonists.”