Trial watch: STING agonists in cancer therapy

Abstract

Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer

“…Based on these findings, we hypothesized that pharmacological activation of the cGAS/STING pathway would further augment PARP inhibitor-induced inflammatory signaling and consequent anti-tumor immune responses. We utilized the PARP inhibitor olaparib and the STING agonist ADU-S100, which has been shown to lead to potent anti-tumor immunity in multiple tumor models (9,10) and is currently in clinical trials (8).…”

“…Here, we have investigated an alternative approach to improving efficacy in BRCA-associated breast cancer by combining PARP inhibition with STING agonism. STING agonists have entered clinical trials and combinations with chemotherapy or immune checkpoint blockade have demonstrated preliminary safety and efficacy (8). In this study, we sought to develop the preclinical rationale for combining STING agonists with PARP inhibition.…”

The dark side of ferroptosis in pancreatic cancer

“…5 Similar, in addition to the chronic activation of the STING1 pathway that mediates genomic instability-induced tumorigenesis and metastasis, 6 the robust activation of the STING1 pathway by reagents (e.g., MSA-2, DMXAA, ADU-S100, and zalcitabine) or radiation therapy is an approach to enhance antitumor immunity or direct killing cancer cells in mouse models or clinical trials. [7][8][9] Acute activation of STING1-mediated T cell apoptosis may weaken anti-tumor immunity, 10 further arguing the dual role of STING1 in tumor therapy. Thus, it will be important to identify key DAMP mediators and to decipher the molecular mechanisms that explain reprogramming from immune activation to tolerance during tumor progression.…”

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

“…The nanoparticle-based delivery of the STING activator has also increased the antitumor immune response (increased M2 to M1 macrophage polarization, IFN-γ producing T cells, tumor cell apoptosis, and CD4 + and CD8 + T cell infiltration in the tumor microenvironment) in the PD-L1-insensitive triple-negative breast cancer ( 160 ). Different STING agonists are under phase I and II clinical trials ( 161 ). The results will determine their progression to the large phase III clinical trials.…”