ADU-S100

Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. This approach may be particularly effective in tumors that are already infiltrated by inflammatory cells in the TME but are evading immune detection via HLA-I downregulation.

This study evaluated whether combining a cationic plant-derived nanoparticle adjuvant (Nano-11) with the clinically tested STING agonist ADU-S100 (MIW815) could stimulate anticancer immunity by intradermal vaccination...Therapeutic vaccination with NanoST increased mouse survival by inhibiting B16-OVA tumor growth, and this effect was further enhanced by PD-1 checkpoint blockade. Our study provides a strong rationale for developing NanoST as an adjuvant for intradermal vaccination and next-generation preventative and therapeutic cancer vaccines by STING-targeted activation.

An alternative phosphorothioate (referred to as endo-S-phosphorothioate) whereby the sulfur atom is endo to the cyclic phosphate ring (i.e. 5'-S-phosphorothioester linkage) would not have chirality at phosphorus and hence not pose diastereomer separation problems. Herein, we report the design and synthesis of novel 5'-endo-phosphorothioate substituted 2'3'cGAMP analogues that are hydrolytically stable towards both ectonucleotide phosphodiesterase I (ENPP1, a mammalian phosphodiesterase) and poxvirus immune nucleases (poxin, a phosphodiesterase in Poxvirus) but retains STING-TBK1-IRF activation, comparable to clinical candidate, ADU-S100 in THP1 monocytes.

Interestingly, some of our synthesized LNA 3'3'-endo-S-CDNs can moderately activate hSTING REF haplotype (R232H), which exhibit diminished response to both 2'3'-cGAMP and ADU-S100. Also, we show that one of our most potent endo-S-CDNs has remarkable chemical (oxidants I2 and H2O2) and phosphodiesterase stability.

Furthermore, uniSTING displays an effective antitumour response superior to 2'3'-cGAMP and ADU-S100...Extracellular vesicles released from uniSTING-treated tumour cells further sensitize dendritic cells via exosome-containing miRNAs that reduced the immunosuppressive Wnt2b, and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibits tumour growth and prolongs animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.

We hypothesized that combined treatment of melanoma-bearing mice with STING agonist ADU-S100 together with antagonists of regulatory ISGs would result in improved control of tumor growth vs. treatment with ADU-S100 alone...Immune changes in the TME associated with improved treatment outcomes were subtle but included increases in proinflammatory innate immune cells and activated CD8+CD69+ T cells and varied between the two tumor models. These data suggest contextual differences in the relative contributions of individual regulatory ISGs that serve to operationally limit the anti-tumor efficacy of STING agonists which should be considered in future design of novel combination protocols for optimal treatment benefit.

Moreover, IFN-α and CXCL10 production by in vitro stimulated (i.e. with R848, CpG-A, ADU-S100) pDCs exposed to melanoma cell lines supernatants (SN-mel) was tested by intracellular flow cytometry and ELISA...Melanoma-derived immunosuppressive cytokines and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape. These findings propose a new window of intervention for novel immunotherapy approaches to amplify the antitumor innate immune response in cutaneous melanoma (CM).

In THP1-Lucia cells, prodrug 9 also retained a high bioactivity with the EC of 0.96 μM, which was 51-, 43-, and 3-fold more than the 2',3'-cGAMP (EC = 48.6 μM), the parent compound 3',3'-c-di-dAMP (EC = 41.3 μM), and ADU-S100 (EC = 2.9 μM)...Furthermore, prodrug 9 could also improve the transcriptional expression levels of IFN-β, CXCL10, IL-6, and TNF-α in THP-1 cells. These results will be helpful to the development of chemically controllable CDN prodrugs with a high cellular permeability and potency.

Of particular interest, 2'3'-c-di-AM(PS)(Rp,Rp) reduces IL-17A production and IL23R expression by human T17 cells while it favors the generation of regulatory T (T) cells. These findings suggest that STING agonists may be promising approaches for treating human T17-mediated chronic inflammation.

In this study, we investigated the immunotherapeutic effects of ADU-S100 as a STING agonist and CpG ODN1826 as a TLR9 agonist in a preclinical model of colon carcinoma. Remarkably, the significant downregulation of CAFs in the TME indicated that suppression of tumorigenesis occurred after immunoadjuvant therapy. The results illustrate the potential of targeting the STING and TLR9 pathways as powerful immunoadjuvants in the treatment of preclinical colon carcinoma and the possibility of harnessing these pathways in future therapeutic approaches.

In vitro, acyloxymethyl phosphate/phosphonate prodrugs of these vinylphosphonate CDNs were up to 1000-fold more potent than the clinical candidate ADU-S100...Moreover, we solved the crystal structure of this ligand bound to the STING protein. Therefore, our findings not only validate the therapeutic potential of vinylphosphonate CDNs but also open up opportunities for drug development in cancer immunotherapy bridging innate and adaptive immunity.

While ADU-S100 led to an ulcerative pathology at the injection site, no other adverse effects were observed. Localised administration of a STING agonist together with cyto-IL-15 can confer significant systemic benefits and long-lasting immunity against prostate tumors while reducing immune related toxicities.

In the dual flank syngeneic mouse tumor model, CT26 cells were implanted on both sides of a mouse, and then one tumor was injected with reovirus, ADU-S100, or reovirus and ADU-S100, while the other tumor remained untreated... We demonstrated the ability of oncolytic reovirus to induce tumor regression in a CT26 syngeneic tumor model and showed that the combination treatment of reovirus and a STING agonist enhanced antitumor immunity. This enhanced antitumor response was partially mediated by IFN-induced T cell activation. Although further investigation is required to clarify the mechanism underlying the synergy between STING agonist and reovirus in promoting immune responses and anti-tumor activity, our combination treatment strategy may have potential as an immunotherapy against colorectal cancer.

NP-AS induced tumor cell apoptosis/necrosis, activated the innate immune response and exhibited useful antitumor effects. NP-AS effectively treated breast cancer.

No abstract available

In this study, we developed liposomes encapsulating oxaliplatin and combine this formulation with a STING agonist (ADU-S100) for treating colorectal cancer...Mechanistic studies showed this potent anti-cancer effect was related to the significant recruitment of infiltrating CD8 and CD4 T cells, reduction of suppressive Treg cells, and a shift in the phenotype of tumor-associated suppressive macrophages that promote cancer to immune stimulating macrophages. Thus, our study demonstrated the potential of combining oxaliplatin-loaded liposomes with a STING agonist to reduce tumor growth by regulating the immunosuppressive state in the tumor.

Rab7 CRISPR-Cas9 knockout or treatment of MDA-MB-231 cells with CID1067700 and the STING agonist (ADU-S100) impaired trafficking of STING for lysosomal degradation, upregulated T cell chemokines, and enhanced growth inhibition...We found that the enhanced CXCL10 levels resulting from addition of CID1067700 to MDA-MB-231 cells led to T-cell recruitment to the tumor spheroids. Taken together, our study identifies PTEN null status as a specific genomic context in TNBC that has exquisite sensitivity to STING agonist therapy and combination with Rab7 inhibition could amplify therapeutic STING agonism in PTEN wild-type TNBCs.

Both mechanisms of eribulin-mediated activation of interferon expression occur in immune and TNBC cells and are shared with other microtubule destabilizers but not with the microtubule stabilizer paclitaxel. Our current studies demonstrate the in vivo immunological effects of the microtubule destabilizer eribulin with the STING agonist ADU-S100 that lead to a significant decrease in tumor growth in the spontaneous MMTV-PyVT mammary tumor model upon combination treatment...Together, these data contribute to accumulating evidence that there are important mechanistic differences between the microtubule targeted chemotherapeutics currently used in the treatment of TNBC that could inform on their more rational use in the clinic as single agents or as chemotherapeutic backbones in combination with targeted therapy, including immunotherapeutics. More specifically, our data demonstrate that eribulin can act as an immune adjuvant to promote STING signaling and T-cell activation in multiple in vivo TNBC models in addition to its well established anti-mitotic effects to enhance antitumor efficacy.

Theise data demonstrates that ADU-S100 was able to activate the STING pathway in MPNST cell lines leading to proinflammatory cytokine/chemokine production. We will next test STING agonist in vivo use to determine whether ADU-S100 treatment inin mouse MPNST modelss of MPNST to is able to reprogram the tumor microenvironment into an immune inflamed one amenable to immunotherapy.

In vitro studies in cultured GBM cell lines and normal cells found in the GBM TME such as human cerebral microvascular endothelial cells (HCMECs) in the presence of ADU-S100 showed a robust type I IFN response in endothelial cells but not in tumor cells...In conclusion, STING agonists are promising agents for local immunostimulation in GBM, and their activity may be enhanced by combination with manganese. Ongoing experiments are aimed at elucidating mechanistic insights into these concepts.

Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin's ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies.

The combination of MIW815 and spartalizumab, was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal anti-tumor responses were seen.

We also evaluated their activation of STING following stimulation with the STING agonist ADU-S100...Conclusions We have shown that although epigenetic silencing of STING in melanoma cells can confer resistance to STING agonist therapy, a rational combination of a clinically available DNA methylation inhibitor with a STING agonist can reverse this silencing and lead to robust antitumor responses in the setting of two STING low murine models of melanoma. Therefore, identification and pharmacologic restoration of tumor cell-intrinsic STING defects through epigenetic reprograming might be critical for the successful use of STING agonists in the clinic.

Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100...Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade.

Compared to the clinical CDN STING agonist ADU-S100, SHR1032 has much higher activity in human cells with different STING haplotypes and robustly induces interferon β (IFNβ) production...More importantly, we found SHR1032 directly causes cell death in acute myeloid leukemia (AML) cells. In conclusion, our findings demonstrate that in addition to their established ability to boost anti-tumor immune responses, STING agonists can directly eradicate AML cells, and SHR1032 may present a new and promising therapeutic agent for cancer patients.

Induction of immunosuppressive M-MDSCs by ADU-S100 or BCG-WT suggests unique advantages of BCG-STING. The therapeutic targeting of M-MDSCs as combination may improve therapeutic efficacies of BCGs.

Here, we report that reduction-responsive biodegradable chimaeric polymersomes (CPs) markedly enhance tumor retention and cytosolic delivery of a synthetic CDN, ADU-S100, and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes, giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control. The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation, which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge. The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.

The varying therapeutic outcomes of IT vs IV treatment regimens of ADU-S100 over BCG-STING or BCG-WT in different urothelial carcinoma models suggest the important role of varying tumor microenvironment and dosing regimens on relative antitumor efficacy. Increased percentage of immunosuppressive M-MDSCs specifically in response to ADU-S100 or BCG-WT suggests unique advantages associated with BCG-STING.

To date, only two early clinical trials of the STING agonist ADU-S100 in combination with checkpoint inhibitors are underway (NCT02675439 and NCT03172936)...Preclinical studies indicate that STING agonists, used as adjuvants in combination with other agents or radiation therapy, suppress tumor progression, reduce cellular toxicity, and eliminate metastases in breast and pancreatic cancer models. Phenotypic assays that provide human, translational data early in discovery are a valuable tool to accelerate progress in this area.

Furthermore, combination treatment of VPS34 inhibitor SB02024 with STING agonist ADU-S100 or cGAMP increased the mRNA expression and release of proinflammatory cytokines in human and murine RCC and melanoma cancer cell lines...Taken together, our data demonstrates that targeting of VPS34 results in a cGAS/STING-mediated increase of pro-inflammatory cytokine secretion and synergizes with a STING agonist. We believe that systemic VPS34 inhibition using SB02024 would be of major interest in combination or as an alternative to STING agonists to improve anti-tumor immune responses.

In in vitro experiments, combined olaparib-mediated PARP inhibition and ADU-S100-mediated STING agonism induced a greater degree of STING pathway activation and proinflammatory cytokine production compared to monotherapies in BRCA1-deficient human MDA-MB-436 cells and mouse triple-negative breast cancer cell lines derived from a genetically engineered model of BRCA-deficient breast cancer. Finally, in mice treated with the combination, tumors could not be re-established upon rechallenge, indicating the induction of immunologic memory. These results support the development of combined PARP inhibition and STING agonism in BRCA-associated breast cancer.

P1, N=47, Terminated, Chinook Therapeutics, Inc. (formerly Aduro) | Active, not recruiting --> Terminated; No substantial anti-tumor activity was observed.

MIW815 was well tolerated in patients with advanced/metastatic cancers. Clinical activity of single-agent MIW815 was limited in this first-in-human study, however, evidence of systemic immune activation was seen.

Combined treatment of melanoma-bearing mice with STING agonist ADU-S100 along with immune regulatory inhibitors (ARGi, NOSi, Celecoxib) slows tumor growth vs. individual monotherapies and is expected to extend overall survival. Conclusions Combination of STING agonism with inhibitors of various immune regulatory molecules (ARG2, COX2) has the potential to improve the anti-tumor benefits of STING agonism alone.

This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.

STING activation can normalize the peritoneal vascular and immune microenvironment, providing a rationale for a novel combination therapeutic strategy for peritoneal carcinomatosis in colon cancer.

Due to the success of immunotherapies in treating other cancers, this treatment modality has been investigated for Prostate cancer, however, the sole FDA approved immunotherapy so far (Provenge™) only extends life by a few months. NK cells are responsible for killing of the cancer cells, as shown by a lack of cytotoxicity in NK depleted lymphocyte-tumor cell co-cultures, or in co-cultures of B and T cells with tumor cells. In summary, we propose that the combination of IL-15 and the sting agonist ADU-S100 analog may be potently effective in treatment of prostate cancer.

P2, N=16, Active, not recruiting, Chinook Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=33 --> 16 | Trial completion date: Jan 2022 --> Dec 2022 | Trial primary completion date: Dec 2020 --> Dec 2022