- |||||||||| ADU-S100 / Novartis
Mannose-chitosan nanoparticle surface adsorbed inactivated influenza virus vaccine elicits cross-protective humoral immunity in pigs (Exhibit Hall F1; Poster Board Number: B1027) - Mar 29, 2024 - Abstract #IMMUNOLOGY2024IMMUNOLOGY_1327;
We developed whole inactivated SwIV H1N2 based mannose-chitosan nanoparticle (mChit-SwIV-NP) vaccine containing STING (stimulator of interferon gene) adjuvant ADU-S100, either both encapsulated (mChit-SwIV+S100-eNP) or surface adsorbed (mChit-SwIV+S100-sNP)...In summary, intranasal mChit-SwIV+S100-sNP vaccine elicited cross-reactive antibody while mChit-SwIV+S100-eNP vaccine induced mucosal and systemic cell-mediated immune responses higher than commercial SwIV vaccinates. Suggesting that mannose-chitosan nanoparticle vaccine has a promise in mitigating SwIV infections and transmission in swine herds.
- |||||||||| ADU-S100 / Novartis
Journal, IO biomarker: Mn-phenolic networks as synergistic carrier for STING agonists in tumor immunotherapy. (Pubmed Central) - Mar 22, 2024
In this study, we present Mn-phenolic networks as a novel carrier for ADU-S100, a hydrophilic STING agonist, aimed at bolstering immunotherapy...This includes the promotion of cytokine release, dendritic cell maturation, and T cell infiltration, leading to pronounced suppression of tumor growth. Combining with the excellent biocompatibility and biodegradability, this Mn-based nanocarrier represents a promising strategy for enhancing tumor immunotherapy through the cGAS-STING pathway.
- |||||||||| ADU-S100 / Novartis
Journal: Universal STING mimic boosts antitumour immunity via preferential activation of tumour control signalling pathways. (Pubmed Central) - Mar 14, 2024
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 ?-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.
- |||||||||| ADU-S100 / Novartis
Role of major facilitative folate transporters SLC19A1 and SLC46A1 in cyclic dinucleotide transport and STING signaling (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_8068;
was seen in THP-1 and R1-11/Tet-on-RFC cells by ADU-S100 treatment at pH 7.2 (RFC pH optimum) in the presence of 25 nM leucovorin...In conclusion, RFC mediates ADU-S100 uptake and STING activation under physiologic conditions and this process is enhanced by concomitant expression of PCFT. Additional characterization of key molecular and biochemical determinants of CDN-based cancer therapeutics may lead to improved approaches for CDN therapy based on enhanced cellular uptake.
- |||||||||| ADU-S100 / Novartis
Journal, PD(L)-1 Biomarker, IO biomarker: Antagonism of regulatory ISGs enhances the anti-melanoma efficacy of STING agonists. (Pubmed Central) - Feb 9, 2024
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.
- |||||||||| ADU-S100 / Novartis
Journal, IO biomarker: A clinically-relevant STING agonist restrains human T17 cell inflammatory profile. (Pubmed Central) - Nov 3, 2023
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.
- |||||||||| ADU-S100 / Novartis
Journal: Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy. (Pubmed Central) - Aug 22, 2023
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.
- |||||||||| ADU-S100 / Chinook Therap
HAQ and AQ STING/MPYS Are Resistant to STING-Mediated T Cell Death (Walter E. Washington Convention Center, Area A, Hall C (Lower Level)) - Mar 25, 2023 - Abstract #ATS2023ATS_4623;
Spleen cells are treated with STING agonists DMXAA, RpRp-ssCDA (ADU-S100), and diABZi for 4 hours or overnight in culture...Conclusions. The HAQ and AQ-STING are resistant to T cell death and may be protected from SAVI disease.
- |||||||||| ADU-S100 / Chinook Therap
Targeting Rab7-mediated STING degradation to amplify therapeutic STING agonism in TNBC (Section 25; Poster Board #18) - Mar 14, 2023 - Abstract #AACR2023AACR_8556;
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.
- |||||||||| Halaven (eribulin mesylate) / Eisai
Eribulin acts as an immune adjuvant to enhance the antitumor efficacy of STING agonists in triple-negative breast cancer models (Section 24; Poster Board #10) - Mar 14, 2023 - Abstract #AACR2023AACR_8496;
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.
- |||||||||| ADU-S100 / Chinook Therap
Reprogramming (Section 41; Poster Board #24) - Mar 14, 2023 - Abstract #AACR2023AACR_5905;
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.
- |||||||||| ST317 / STipe Therap
Systemic delivery of ST317, a cell penetrating STING pathway sensitizer, results in strong anti-tumor activity (Section 24; Poster Board #24) - Mar 14, 2023 - Abstract #AACR2023AACR_4000;
In vitro, ST317 sensitizes STING to pathway activators (Cytoplasmic DNA and cGAMP) and pharmacological STING agonists including ADU-S100 and diABZI compound 3, reducing the EC50 values of agonist-induced STING pathway activation while inducing supraphysiological (i.e. increasing the EMax) levels of pro-inflammatory cytokines/chemokines (e.g. Type I interferon and CXCL10) in cell line and primary cells. J
- |||||||||| ADU-S100 / Chinook Therap
Assessment of the response to STING agonist treatment and potentiation by manganese in glioblastoma cells and the tumor microenvironment (Section 43; Poster Board #24) - Mar 14, 2023 - Abstract #AACR2023AACR_3591;
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.
- |||||||||| ADU-S100 / Chinook Therap
Journal: Liposomal Delivery of MIW815 (ADU-S100) for Potentiated STING Activation. (Pubmed Central) - Feb 25, 2023
In this study, we investigated the design criteria for DOTAP/cholesterol liposomes for the systemic delivery of ADU-S100 and delineated the impact of key formulation factors on the loading efficiency, serum stability, and STING agonistic activity of ADU-S100. Our findings demonstrate that the cationic liposomal formulation of ADU-S100 can be optimized to greatly potentiate STING activation in antigen-presenting cells.
- |||||||||| PORT-5 / Stimunity, Portage, ADU-S100 / Chinook Therap
Journal: Selective STING stimulation in dendritic cells primes antitumor T cell responses. (Pubmed Central) - Jan 14, 2023
Subcutaneous administration of cGAMP-VLP showed synergy when combined with PD1 blockade or a tumor T-depleting antibody to elicit systemic tumor-specific T cells and antitumor activity, leading to complete and durable tumor eradication in the case of tumor T depletion. These findings show that cell targeting of STING stimulation shapes the antitumor T cell response and identify a therapeutic strategy to enhance T cell-targeted immunotherapy.
- |||||||||| Halaven (eribulin mesylate) / Eisai
Preclinical, Journal, IO biomarker: The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models. (Pubmed Central) - Dec 12, 2022
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.
- |||||||||| ADU-S100 / Chinook Therap
Journal: A split influenza vaccine formulated with a combination adjuvant composed of alpha-D-glucan nanoparticles and a STING agonist elicits cross-protective immunity in pigs. (Pubmed Central) - Nov 15, 2022
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. Despite vast genetic difference (77% HA gene identity) between the H1N2 and H1N1 SwIAV, the NanoS100 adjuvanted vaccine elicited cross protective cell mediated immune responses, suggesting the potential role of this combination adjuvant in inducing cross-protective immunity in pigs.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS, ADU-S100 / Chinook Therap
Integrative Analysis of Single-Cell Multi-Omics Data using Deep Learning to Identify Immune-Related Biomarkers in a Patient Derived 3D ex vivo Tumoroid Platform (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_1741;
Conclusions Our results revealed that the ScaiVision platform allows the integration of high-parameter single-cell data together with multiple types of omics data derived from Nilogen’s 3D-EXplore platform to better understand molecular and cellular mechanisms of drug mode of action that may allow the discovery of new clinically-relevant immune-related biomarkers to predict clinical outcome of immunotherapy. Ethics Approval All tissues were collected under proper patient consent and the study approved by the Institutional Ethics Board, approval number Pro00014313
- |||||||||| E7766 / Eisai, ADU-S100 / Chinook Therap
Use of small molecule STING agonist immunotherapy for canine soft tissue sarcoma: a cross-species analysis (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_1467;
Conclusions Overall, our findings suggest that STING agonists – in particular, ADU-S100 – possess potential as a novel and effective therapeutic approach for canine STS. As sarcomas are highly metastatic and commonly fatal in dogs, further evaluating STING agonist therapy in canines may provide therapeutic insights into similar challenges for treating human disease using a comparative biology approach.
- |||||||||| ADU-S100 / Chinook Therap
Epigenetic remodeling enhances therapeutic responses to STING agonism in vivo (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_1224;
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.
- |||||||||| ADU-S100 / Chinook Therap
Journal: Structure-Activity relationship study of benzothiophene oxobutanoic acid analogues leading to novel stimulator of interferon gene (STING) agonists. (Pubmed Central) - Sep 3, 2022
Particularly, 57 displayed more potent and rapid activation of the STING signaling pathway than ADU-S100 in THP1-Dual cells...Intriguingly, treatment with 57 eradicated all the CT26 tumor without further recurrence in all treated mice, which could also reject the same tumor re-inoculation, indicating an induction of immune memory by 57. Taken together, acyloxyamino derivative 57 represents a new chemotype of STING agonist with well-demonstrated in vivo anti-tumor activity, which is deserved for further investigation.
- |||||||||| belnacasan (VX-765) / Vertex, ADU-S100 / Chinook Therap
Journal: STING mediates neuroinflammatory response by activating NLRP3-related pyroptosis in severe traumatic brain injury. (Pubmed Central) - Sep 2, 2022
Further, NLRP3 inhibitor MCC950 or activator nigericin, or caspase-1 inhibitor VX765, was given as an intracerebroventricular injection 30 min before modeling...However, pharmacologic inhibition of STING led to a remarkable improvement of neuroinflammation partly through suppressing NLRP3 signaling. The STING-NLRP3 signaling is a potential therapeutic target in TBI-induced neurological dysfunction.
- |||||||||| ADU-S100 / Chinook Therap
Journal: Discovery of isonucleotidic CDNs as potent STING agonists with immunomodulatory potential. (Pubmed Central) - Aug 11, 2022
Besides naturally occurring CDNs, various synthetic CDNs, such as ADU-S100, have been reported to effectively activate STING and are being evaluated in clinical trials for the treatment of cancer...The compounds are very potent inducers of inflammatory cytokines by peripheral blood mononuclear cells (PBMCs). We also report the X-ray crystal structure of the lead inhibitor bound to the wild-type (WT) STING.
- |||||||||| ADU-S100 / Chinook Therap
Journal: STING activation promotes robust immune response and NK cell-mediated tumor regression in glioblastoma models. (Pubmed Central) - Jul 5, 2022
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.
- |||||||||| ADU-S100 / Chinook Therap
Journal: SHR1032, a novel STING agonist, stimulates anti-tumor immunity and directly induces AML apoptosis. (Pubmed Central) - May 29, 2022
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.
- |||||||||| ADU-S100 / Chinook Therap
Journal: Polymersome-mediated cytosolic delivery of cyclic dinucleotide STING agonist enhances tumor immunotherapy. (Pubmed Central) - Apr 8, 2022
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.
- |||||||||| ADU-S100 / Chinook Therap
Optimizing vaccine performance through improved cross-presentation with a nanoparticle adjuvant (Exhibit Hall; P1000) - Apr 8, 2022 - Abstract #IMMUNOLOGY2022IMMUNOLOGY_1960;
The goal of this study was to determine if a combination adjuvant (NanoS100) comprised of cationic plant-derived adjuvant nanoparticles (Nano-11) and the synthetic STING agonist ADU-S100 stimulates cross-presentation in vitro and in vivo after intradermal and intranasal vaccination...The cross-presentation was inhibited by preincubation of DCs with chlorpromazine and chloroquine, suggesting that NanoS100 supports endosomal processing of OVA...Intranasal immunization induced a greater percentage of IFNγ+ CD8 T cells in the lungs compared with intradermal immunization. These findings support the potential utility of NanoS100 as a vaccine adjuvant.
- |||||||||| ADU-S100 / Chinook Therap
VPS34 inhibitor SB02024 activates cGAS-STING signaling and sensitizes tumors to STING agonist (Section 40) - Mar 9, 2022 - Abstract #AACR2022AACR_4123;
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.
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