Combination of the STING Agonist MIW815 (ADU-S100) and PD-1 Inhibitor Spartalizumab in Advanced/Metastatic Solid Tumors or Lymphomas: An Open-Label, Multicenter, Phase Ib Study

Meric‐Bernstam, Funda; Sweis, Randy F.; Kasper, Stefan; Hamid, Omid; Bhatia, Shailender; Dummer, Reinhard; Stradella, Agostina; Long, Georgina V.; Spreafico, Anna; Shimizu, Toshio; Steeghs, Neeltje; Luke, Jason J.; McWhirter, Sarah M.; Müller, Thomas; Nair, Nitya; Lewis, Nancy; Chen, Xinhui; Bean, Andrew J.; Kattenhorn, Lisa; Pelletier, Marc; Sandhu, Shahneen

doi:10.1158/1078-0432.ccr-22-2235

Cited by 70 publications

(59 citation statements)

References 37 publications

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“…Considering the importance of the cGAS–STING–type I IFN signaling pathway in cancer immunity, STING agonists are being developed [ 13 , 14 ]. Indeed, there are several ongoing clinical trials evaluating the efficacy of combination therapy using STING agonists in combination with anti-PD-1 antibodies on solid cancers, including melanoma [ 13 , 15 ]. In addition, recent studies have investigated whether there are existing therapies that can activate the cGAS–STING–type I IFN signaling pathway or increase the efficacy of STING agonists, with the following findings: By using melanoma, colon, and breast cancer mouse models and human cDC1 and cDC2 subsets from the peripheral blood, it was demonstrated that radiation therapy destroys tumor cells, which then release their dsDNA into the tumor microenvironment; cDC1 and cDC2 take up the dsDNA into their own cytoplasm.…”

Section: The Role Of Cgas and Sting In Immune Cells In The Tumor Micr...mentioning

confidence: 99%

“…Importantly, pharmacokinetic analyses revealed that MIW815 was rapidly absorbed from the injection site into the systemic circulation and had a short half-life of 24 min. Furthermore, a phase Ib dose-escalation trial of MIW815 in combination with anti-PD-1 Ab was conducted [ 15 ], in which 106 patients with advanced solid tumors or lymphomas were treated. The combination therapy was well tolerated; however, the antitumor response was minimal, and the ORR was only 10.4%.…”

Section: Sting Agonists In Clinical Trials and Next-generation Sting ...mentioning

confidence: 99%

“…A phase I anti-PD-1 antibody + STING agonist trial has reported a slight increase in the antitumor immune response [ 15 ], which suggests that in addition to STING-dependent type I IFN production, other immune pathways contribute to immune infiltration into tumors. This demonstrates the importance of conceiving a therapeutic strategy that increases the efficacy of cancer immunotherapy.…”

Section: The Role Of Aim2 In Tumor-infiltrating Dendritic Cellsmentioning

confidence: 99%

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Immune Regulation by Cytosolic DNA Sensors in the Tumor Microenvironment

Fukuda

2023

Cancers

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cGAS and AIM2 are CDSs that are activated in the presence of cytosolic dsDNA and are expressed in various cell types, including immune and tumor cells. The recognition of tumor-derived dsDNA by CDSs in the cytosol of tumor-infiltrating dendritic cells (TIDCs) activates the innate and acquired immunity, thereby enhancing anti-tumor immune responses. STING is the downstream signaling effector of cGAS that induces type I interferon (IFN) signaling. Owing to their ability to activate TIDCs, STING agonists have been intratumorally injected in several clinical trials to enhance the anti-tumor immune response elicited by immune checkpoint antibodies. However, they have shown minimal effect, suggesting the importance of optimizing the dose and route of administration for STING agonists and deciphering other immune pathways that contribute to anti-tumor immune responses. Recent studies have revealed that AIM2 activity induces pro-tumor growth through multiple parallel pathways, including inhibition of STING-type I IFN signaling. Thus, AIM2 could be a potential molecular target for cancer immunotherapies. This review summarizes the current research on the roles of cGAS, STING, and AIM2 in immune cells and tumor cells in the tumor microenvironment and discusses the future prospects of anti-tumor treatment approaches based on these molecules.

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Section: The Role Of Cgas and Sting In Immune Cells In The Tumor Micr...mentioning

confidence: 99%

Section: Sting Agonists In Clinical Trials and Next-generation Sting ...mentioning

confidence: 99%

Section: The Role Of Aim2 In Tumor-infiltrating Dendritic Cellsmentioning

confidence: 99%

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Immune Regulation by Cytosolic DNA Sensors in the Tumor Microenvironment

Fukuda

2023

Cancers

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“…Natural STING agonists are CDNs such as c-di-GMP (CDG), c-di-AMP, and cGAMP, which have intrinsic small molecular weight, great hydrophilicity, and negative electrostatic charges. , As a result, these CDNs are difficult to cross the cellular plasma membrane and endosomal membrane to access the endoplasmic reticulum in the cytosol where STING is located. , In parallel to these cellular barriers, the susceptibility to enzymatic degradation also inhibits the delivery efficacy to target tissues, leading to poor therapeutic results. , To address these challenges, drug delivery systems have been engineered for the optimal delivery, immunomodulatory, and therapeutic efficacies of CDNs. , STING agonists have been extensively tested, most in preclinical studies, for the treatment of many types of cancers and infectious diseases. − In this section, we will discuss our research on the applications of STING agonists for cancer combination immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Engineering and Delivery of cGAS-STING Immunomodulators for the Immunotherapy of Cancer and Autoimmune Diseases

Zhou,

Cheng,

Zhang

et al. 2023

Acc. Chem. Res.

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The cyclic GMP-AMP synthase-stimulator interferon gene (cGAS-STING) pathway is an emerging therapeutic target for the prophylaxis and therapy of a variety of diseases, ranging from cancer, infectious diseases, to autoimmune disorders. As a cytosolic double stranded DNA (dsDNA) sensor, cGAS can bind with relatively long dsDNA, resulting in conformational change and activation of cGAS. Activated cGAS catalyzes the conversion of adenosine triphosphate (ATP) and guanosine triphosphate (GTP) into cGAMP, a cyclic dinucleotide (CDN). CDNs, including 2′3′-cGAMP, stimulate adapter protein STING on the endoplasmic membrane, triggering interferon regulatory factor 3 (IRF3) phosphorylation and nuclear factor kappa B (NF-κB) activation. This results in antitumor and antiviral type I interferon (IFN-I) responses. Moreover, cGAS-STING overactivation and the resulting IFN-I responses have been associated with a number of inflammatory and autoimmune diseases. This makes cGAS-STING appealing immunomodulatory targets for the prophylaxis and therapy of various related diseases. However, drug development of CDNs and CDN derivatives is challenged by their limited biostability, difficult formulation, poor pharmacokinetics, and inefficient tissue accumulation and cytosolic delivery. Though recent synthetic small molecular CDN-or non-CDN-based STING agonists have been reported with promising preclinical therapeutic efficacy, their therapeutic efficacy and safety remain to be fully evaluated preclinically and clinically. Therefore, it is highly desirable and clinically significant to advance drug development for cGAS-STING activation by innovative approaches, such as drug delivery systems and drug development for pharmacological immunomodulation of cGAS. In this Account, we summarize our recent research in the engineering and delivery of immunostimulatory or immunoregulatory modulators for cGAS and STING for the immunotherapy of cancer and autoimmune diseases. To improve the delivery efficiency of CDNs, we developed ionizable and pHresponsive polymeric nanocarriers to load STING agonists, aiming to improve the cellular uptake and facilitate the endosomal escape to induce efficient STING activation. We also codelivered STING agonists with complementary immunostimulatants in nanoparticle-in-hydrogel composites to synergetically elicit potent innate and adaptive antitumor responses that eradicate local and distant large tumors. Further, taking advantage of the simplicity of manufacturing and the established nucleic acid delivery system, we developed oligonucleotide-based cGAS agonists as immunostimulant immunotherapeutics as well as adjuvants for peptide antigens for cancer immunotherapy. To suppress the overly strong proinflammatory responses associated with cGAS-STING overactivation in some of the autoimmune disorders, we devised nanomedicine-in-hydrogel (NiH) that codelivers a cGAS inhibitor and cell-free DNA (cfDNA)-scavenging cationic nanoparticles (cNPs) for systemic immunosuppression in rheumatoid arthritis (RA) therapy. Lastly, we di...

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“…39,[137][138][139][140] Results of the recent clinical trials on ADU-S100 (MIW815) and MK-1454 also reaffirmed the importance of targeted immune activation and patient selection. [141][142][143] With the new knowledge in cGAS-STING signaling, we can now design of a mechanism-based [144][145][146][147][148][149][150] clinical development plan to better harness the antitumor potential of CDNs. As we look forward to seeing this new chemical modality benefiting cancer patients, we also anticipate that the chemistry-biology feedforward loop will continue to stimulate the development of new chemistry and to fuel the discovery of new biology, the two indispensable elements of drug research.…”

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confidence: 99%