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Phase I Dose-Escalation Trial of MIW815 (ADU-S100), an Intratumoral STING Agonist, in Patients with Advanced/Metastatic Solid Tumors or Lymphomas
Open accessPublished version of a preprint
Abstract
Purpose: This phase I study assessed the safety, pharmacokinetics (PKs), and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates the stimulator of IFN genes (STING) pathway, in patients with advanced/metastatic cancers. Patients and Methods: Patients (n = 47) received weekly i.t. injections of MIW815, 50 to 6,400 μg, on a 3-weeks-on/1-week-off schedule. Results: A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills, and injection-site pain (each 15%). MIW815 was rapidly absorbed from the injection site with dose-proportional PK, a rapid terminal plasma half-life (approximately 24 minutes), and high interindividual variability. One patient had a partial response (PR; Merkel cell carcinoma); two patients had unconfirmed PR (parotid cancer, myxofibrosarcoma). Lesion size was stable or decreased in 94% of evaluable, injected lesions. RNA expression and immune infiltration assessments in paired tumor biopsies did not reveal significant on-treatment changes. However, increases in inflammatory cytokines and peripheral blood T-cell clonal expansion suggested systemic immune activation. Conclusions: 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.
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STING-activating agents have shown limited efficacy in early-phase clinical trials in cancer patients, either as monotherapy or in combination with immune checkpoint inhibitors.
“early-phase clinical trials with these agents in cancer patients, either as monotherapy or in combination with immune checkpoint inhibitors, have so far shown lack of efficacy26–28.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [28]
The Translational Relevance section describes limited clinical activity with single-agent MIW815, and the Efficacy section reports one confirmed partial response (2.1% overall response rate). This trial did not test MIW815 with a checkpoint inhibitor; the Discussion instead describes emerging clinical data suggesting greater activity with combined treatment. The source therefore supports the monotherapy part, but not the claim that combination trials have shown a lack of efficacy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredClinical trials in cancer patients currently testing STING activating drugs as monotherapy or in combination with immune checkpoint inhibitors have so far provided little, if any, evidence of objective responses.
“However, clinical trials in cancer patients currently testing STING activating drugs as a monotherapy or in combination with immune checkpoint inhibitors have so far provided little, if any, evidence of objective responses26–28.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [28]
The Efficacy section reports one confirmed partial response among patients receiving MIW815 alone, an objective response rate of 2.1%, supporting the claim of little response to monotherapy. The paper does not establish that objective responses have been similarly scarce across STING-agonist trials combined with checkpoint inhibitors; its Discussion instead notes emerging clinical data showing greater activity with combination treatment. Page numbers were not available in our copy. (LLM, conf=0.84)
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Epigenetic state determines the in vivo efficacy of STING agonist therapy
Falahat, R., Berglund, A., Perez-Villarroel, P., Putney, R. M., Hamaidi, I., Kim, S., Pilon-Thomas, S., Barber, G. N., & Mulé, J. J. (2023) · Nature Communications · doi:10.1038/s41467-023-37217-1 · Cited by 94
Metadata
- Authors
- Meric-Bernstam, F., Sweis, R. F., Hodi, F. S., Messersmith, W. A., Andtbacka, R. H. I., Ingham, M., Lewis, N., Chen, X., Pelletier, M., Chen, X., Wu, J., Dubensky, T. W., McWhirter, S. M., Müller, T., Nair, N., & Luke, J. J.
- Affiliations
- 1Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- University of Chicago (US)
- Dana-Farber Cancer Institute (US)
- University of Colorado Cancer Center (US)
- University of Utah (US)
- Columbia University Irving Medical Center (US)
- 7Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
- 8Novartis Institutes for BioMedical Research, East Hanover, New Jersey.
- 9Novartis Institute for Biomedical Research, Cambridge, Massachusetts.
- Aduro BioTech (United States) (US)
- UPMC Hillman Cancer Center (US)
- Corresponding author
- Luke, Jason J.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-10-28
- Volume
- 28
- Issue
- 4
- Pages
- 677-688
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W3210892875
- Cited by
- 418
- References
- 10
- Citations by year
- 2026: 118 · 2025: 106 · 2024: 89 · 2023: 72 · 2022: 33
- FWCI
- 18.19
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-06-13)
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis Pharmaceuticals Corporation (n/a)
- Aduro Biotech (n/a)
- National Center for Advancing Translational Sciences (12713238)
- University of Texas MD Anderson Cancer Center (P30CA016672)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- ADU-S100, STING agonist, cyclic dinucleotides, intratumoral injection, maximum tolerated dose, pharmacokinetics, safety, Merkel cell carcinoma, parotid cancer, myxofibrosarcoma, systemic immune activation, T cell clonal expansion, inflammatory cytokines, advanced solid tumors, lymphoma
- MeSH terms
- Adult, Humans, Immunotherapy, Lymphoma, Neoplasms, Neoplasms, Second Primary, Maximum Tolerated Dose
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