Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy

Dejmek, Milan; Brázdová, Andrea; Otava, Tomáš; Polidarová, Markéta Pimková; Klíma, Martin; Smola, Miroslav; Vavřina, Zdeněk; Budêšínský, Miloś; Dračínský, Martin; Liboska, Radek; Bouřa, Evžen; Birkuš, Gabriel; Nencka, Radim

doi:10.1016/j.ejmech.2023.115685

Cited by 5 publications

(2 citation statements)

References 44 publications

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“…A novel STING agonist of vinylphosphonate-based CDNs was engineered to elicit a more potent immune response than other STING agonists evaluated in clinical trials, such as ADU-S100 ( 124 ). Additionally, masking the negative charge of the CDN by synthesizing it into a prodrug, enhanced potency, both in vivo and in vitro .…”

Section: Preclinical Studiesmentioning

confidence: 99%

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Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

Mantooth,

Abdou,

Saez-Ibañez

et al. 2024

Front. Immunol.

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Breast cancer poses one of the largest threats to women’s health. Treatment continues to improve for all the subtypes of breast cancer, but some subtypes, such as triple negative breast cancer, still present a significant treatment challenge. Additionally, metastasis and local recurrence are two prevalent problems in breast cancer treatment. A newer type of therapy, immunotherapy, may offer alternatives to traditional treatments for difficult-to-treat subtypes. Immunotherapy engages the host’s immune system to eradicate disease, with the potential to induce long-lasting, durable responses. However, systemic immunotherapy is only approved in a limited number of indications, and it benefits only a minority of patients. Furthermore, immune related toxicities following systemic administration of potent immunomodulators limit dosing and, consequently, efficacy. To address these safety considerations and improve treatment efficacy, interest in local delivery at the site of the tumor has increased. Numerous intratumorally delivered immunotherapeutics have been and are being explored clinically and preclinically, including monoclonal antibodies, cellular therapies, viruses, nucleic acids, cytokines, innate immune agonists, and bacteria. This review summarizes the current and past intratumoral immunotherapy clinical landscape in breast cancer as well as current progress that has been made in preclinical studies, with a focus on delivery parameters and considerations.

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Section: Preclinical Studiesmentioning

confidence: 99%

“…deliveries, three days apart, of the highest concentration of prodrug led to tumor regression but not elimination, and this cohort had higher anti-tumoral CD8+ T cell levels compared to the vehicle treated group. Overall, prodrugs outperformed their parent compound, resulting in greater tumor growth delay ( 124 ).…”

Section: Preclinical Studiesmentioning

confidence: 99%

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

Mantooth,

Abdou,

Saez-Ibañez

et al. 2024

Front. Immunol.

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Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

Xuan,

2023

ChemMedChem

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Stimulator of interferon genes (STING) is a crucial adaptor protein in the innate immune response. STING activation triggers cytokine secretion, including type Ⅰ interferon and initiates T cell‐mediated adaptive immunity. The activated immune system converts "cold tumors" into "hot tumors" that are highly responsive to T cells by recruiting them to the tumor microenvironment, ultimately leading to potent and long‐lasting anti‐tumor effects. Unlike most immune checkpoint inhibitors, STING agonists represent a groundbreaking class of innate immune agonists that hold great potential for effectively targeting various cancer populations and are poised to become a blockbuster in tumor immunotherapy. This review will focus on the correlation between the STING signaling pathway and tumor immunity, as well as explore the impact of STING activation on other biological processes. Ultimately, we will summarize the development and optimization of STING agonists from a medicinal chemistry perspective, evaluate their potential in cancer therapy, and identify possible challenges for future advancement.

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