Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas

Harrington, Kevin; Brody, Joshua; Ingham, M.; Strauss, James; Čemerski, Sašo; Wang, M.; Tse, Archie; Khilnani, Anuradha; Marabelle, Aurélien; Golan, Talia

doi:10.1093/annonc/mdy424.015

Cited by 179 publications

(127 citation statements)

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“…Unfortunately, this approach was not effective as monotherapy, although it showed partial response in combination with anti-PD-1 in patients with advanced solid tumors or lymphomas. 55 Another STING agonist (ADU-S100, Aduro Biotech), in combination with anti-PD1 or anti-CTLA4, is in multiple clinical trials including head and neck, advanced/metastatic solid tumors or lymphomas ( clinicaltrials. gov identifier: NCT03937141, 02675439, 03172936).…”

Section: Open Accessmentioning

confidence: 99%

Lifting the innate immune barriers to antitumor immunity

Rothlin

Ghosh

2020

J Immunother Cancer

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The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.

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Section: Open Accessmentioning

confidence: 99%

Lifting the innate immune barriers to antitumor immunity

Rothlin

Ghosh

2020

J Immunother Cancer

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“…The effects of cGAMP on tumor shrinkage in mice has led to the development of multiple CDN-based STING agonists. However, preliminary results from monotherapy CDN trials indicate that the drugs lack the robust antitumoral effect previously observed in mice (Meric-Bernstam et al 2018;Harrington et al 2018), and that different CDN analogs exhibited varying efficacies. One possible explanation is that these CDNs are unable to activate STING in responder cells due to inefficient cellular import.…”

Section: Discussionmentioning

confidence: 99%

SLC19A1 is an importer of the immunotransmitter cGAMP

Cordova

Ritchie

Hess

et al. 2019

Preprint

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2'3'-cyclic-GMP-AMP (cGAMP) is a second messenger that activates the antiviral Stimulator of Interferon Genes (STING) pathway. We recently identified a novel role for cGAMP as a soluble, extracellular immunotransmitter that is produced and secreted by cancer cells. Secreted cGAMP is then sensed by host cells, eliciting an antitumoral immune response. Due to the antitumoral effects of cGAMP, other CDN-based STING agonists are currently under investigation in clinical trials for metastatic solid tumors.However, it is unknown how cGAMP and other CDNs cross the cell membrane to activate intracellular STING. Using a genome-wide CRISPR screen we identified SLC19A1 as the first known importer of cGAMP and other CDNs, including the investigational new drug 2'3'-bisphosphosphothioate-cyclic-di-AMP (2'3'-CDA S ). These discoveries will provide insight into cGAMP's role as an immunotransmitter and aid in the development of more targeted CDN-based cancer therapeutics.

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“…Twenty-five patients were enrolled in the MK-1454/pembrolizumab combination group; there were no CRs, but 6 of 25 patients achieved a PR, and 6 had SD. 17 Both injected tumors and other metastatic tumors showed regression in responders, with a median 83% reduction in tumor size. All responders had not received prior immunotherapy, and 3 of the 6 responders were HNSCC patients.…”

Section: Mk-1454mentioning

confidence: 96%

“…Twenty patients were enrolled in the monotherapy group, with no responders and 4 of 20 patients showing stable disease (SD). Twenty‐five patients were enrolled in the MK‐1454/pembrolizumab combination group; there were no CRs, but 6 of 25 patients achieved a PR, and 6 had SD . Both injected tumors and other metastatic tumors showed regression in responders, with a median 83% reduction in tumor size.…”

Section: Small Moleculesmentioning

confidence: 99%

Novel immune‐modulating drugs for advanced head and neck cancer

2019

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Background Recently, two anti‐PD‐1 immune checkpoint inhibitors, pembrolizumab and nivolumab, have been approved by the US Food and Drug Administration for patients who fail on platinum‐based chemotherapy. However, overall response and progression‐free survival are still limited, and multiple novel agents are under development to fulfill this unmet clinical need. Methods Publications between 1992 and 2019 regarding the immunological/biological mechanisms and early phase clinical trial outcomes of immunomodulatory agents for head and neck cancer were described in this review article. Results Eleven immunomodulatory agents for advanced head and neck, including small molecules, antibodies, and therapeutic vaccines were described. Treatment responses were noted in nearly all 11 agents, as monotherapy or combination therapy. Conclusions Potentials of the novel immunomodulatory agents to improve treatment efficacy of head and neck cancer and to maintain tolerable safety profile have been disclosed.

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Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas

Cited by 179 publications

References 0 publications

Lifting the innate immune barriers to antitumor immunity

Lifting the innate immune barriers to antitumor immunity

SLC19A1 is an importer of the immunotransmitter cGAMP

Novel immune‐modulating drugs for advanced head and neck cancer

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