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Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I–deficient and MHC I+ tumors

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johan
(@j)
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Immunotherapy provides long-term remissions in numerous types of cancer but is ineffective in most tumors with poor immune cell infiltrates or lacking T cell epitopes or MHC I molecules. Agents that activate the STING protein showed promise in several MHC I+ and MHC-deficient tumor models in mice, where they induced powerful antitumor CD8+ T cell and natural killer (NK) cell responses, respectively. They were less effective in numerous other tumor models and yielded mixed results in the clinic in human patients. This report demonstrates strong synergy between a STING agonist and an IL-2 superkine in effectively curing difficult-to-treat MHC-deficient and MHC-positive tumor models in mice by mobilizing T cells and NK cells. This combination therapy shows considerable promise for clinical application.

 

https://www.pnas.org/doi/10.1073/pnas.2200568119


   
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medline
(@aliml2)
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Pharmacological activation of the host STING pathway can trigger T cell-mediated tumor regression and make immunologically ‘cold’ tumors ‘hot’.

‘Cold’, nonimmunogenic tumors are less responsive to immune checkpoint inhibitors; therefore, promoting T cells infiltration in the tumor microenvironment is a promising approach to increase efficacy of immunotherapeutic drugs and ‘heating’ up the tumors.

The combination of STING agonists with current immunotherapy regimens is showing great promise, considering that a cold tumor microenvironment appears to be the Achilles heel of immunotherapy, and that STING pathway activation could ‘heat up’ the tumor and trigger infiltration by immune cells, which in turn can be unleashed by the checkpoint blockade. 

https://future-science.com/doi/full/10.4155/ppa-2019-0013

STING brings heat to tumors!


   
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laika
(@laika)
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Does anyone know of any accessible STING agonists? It looks like cGAMP is an option, but not available anywhere I can find for a reasonable price. Maybe a possibility for MCS formulas?

 

https://pubmed.ncbi.nlm.nih.gov/27287182/


   
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medline
(@aliml2)
Joined: 9 months ago
Posts: 124
 
Posted by: @laika

Does anyone know of any accessible STING (stimulator of interferon genes) agonists? It looks like cGAMP (cyclic guanosine monophosphate adenosine monophosphate) is an option, but not available anywhere I can find for a reasonable price.

Vadimzan (dimethyl-xanthone acetic acid) is the only STING agonist.

Despite positive results at the preclinical stage, vadimezan failed in human clinical trials. Studies have demonstrated the reason for the inefficacy. Vadimezan was shown to target the STING pathway.

https://en.wikipedia.org/wiki/Vadimezan

As an alternative to STING agonists, you can look for compounds that stimulate type 1 interferons, such as dipyridamole.

STING induces type I interferon

https://en.wikipedia.org/wiki/Stimulator_of_interferon_genes

Dipyridamole induces interferon in man

https://pubmed.ncbi.nlm.nih.gov/6084526

Dipyridamole is an interferon inducer

https://pubmed.ncbi.nlm.nih.gov/6181668

Dipyridamole promotes type I interferon responses

https://medrxiv.org/content/10.1101/2020.02.27.20027557v1.full

Dipyridamole increases plasma adenosine and cGAMP also contains adenosine.

Oral dipyridamole increases plasma adenosine levels in human beings

https://pubmed.ncbi.nlm.nih.gov/2910640

Adenosine actually has a pyrogenic effect, an agent that induces fever, by generating heat. Type 1 interferons acts also as a pyrogenic agent, thus causing fever.

Pyrogenics:

  • Adenosine
  • Caffeine
  • Capsaicin
  • Reticuline

https://selfdecode.com/health-effect/pyrogenic

Guanosine, like Adenosine and also Uridine or Cytidine, is a nucleoside. Interestingly, uridine also causes fever in humans.

Effect of pyrimidine nucleosides on body temperatures of man and rabbit in relation to pharmacokinetic data

https://pubmed.ncbi.nlm.nih.gov/3151015

Acyclovir is structurally similar to guanosine, so the combination of dipyridamole and acyclovir may act like cGAMP.

Guanosine analogues as anti-herpesvirus agents

https://pubmed.ncbi.nlm.nih.gov/11200257

 


   
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medline
(@aliml2)
Joined: 9 months ago
Posts: 124
 

Screening of different nutritional metal ions shows that Manganese ion (Mn2+) and Cobalt ion (Co2+) synergize with STING agonists and significantly enhance type-I interferon (IFN-I) responses.

https://doi.org/10.1158/1538-7445.AM2022-314


   
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