Friday, May 12, 2017

Phenformin improves activity of anti-PD-1

I've talked about Phenformin before:

Here, in 2016:  A look at effect of routine meds used by patients when on ipi....    Where though metformin was among many of the meds folks on ipi were taking, "only PPIs were found to have an increased odds of experiencing a partial response or a complete response to ipilimumab on the basis of a case-control analysis"  However, one should remember this was 'metformin' NOT phformin.

Here, in 2017:  Phenformin (not metformin) can reduce growth of melanoma cells   In the first report it notes that thought phenformin has some effect on melanoma cells, metformin has none.  The second report notes:  Consistently, phenformin reduces melanoma cell viability and growth independently from SOX2 levels.

And now, there's this:

Phenformin inhibits myeloid-derived suppressor cells and enhances the anti-tumor activity of PD-1 blockade in melanoma. Kim, Li, Trousil, et al. J Invest Dermatol. 2017 Apr 19.

Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin selectively inhibits granulocytic myeloid-derived suppressor cells (G-MDSCs) in spleens of tumor bearing mice and ex vivo. Phenformin induces production of reactive oxygen species in G-MDSC, whereas the antioxidant N-acetylcysteine attenuates the inhibitory effects of phenformin. Importantly, co-treatment of phenformin enhances the effect of anti-PD-1 antibody therapy on inhibiting tumor growth in the BRAF V600E/PTEN null melanoma mouse model. Combination of phenformin and anti PD-1 cooperatively induces CD8+ T cell infiltration and decreases levels of proteins that are critical for immune suppressive activities of MDSCs. Our findings demonstrate a selective, inhibitory effect of phenformin on G-MDSCs-driven immune suppression and support that phenformin improves the anti-tumor activity of PD-1 blockade immunotherapy in melanoma.

When it comes to myeloid suppressor cells, remember I've posted reports from many sources that note that they stand in the way of a response for many:  Markers for response to immunotherapy: Increased eosinophils = good. Increased Myeloid Suppressor cells = not so good.

For what it's worth!  - c

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