Monday, March 13, 2017

The whole she-bang - immunotherapy WITH BRAF/MEK for melanoma...

I posted this in November:  BRAF/MEK combined with immunotherapy!!!

Now there is this:

Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma.  Deken, Gadiot, Jordanova, et al.  Oncoimmunology. 2016 Oct 14.

Immunotherapy of advanced melanoma with CTLA-4 or PD-1/PD-L1 checkpoint blockade induces in a proportion of patients long durable responses. In contrast, targeting the MAPK-pathway by selective BRAF and MEK inhibitors induces high response rates, but most patients relapse. Combining targeted therapy with immunotherapy is proposed to improve the long-term outcomes of patients. Preclinical data endorsing this hypothesis are accumulating. Inhibition of the PI3K-Akt-mTOR pathway may be a promising treatment option to overcome resistance to MAPK inhibition and for additional combination with immunotherapy. We therefore evaluated to which extent dual targeting of the MAPK and PI3K-Akt-mTOR pathways affects tumor immune infiltrates and whether it synergizes with PD-1 checkpoint blockade in a BRAFV600E/PTEN-/--driven melanoma mouse model. Short-term dual BRAF + MEK inhibition enhanced tumor immune infiltration and improved tumor control when combined with PD-1 blockade in a CD8+ T cell dependent manner. Additional PI3K inhibition did not impair tumor control or immune cell infiltration and functionality. Analysis of on-treatment samples from melanoma patients treated with BRAF or BRAF + MEK inhibitors indicates that inhibitor-mediated T cell infiltration occurred in all patients early after treatment initiation but was less frequent found in on-treatment biopsies beyond day 15. Our findings provide a rationale for clinical testing of short-term BRAF + MEK inhibition in combination with immune checkpoint blockade, currently implemented at our institutes. Additional PI3K inhibition could be an option for BRAF + MEK inhibitor resistant patients that receive targeted therapy in combination with immune checkpoint blockade.

Granted this is in real live mousies....but when BRAF/MEK was given with anti-PD-1.... T cell infiltration of the tumor was facilitated early on...but not so much after 15 days. So....maybe the full barrage of the combo early....could actually benefit human ratties!!

Thanks to the mousies...and hang tough, ratties! - c

PS  It was tough...but we survived our recent blizzard:

Hope all my more northern peeps have their fur panties and snow boots at the ready!! Y'all stay safe and warm, now.... you hear???? - les


  1. This is the trial I am trying to get on at MDA. Hopefully my liver enzymes are back to normal by next week and I can start. Thanks for posting this. The trial at MDA is Dab/Tram and Nivo. The snow looks beautiful. Much better than the rain in Seattle right now
    Vicki in Seattle.

  2. Will keep my fingers crossed for you!!! Hang in there!