Folks with melanoma liver mets show less response to Pembro. Why?

Abstract 2857:  Metastatic site and response to pembrolizumab (anti-PD1 antibody) in melanoma.  Tumeh, Rosenblum, Handly, Daud, et al.  AACR 106th Annual Meeting April 2015.  Cancer Research.

Therapies that block the PD-1/PD-L1 axis have shown significant clinical activity in melanoma.  Evidence has shown that pre-existing CD8 T cells infiltrates at the invasive tumor margin of metastatic melanoma are associated with the presence of the PD-1/PD-L1 immune axis and may predict response to therapy.  We examined the relationship between site of metastatic disease, local immune response, and treatment outcome in patients with advanced melanoma treated with pembro.

We studied patients enrolled in the pembro Phase 1 trial in the intention to treat (n=112) and full analysis set (n=96).  Pre-treatment metastatic samples were evaluated for immune response, organ site and treatment outcome.

Overall response rate = 40% with median PFS of 5.58 months.  Presence of melanoma to the liver had an objective response rate of 16% and median PFS of 2.79 months.  Melanoma to the lungs had an objective response rate of 64% and median PFS of 14.48 months.  Analysis of samples from liver mets showed reduced tumor infiltrating CD8+ T cells (TILs), PD-1 expression and tumor PD-L1 expression in distant metastasis.  Further analysis of TILs showed reduced percentages of partially exhausted PD-1, CTLA-4, and CD8 cells which correlated with progression and liver mets.  These cells were shown to make IFNy but not TNF or IL-2.  Additionally, presence of liver mets prior to starting anti-PD1 therapy correlated with treatment failure.  Liver mets was associated with fewer associated PD-1, CTLA4, and TILs in distant tumors.  These preliminary results warrant further investigation into determining whether side of metastasis modulates the systemic immune response to PD-1/PD-L1 blocking therapies.

Ok...smart researcher peeps.  This is a start.  We know patients with melanoma mets to their livers do less well, while those with lung mets do better, in response to immunotherapy.  A glimpse of why is posited here.  Now...let's figure out how to "MAKE IT WORK"!!!! For those of you looking for more immediate help with liver mets, I know that many are finding better responses when liver mets are removed surgically (when possible) before starting immunotherapy.  Patients are also experiencing some success with embolization and ablation of liver mets.  But...I think we can do better!!!  Come on...smart researcher peeps!  You can do this!  Hang in there, ratties.  Love - c