More of the same, this time trametinib rather than selumetinib.......
Clin Cancer Res. 2015 Jan 14. pii: clincanres.2339.2014. [Epub ahead of print]
The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD1, PD-L1 and CTLA-4.
Liu L1, Mayes PA2, Eastman S3, Shi H4, Yadavilli S4, Zhang T4, Yang J1, Seestaller-Wehr L4, Zhang SY4, Hopson C4, Tsvetkov L4, Jing J5, Zhang S6, Smothers J4, Hoos A7.
Author information
1Oncology R&D, GlaxoSmithKline.2Oncology, Glaxosmithkline.3Cancer Metabolism Drug Discovery, GlaxoSmithKline.4Oncology Translational Research, GlaxoSmithKline.5Cancer Research, GlaxoSmithKline.6Statistical Science, GlaxoSmithKline.7Oncology R&D, GlaxoSmithKline axel.x.hoos@gsk.com.
Abstract
Purpose: To assess the immunological effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo. Experimental Design: Immune effects of dabrafenib and trametinib were evaluated in human CD4+ and CD8+ T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model. Results: Dabrafenib enhanced pERK expression levels and did not suppress human CD4+ or CD8+ T cell function. Trametinib reduced pERK levels, and resulted in partial/transient inhibition of T cell proliferation/expression of a cytokine and immunomodulatory gene subset, which is context dependent. Trametinib effects were partially offset by adding dabrafenib. Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild type tumor cells induced apoptosis markers, up-regulated HLA molecule expression, and down-regulated certain immunosuppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA. PD-L1 expression in tumor cells was up-regulated after acquiring resistance to BRAF inhibition in vitro. Combinations of trametinib with immunomodulators targeting PD1, PD-L1, or CTLA4 in a CT26 model were more efficacious than any single agent. The combination of trametinib with anti-PD1 increased tumor-infiltrating CD8+ T cells in CT26 tumors. Concurrent or phased sequential treatment, defined as trametinib lead-in followed by trametinib plus anti-PD1 antibody, demonstrated superior efficacy compared with anti-PD1 antibody followed by anti-PD1 plus trametinib. Conclusion: These findings support the potential for synergy between targeted therapies dabrafenib and trametinib and immunomodulatory antibodies. Clinical exploration of such combination regimens is under way.
(and just for the sake of having it here, here's the SITC14 abstract that I pointed to previously.....)
Immune mediated therapy and MEK inhibition: preclinical assessment of immunobiology and combination activity in vitro and in vivo
Ross Stewart 1*, Edmund Poon 1, Stefanie Mullins 1, Amanda Watkins 1, Paul D Smith 2 andRobert W Wilkinson 1
1MedImmune, Cambridge, UK
2Astra Zeneca, Macclesfield, UK
Journal for ImmunoTherapy of Cancer 2014, 2(Suppl 3):P128 doi:10.1186/2051-1426-2-S3-P128
| Published: | 6 November 2014 |
Immune mediated therapies (IMT), such as anti-CTLA-4 and anti-PD-1/PD-L1, are showing significant promise in the treatment of solid tumors. However, although these treatments can show significant overall benefit, a subset of patients fails to respond. It is believed that activity in these patients is limited by a lack of immune priming or by immunosuppression. Combination with molecular targeted therapies has the potential to overcome these hurdles to response and maximize patient benefit. In order to select the best combination partners, a greater understanding is needed of how other therapies affect the immune system both directly, through effects on leukocytes, and indirectly, through effects on tumor immunogenicity and induction of tumor cell death.
Selumetinib (AZD6244, ARRY-142886) is a potent inhibitor of the mitogen-activated protein/extracellular signal-regulated kinase kinases 1/2 (MEK1/2), involved in the activation of signaling pathways which regulates cellular growth, proliferation and survival. Given that these pathways are often found aberrantly activated in human tumours and also play key roles in the regulation of immunological processes, it is difficult to predict the combinatorial effect of MEK1/2 inhibition and IMT. Here we detail a systematic approach taken towards examining the effects of MEK1/2 inhibition on tumour immunogenicity in vitro and in vivo and the direct effects it may have on the function of the immune system. We also present preclinical data demonstrating the anti-tumour activity of combining selumetinib and IMT mAbs in a syngeneic mouse model and report on possible mechanisms of synergism in promoting an anti-tumour immune response through promotion of antigen presentation. |
