Vorinostat Downregulates CD30 and Decreases Brentuximab Vedotin Efficacy in Human Lymphocytes
Menée sur des lignées cellulaires de lymphome anaplasique à grandes cellules, cette étude met en évidence des mécanismes par lesquels le vorinostat, un inhibiteur d'histone désacétylase, réduit l'efficacité du brentuximab vedotin
With an increasing number of clinical trials looking at combination therapies in cancer, potential drug-drug interactions require particular attention. One such instance is the treatment of CD30+ tumors after previous vorinostat (SAHA) failure with the anti-CD30 antibody-drug conjugate brentuximab vedotin. Using B-, T- and NK-cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50% or more. Interestingly, low dose SAHA treatment that maintained 50% or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced anti-tumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30dim tumors may decrease efficacy. Combination treatment in highly CD30+ tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm.
http://mct.aacrjournals.org/content/early/2014/10/15/1535-7163.MCT-14-0593.abstract