Blood mRNA expression profiling predicts survival in patients treated with tremelimumab

Yvonne Saenger, Jay Magidson, Bobby Liaw, Ellen De Moll, Sara Harcharik, Yichun Fu, Karl Wassmann, David Fisher, John Kirkwood, William K. Oh, Philip Friedlander

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Purpose: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb) targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug Administration (FDA). Biomarkers are needed to identify the subset of patients who will achieve tumor control with CTLA-4 blockade. Experimental Design: Pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score based on four genes that were highly predictive of survival (P < 0.001). This signature was validated in an independent population of 260 treatment-naïve patients with melanoma enrolled in a multicenter phase III study of tremelimumab. Results: Median follow-up was 297 days for the training population and 386 days for the test population. Expression levels of the 169 genes were closely correlated across the two populations (r = 0.9939). A fourgene model, including cathepsinD(CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1 (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted survival in the test population (P = 0.001 by log-rank test). This four-gene model added to the predictive value of clinical predictors (P <0.0001). Conclusions: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.

Original languageEnglish (US)
Pages (from-to)3310-3318
Number of pages9
JournalClinical Cancer Research
Volume20
Issue number12
DOIs
StatePublished - Jun 15 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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