T cell profiling reveals high CD4+CTLA-4+ T cell frequency as dominant predictor for survival after Prostate GVAX/ipilimumab treatment

Saskia J.A.M. Santegoets, Anita G.M. Stam, Sinéad M. Lougheed, Helen Gall, Petra E.T. Scholten, Martine Reijm, Karin Jooss, Natalie Sacks, Kristen Hege, Israel Lowy, Jean Marie Cuillerot, B. Mary E. Von Blomberg, Rik J. Scheper, Alfons J.M. Van Den Eertwegh, Winald R. Gerritsen, Tanja D. De Gruijl

Research output: Contribution to journalArticlepeer-review

Abstract

Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4+ T cell differentiation, and CD4+ and CD8+ T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4 +CTLA-4+, CD4+PD-1+, or differentiated (i.e., non-naive) CD8+ T cells or low pre-treatment frequencies of differentiated CD4+ or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4+ in CD4+ T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.

Original languageEnglish (US)
Pages (from-to)245-256
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume62
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • Biomarker
  • Ipilimumab
  • Patient selection
  • Prostate GVAX
  • Survival prediction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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