Cancer Immunology, Immunotherapy

, Volume 62, Issue 2, pp 245–256

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
Original article

DOI: 10.1007/s00262-012-1330-5

Cite this article as:
Santegoets, S.J.A.M., Stam, A.G.M., Lougheed, S.M. et al. Cancer Immunol Immunother (2013) 62: 245. doi:10.1007/s00262-012-1330-5

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.

Keywords

IpilimumabProstate GVAXBiomarkerPatient selectionSurvival prediction

Abbreviations

CTLA-4

CTL antigen-4

CRCP

Castration-resistant prostate cancer

HPS

Halabi predicted survival

IRAE

Immune-related adverse events

OS

Overall survival

PD-1

Programmed death-1

PD

Progressive disease

PR

Partial response

SD

Stable disease

Tregs

Regulatory T cells

Supplementary material

262_2012_1330_MOESM1_ESM.pdf (41 kb)
Supplementary material 1 (PDF 40 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Saskia J. A. M. Santegoets
    • 1
  • Anita G. M. Stam
    • 2
  • Sinéad M. Lougheed
    • 1
  • Helen Gall
    • 1
  • Petra E. T. Scholten
    • 2
  • Martine Reijm
    • 2
  • Karin Jooss
    • 3
  • Natalie Sacks
    • 3
  • Kristen Hege
    • 3
  • Israel Lowy
    • 4
  • Jean-Marie Cuillerot
    • 4
  • B. Mary E. von Blomberg
    • 2
  • Rik J. Scheper
    • 2
  • Alfons J. M. van den Eertwegh
    • 1
  • Winald R. Gerritsen
    • 1
  • Tanja D. de Gruijl
    • 1
  1. 1.Department of Medical Oncology, Cancer Center AmsterdamVU University Medical CenterAmsterdamThe Netherlands
  2. 2.Department of Pathology, Cancer Center AmsterdamVU University Medical CenterAmsterdamThe Netherlands
  3. 3.Cell Genesys Inc.South San FranciscoUSA
  4. 4.Medarex, Bloomsbury, NJ/Bristol-Myers Squibb CompanyWallingfordUSA