Cancer Immunology, Immunotherapy

, Volume 62, Issue 2, pp 245–256 | Cite as

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. SantegoetsEmail author
  • 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 GruijlEmail author
Original article


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.


Ipilimumab Prostate GVAX Biomarker Patient selection Survival prediction 



CTL antigen-4


Castration-resistant prostate cancer


Halabi predicted survival


Immune-related adverse events


Overall survival


Programmed death-1


Progressive disease


Partial response


Stable disease


Regulatory T cells



This research was financially supported by awards and grants from the Prostate Cancer Foundation (PCF to T.D.G.), Stichting VUmc-CCA, and the Dutch Cancer Society (KFW; VU 2006-3697). The authors thank Dr. S.A.G.M. Cillessen for her assistance with the unsupervised clustering analysis.

Conflict of interest

J. M. C. is a Bristol-Myers Squibb employee, and J. M. C and I. L. own stock and/or stock options from Bristol-Myers Squibb. A.J.M.v.d.E. and W.R.G. have served as consultants and received honoraria from Bristol-Myers Squibb. T.D.G and W.R.G. received an educational grant from Cell Genesys Inc. All other authors declare that they have no conflict of interest.

Supplementary material

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


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Saskia J. A. M. Santegoets
    • 1
    Email author
  • 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
    Email author
  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

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