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

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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.

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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

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Saskia J. A. M. Santegoets, Sinéad M. Lougheed, Helen Gall, Alfons J. M. van den Eertwegh, Winald R. Gerritsen & Tanja D. de Gruijl

  2. Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

    Anita G. M. Stam, Petra E. T. Scholten, Martine Reijm, B. Mary E. von Blomberg & Rik J. Scheper

  3. Cell Genesys Inc., South San Francisco, CA, USA

    Karin Jooss, Natalie Sacks & Kristen Hege

  4. Medarex, Bloomsbury, NJ/Bristol-Myers Squibb Company, Wallingford, CT, USA

    Israel Lowy & Jean-Marie Cuillerot

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  1. Saskia J. A. M. Santegoets
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  2. Anita G. M. Stam
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  4. Helen Gall
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  9. Kristen Hege
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Correspondence to Saskia J. A. M. Santegoets or Tanja D. de Gruijl.

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Santegoets, S.J.A.M., Stam, A.G.M., Lougheed, S.M. et al. T cell profiling reveals high CD4+CTLA-4+ T cell frequency as dominant predictor for survival after Prostate GVAX/ipilimumab treatment. Cancer Immunol Immunother 62, 245–256 (2013). https://doi.org/10.1007/s00262-012-1330-5

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