Cancer Immunology, Immunotherapy

, Volume 63, Issue 4, pp 407–418 | Cite as

A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates

  • Caroline Jochems
  • Jo A. Tucker
  • Kwong-Yok Tsang
  • Ravi A. Madan
  • William L. Dahut
  • David J. Liewehr
  • Seth M. Steinberg
  • James L. Gulley
  • Jeffrey Schlom
Original Article

Abstract

We recently reported the clinical results of a Phase I trial combining ipilimumab with a vaccine containing transgenes for prostate-specific antigen (PSA) and for a triad of costimulatory molecules (PROSTVAC) in patients with metastatic castration-resistant prostate cancer. Thirty patients were treated with escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naïve patients, 58 % had a PSA decline. Combination therapy did not exacerbate the immune-related adverse events associated with ipilimumab. Here, we present updated survival data and an evaluation of 36 immune cell subsets pre- and post-therapy. Peripheral blood mononuclear cells were collected before therapy, at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow cytometry for the subsets of T cells, regulatory T cells, natural killer cells, and myeloid-derived suppressor cells. Associations between overall survival (OS) and immune cell subsets prior to treatment, and the change in a given immune cell subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63 years (1.77–3.45). There were trends toward associations for longer OS and certain immune cell subsets before immunotherapy: lower PD-1+Tim-3NEGCD4EM (P = 0.005, adjusted P = 0.010), higher PD-1NEGTim-3+CD8 (P = 0.002, adjusted P = 0.004), and a higher number of CTLA-4NEG Tregs (P = 0.005, adjusted P = 0.010). We also found that an increase in Tim-3+ natural killer cells post- versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P = 0.015). These results should be considered as hypothesis generating and should be further evaluated in larger immunotherapy trials.

Keywords

Ipilimumab Vaccine PROSTVAC T cells NK cells Immunotherapy 

Abbreviations

ALC

Absolute lymphocyte count

CTLA-4

Cytotoxic T-lymphocyte-associated antigen-4

DT

Doubling time

EM

Effector memory

GM-CSF

Granulocyte–macrophage colony-stimulating factor

ICOS

Inducible costimulator

IFN

Interferon

IL

Interleukin

mCRPC

Metastatic castration-resistant prostate cancer

MDSC

Myeloid-derived suppressor cell

NK

Natural killer

OS

Overall survival

PAP

Prostatic acid phosphatase

PBMC

Peripheral blood mononuclear cell

PD-1

Programmed death 1 receptor

PSA

Prostate-specific antigen

PSMA

Prostate-specific membrane antigen

TIM-3

T-cell immunoglobulin and mucin domain-containing molecule-3

Tregs

Regulatory T cells

TRICOM

Triad of costimulatory molecules (ICAM-1, B7.1, and LFA-3)

Notes

Acknowledgments

Grant support was provided by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors thank Debra Weingarten for her editorial assistance in the preparation of this manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2014

Authors and Affiliations

  • Caroline Jochems
    • 1
  • Jo A. Tucker
    • 1
  • Kwong-Yok Tsang
    • 1
  • Ravi A. Madan
    • 1
    • 2
  • William L. Dahut
    • 2
  • David J. Liewehr
    • 3
  • Seth M. Steinberg
    • 3
  • James L. Gulley
    • 1
    • 2
  • Jeffrey Schlom
    • 1
  1. 1.Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Medical Oncology Branch, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  3. 3.Biostatistics and Data Management Section, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA

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