Cancer Immunology, Immunotherapy

, Volume 63, Issue 4, pp 407–418

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

Authors

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

DOI: 10.1007/s00262-014-1524-0

Cite this article as:
Jochems, C., Tucker, J.A., Tsang, K. et al. Cancer Immunol Immunother (2014) 63: 407. doi:10.1007/s00262-014-1524-0

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

IpilimumabVaccinePROSTVACT cellsNK cellsImmunotherapy

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)

Copyright information

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