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

Cancer Immunol Immunother. 2014 Apr;63(4):407-18. doi: 10.1007/s00262-014-1524-0. Epub 2014 Feb 11.

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-3(NEG)CD4EM (P = 0.005, adjusted P = 0.010), higher PD-1(NEG)Tim-3(+)CD8 (P = 0.002, adjusted P = 0.004), and a higher number of CTLA-4(NEG) 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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenocarcinoma / blood
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / secondary*
  • Adenocarcinoma / therapy
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, Differentiation / analysis
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / therapeutic use*
  • Combined Modality Therapy
  • Flow Cytometry
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Immunophenotyping
  • Ipilimumab
  • Kaplan-Meier Estimate
  • Killer Cells, Natural / chemistry
  • Killer Cells, Natural / immunology
  • Lymphocyte Count
  • Male
  • Membrane Proteins / analysis
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / therapy*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / chemistry
  • T-Lymphocytes, Regulatory / immunology
  • Th17 Cells / immunology
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / therapeutic use

Substances

  • Antibodies, Monoclonal
  • Antigens, Differentiation
  • Cancer Vaccines
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Ipilimumab
  • Membrane Proteins
  • PROSTVAC
  • Vaccines, Synthetic
  • Prostate-Specific Antigen