Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy

J Immunother. Sep-Oct 2004;27(5):354-67. doi: 10.1097/00002371-200409000-00004.

Abstract

MART-1(27-35)-peptide-pulsed immature dendritic cells (DCs) resulted in immunologic and clinical activity in a prior phase 1 trial. A phase 2 cohort expansion was initiated to further characterize the phenotype and cytokine milieu of the DC vaccines and their immunologic activity in vitro and to further examine a possible link between clinical activity and determinant spreading. In an open-label phase 2 trial, 10(7) autologous ex vivo generated DCs pulsed with the HLA-A*0201 immunodominant peptide MART-1(27-35) were administered to 10 subjects with stage II-IV melanoma. The experimental vaccines were administered intradermally in a biweekly schedule for a total of three injections, and blood for immunologic assays was obtained before each administration and at three time points after. DC vaccine preparations had wide intra- and interpatient variability in terms of cell surface markers and preferential cytokine milieu, but they did not correlate with the levels of antigen-specific T cells after vaccination. Of four patients with measurable disease, one had stable disease for 6 months and another has a continued complete response for over 2 years, which is confounded by receiving a closely sequenced CTLA4 blocking antibody. The DC vaccines induced determinant spreading in this subject, and CTLA4 blockade reactivated T cells with prior antigen exposure. The DC phenotype and cytokine profile do not correlate with the ability to induce antigen-specific T cells, while determinant spreading after DC immunization may be a marker of an efficient antitumor response. Sequential CTLA4 blockade may enhance the immune activity of DC-based immunotherapy.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antibodies, Blocking / therapeutic use
  • Antigens, CD
  • Antigens, Differentiation / immunology
  • Biomarkers / analysis
  • CTLA-4 Antigen
  • Cancer Vaccines / therapeutic use
  • Cytokines / immunology
  • Dendritic Cells / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / immunology
  • Female
  • Humans
  • Immunotherapy*
  • Isoantigens / immunology*
  • Male
  • Melanoma / immunology*
  • Melanoma / therapy*
  • Middle Aged
  • Peptide Fragments / immunology*
  • Phenotype
  • T-Lymphocytes / immunology
  • Treatment Outcome

Substances

  • Antibodies, Blocking
  • Antigens, CD
  • Antigens, Differentiation
  • Biomarkers
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cancer Vaccines
  • Cytokines
  • Epitopes
  • Isoantigens
  • MART-1 antigen (27-35), Leu(28)-beta-HIle(30)-
  • Peptide Fragments