Journal for ImmunoTherapy of Cancer (Nov 2019)

Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer

  • Harm Westdorp,
  • Jeroen H. A. Creemers,
  • Inge M. van Oort,
  • Gerty Schreibelt,
  • Mark A. J. Gorris,
  • Niven Mehra,
  • Michiel Simons,
  • Anna L. de Goede,
  • Michelle M. van Rossum,
  • Alexandra J. Croockewit,
  • Carl G. Figdor,
  • J. Alfred Witjes,
  • Erik H. J. G. Aarntzen,
  • Roel D. M. Mus,
  • Mareke Brüning,
  • Katja Petry,
  • Martin Gotthardt,
  • Jelle O. Barentsz,
  • I. Jolanda M. de Vries,
  • Winald R. Gerritsen

DOI
https://doi.org/10.1186/s40425-019-0787-6
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 15

Abstract

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Abstract Background Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c+ myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs). Methods In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. Results Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm+ and IFN-γ+ antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1–2 toxicity. Conclusions Immunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome. Trial registration ClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.

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