Abstract

Dendritic cells are the most professional antigen-presenting cells of the
immune system. They play a crucial role in the initiation and regulation of
immune responses. Therefore, clinical trials have been conducted, using
tumor-antigen loaded dendritic cells as a cellular immunotherapy in cancer
patients. The Laboratory of Molecular and Cellular Therapy previously
demonstrated that the immunostimulatory capacity of monocyte derived
dendritic cells can be greatly enhanced by electroporating immature
dendritic cells with messenger RNA encoding for CD40 ligand, CD70 and
constitutively active toll-like receptor 4, the so called TriMix formulation.
Moreover, these TriMix-DCs can be co-electroporated with melanomaassociated
antigens and provide superior antigen-specific T-cell stimulation
in vitro.
In this thesis, we evaluated the feasibility, safety, immunogenicity and
activity of the autologous TriMixDC-MEL formulation in melanoma patients in
three consecutive clinical trials. We demonstrated that TriMixDC-MEL
therapy could be succesfully prepared for most of the patients and was well
tolerated when injected intradermally. Antigen-specific immune responses
were found in half of all patients. Moreover, in melanoma patients at high
risk for recurrence after the resection of macrometastases, this therapy
resulted in encouraging overall survival compared with historical controls. In
a dose-escalation phase I clinical trial we documented anti-tumor responses
in pretreated advanced melanoma patients when TriMixDC-MEL was
administered intravenously, hereby underlining the importance of the route
of administration. Finally, we combined TriMixDC-MEL with an anti-CTLA-4
monoclonal antibody in a phase II study and observed increased efficacy
with a high percentage of durable responses in patients with metastatic
melanoma.
Date of Award29 Jun 2017
Original languageEnglish
Awarding Institution
  • Vrije Universiteit Brussel
SupervisorBart Neyns (Promotor), Kris Thielemans (Promotor), Hendrik Everaert (Jury), Jan Gutermuth (Jury), Mark De Ridder (Jury), Jolanda de Vries (Jury), Inge Marie Svane (Jury) & Lieve Brochez (Jury)

Keywords

  • Dendritic cells
  • immune system
  • tumor-antigen
  • cellular immunotherapy
  • cancer

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