Autologous mRNA electroporated dendritic cell-based immunotherapy for melanoma patients.

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.