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Updated: Oct 3, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic
Elias A T Koch1,2,3, Niels Schaft1,2,3, Mirko Kummer1,2,3
1Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Abstract:
Uveal melanoma (UM) is an orphan disease with a mortality of 80% within one year upon the development of metastatic disease. UM does hardly respond to chemotherapy and kinase inhibitors and is largely resistant to checkpoint inhibition. Hence, further therapy approaches are urgently needed. To improve clinical outcome, we designed a trial employing the 3rd generation personalized IKKβ-matured RNA-transfected dendritic cell (DC) vaccine which primes T cells and in addition activates NK cells. This ongoing phase I trial [NCT04335890 (www.clinicaltrials.gov), Eudract: 2018-004390-28 (www.clinicaltrialsregister.eu)] investigates patients with treatment-naive metastatic UM. Monocytes are isolated by leukapheresis, differentiated to immature DCs, matured with a cytokine cocktail, and activated via the NF-κB pathway by electroporation with RNA encoding a constitutively active mutant of IKKβ. Three types of antigen-RNA are co-electroporated: i) amplified mRNA of the tumor representing the whole transcriptome, ii) RNA encoding driver mutations identified by exome sequencing, and iii) overexpressed non-mutated tumor antigens detected by transcriptome sequencing. This highly personalized DC vaccine is applied by 9 intravenous infusions in a staggered schedule over one year. Parallel to the vaccination, standard therapy, usually an immune checkpoint blockade (ICB) as mono (anti-PD-1) or combined (anti-CTLA4 and anti-PD-1) regimen is initiated. The coordinated vaccine-induced immune response encompassing tumor-specific T cells and innate NK cells should synergize with ICB, perhaps resulting in measurable clinical responses in this resistant tumor entity. Primary outcome measures of this trial are safety, tolerability and toxicity; secondary outcome measures comprise overall survival and induction of antigen-specific T cells.
Insights
This study evaluates a personalized dendritic cell (DC) vaccine for metastatic uveal melanoma (UM), aiming to improve outcomes by combining it with immune checkpoint blockade (ICB). The novel vaccine targets tumor antigens and activates immune cells for a synergistic effect.
Area of Science:
- Oncology
- Immunotherapy
- Vaccine Development
Background:
- Uveal melanoma (UM) is a rare cancer with poor prognosis, especially in metastatic stages, showing resistance to conventional therapies.
- Existing treatments like chemotherapy, kinase inhibitors, and checkpoint inhibition have limited efficacy in metastatic UM.
- Novel therapeutic strategies are urgently needed to improve clinical outcomes for patients with metastatic UM.
Purpose of the Study:
- To investigate the safety and efficacy of a novel, personalized dendritic cell (DC) vaccine in patients with treatment-naive metastatic UM.
- To assess the potential synergy between the personalized DC vaccine and standard immune checkpoint blockade (ICB).
- To evaluate the induction of antigen-specific T cells and natural killer (NK) cells as a result of the vaccination.
Main Methods:
- A phase I clinical trial involving patients with treatment-naive metastatic UM.
- Development of a personalized DC vaccine using patient monocytes, electroporated with RNA encoding whole transcriptome, driver mutations, and tumor antigens.
- Vaccine administration via 9 intravenous infusions over one year, concurrently with standard ICB (anti-PD-1 or anti-CTLA4/anti-PD-1).
Main Results:
- The primary outcome measures are safety, tolerability, and toxicity of the personalized DC vaccine combined with ICB.
- Secondary outcome measures include overall survival and the induction of antigen-specific T cells.
- Early data on clinical responses and immune cell activation are being collected in this ongoing trial.
Conclusions:
- The personalized DC vaccine, combined with ICB, represents a novel therapeutic approach for metastatic UM.
- This strategy aims to overcome resistance to current therapies by priming T cells and activating NK cells.
- Further results from this trial are anticipated to determine the clinical benefit and feasibility of this personalized immunotherapy.
