Frontiers in Immunology (Feb 2022)

A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma

  • Elias A. T. Koch,
  • Elias A. T. Koch,
  • Elias A. T. Koch,
  • Niels Schaft,
  • Niels Schaft,
  • Niels Schaft,
  • Mirko Kummer,
  • Mirko Kummer,
  • Mirko Kummer,
  • Carola Berking,
  • Carola Berking,
  • Carola Berking,
  • Gerold Schuler,
  • Gerold Schuler,
  • Gerold Schuler,
  • Kenichiro Hasumi,
  • Jan Dörrie,
  • Jan Dörrie,
  • Jan Dörrie,
  • Beatrice Schuler-Thurner,
  • Beatrice Schuler-Thurner,
  • Beatrice Schuler-Thurner

DOI
https://doi.org/10.3389/fimmu.2022.785231
Journal volume & issue
Vol. 13

Abstract

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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.

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