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

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.

Keywords: IKKβ-matured dendritic cells; Immune checkpoint blockade; metastatic uveal melanoma; personalized vaccine; tumor antigen vaccine; tumor antigens.

Conflict of interest statement

The authors declare the following potential conflict of interest: GS, NS, and JD are named as inventors on a patent on caIKK-RNA-electroporated DCs (WO/2012/055551), which is held by the Friedrich-Alexander-Universtät Erlangen-Nürnberg. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Koch, Schaft, Kummer, Berking, Schuler, Hasumi, Dörrie and Schuler-Thurner.

Figures

Figure 1

DCs present tumor antigens through MHC class I and II to CD8+ and CD4+ T cells, respectively, and are able to activate innate immune cells, like NK cells. T-cell priming is supported by co-stimulatory molecules and the secretion of pro-inflammatory cytokines. NF-κB-activated DCs express increased levels of the classical co-stimulatory molecules CD80 and CD86, but also of CD70, CD40, OX40L, and several pro-inflammatory cytokines, such as IL-12 and TNFα, which support induction of memory T-cell responses and increase NK-cell activation and proliferation. The antigens used in this trial are modified in such a way, that both MHC class I- and class II-restricted presentation is facilitated. Therefore, a comprehensive cellular response of helper T cells, cytotoxic T cells, and NK cells is induced, which in turn produce additional cytokines that support activation.

Figure 2

Treatment schedule: Initially a tumor biopsy is taken, and RNA and DNA preparation and sequencing is performed. To obtain the required numbers of autologous DCs, a monocyte concentrate is collected via leukapheresis. The vaccine is generated by RNA-electroporation of DCs and 9 vaccine injections are given intravenously over a period of one year. Every three months CT/MRI staging is performed.