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

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 impro...

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Autores principales: Koch, Elias A. T., Schaft, Niels, Kummer, Mirko, Berking, Carola, Schuler, Gerold, Hasumi, Kenichiro, Dörrie, Jan, Schuler-Thurner, Beatrice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8854646/
https://www.ncbi.nlm.nih.gov/pubmed/35185883
http://dx.doi.org/10.3389/fimmu.2022.785231
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author Koch, Elias A. T.
Schaft, Niels
Kummer, Mirko
Berking, Carola
Schuler, Gerold
Hasumi, Kenichiro
Dörrie, Jan
Schuler-Thurner, Beatrice
author_facet Koch, Elias A. T.
Schaft, Niels
Kummer, Mirko
Berking, Carola
Schuler, Gerold
Hasumi, Kenichiro
Dörrie, Jan
Schuler-Thurner, Beatrice
author_sort Koch, Elias A. T.
collection PubMed
description 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 3(rd) 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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spelling pubmed-88546462022-02-19 A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma Koch, Elias A. T. Schaft, Niels Kummer, Mirko Berking, Carola Schuler, Gerold Hasumi, Kenichiro Dörrie, Jan Schuler-Thurner, Beatrice Front Immunol Immunology 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 3(rd) 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. Frontiers Media S.A. 2022-02-04 /pmc/articles/PMC8854646/ /pubmed/35185883 http://dx.doi.org/10.3389/fimmu.2022.785231 Text en Copyright © 2022 Koch, Schaft, Kummer, Berking, Schuler, Hasumi, Dörrie and Schuler-Thurner https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Koch, Elias A. T.
Schaft, Niels
Kummer, Mirko
Berking, Carola
Schuler, Gerold
Hasumi, Kenichiro
Dörrie, Jan
Schuler-Thurner, Beatrice
A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma
title A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma
title_full A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma
title_fullStr A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma
title_full_unstemmed A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma
title_short A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma
title_sort one-armed phase i dose escalation trial design: personalized vaccination with ikkβ-matured, rna-loaded dendritic cells for metastatic uveal melanoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8854646/
https://www.ncbi.nlm.nih.gov/pubmed/35185883
http://dx.doi.org/10.3389/fimmu.2022.785231
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