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A Phase I Open‐Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies

LESSONS LEARNED: The novel therapeutic vaccine hVEGF(26–104)/RFASE was found to be safe and well tolerated in patients with cancer. hVEGF(26–104)/RFASE failed to induce seroconversion against native hVEGF(165) and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VE...

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Autores principales: Goedegebuure, Ruben S.A., Wentink, Madelon Q., van der Vliet, Hans J., Timmerman, Peter, Griffioen, Arjan W., de Gruijl, Tanja D., Verheul, Henk M.W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873342/
https://www.ncbi.nlm.nih.gov/pubmed/33105058
http://dx.doi.org/10.1002/onco.13576
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author Goedegebuure, Ruben S.A.
Wentink, Madelon Q.
van der Vliet, Hans J.
Timmerman, Peter
Griffioen, Arjan W.
de Gruijl, Tanja D.
Verheul, Henk M.W.
author_facet Goedegebuure, Ruben S.A.
Wentink, Madelon Q.
van der Vliet, Hans J.
Timmerman, Peter
Griffioen, Arjan W.
de Gruijl, Tanja D.
Verheul, Henk M.W.
author_sort Goedegebuure, Ruben S.A.
collection PubMed
description LESSONS LEARNED: The novel therapeutic vaccine hVEGF(26–104)/RFASE was found to be safe and well tolerated in patients with cancer. hVEGF(26–104)/RFASE failed to induce seroconversion against native hVEGF(165) and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed. Remarkably, hVEGF(26–104)/RFASE induced VEGF(165)‐neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates. BACKGROUND: Targeting vascular endothelial growth factor‐A (VEGF) is a well‐established anticancer therapy. We designed a first‐in‐human clinical trial to investigate the safety and immunogenicity of the novel vaccine hVEGF(26–104)/RFASE. METHODS: Patients with advanced solid malignancies with no standard treatment options available were eligible for this phase I study with a 3+3 dose‐escalation design. On days 0, 14, and 28, patients received intramuscular hVEGF(26–104), a truncated synthetic three‐dimensional (3D)‐structured peptide mimic covering the amino acids 26–104 of the human VEGF(165) isoform, emulsified in the novel adjuvant Raffinose Fatty Acid Sulphate Ester (RFASE), a sulpholipopolysaccharide. Objectives were to determine safety, induction of VEGF‐neutralizing antibodies, and the maximum tolerated dose. Blood was sampled to measure VEGF levels and antibody titers. RESULTS: Eighteen of 27 enrolled patients received three immunizations in six different dose‐levels up to 1,000 μg hVEGF(26–104) and 40 mg RFASE. No dose‐limiting toxicity was observed. Although in four patients an antibody titer against hVEGF(26–104) was induced (highest titer: 2.77 (10)log), neither a reduction in VEGF levels nor neutralizing antibodies against native VEGF(165) were detected. CONCLUSION: Despite having an attractive safety profile, hVEGF(26–104)/RFASE was not able to elicit seroconversions against native VEGF(165) and, consequently, did not decrease circulating VEGF levels. Deficient RFASE adjuvant activity, as well as dominant immunoreactivity toward neoepitopes, may have impeded hVEGF(26–104)/RFASE's efficacy in humans.
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spelling pubmed-78733422021-02-17 A Phase I Open‐Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies Goedegebuure, Ruben S.A. Wentink, Madelon Q. van der Vliet, Hans J. Timmerman, Peter Griffioen, Arjan W. de Gruijl, Tanja D. Verheul, Henk M.W. Oncologist Clinical Trial Results LESSONS LEARNED: The novel therapeutic vaccine hVEGF(26–104)/RFASE was found to be safe and well tolerated in patients with cancer. hVEGF(26–104)/RFASE failed to induce seroconversion against native hVEGF(165) and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed. Remarkably, hVEGF(26–104)/RFASE induced VEGF(165)‐neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates. BACKGROUND: Targeting vascular endothelial growth factor‐A (VEGF) is a well‐established anticancer therapy. We designed a first‐in‐human clinical trial to investigate the safety and immunogenicity of the novel vaccine hVEGF(26–104)/RFASE. METHODS: Patients with advanced solid malignancies with no standard treatment options available were eligible for this phase I study with a 3+3 dose‐escalation design. On days 0, 14, and 28, patients received intramuscular hVEGF(26–104), a truncated synthetic three‐dimensional (3D)‐structured peptide mimic covering the amino acids 26–104 of the human VEGF(165) isoform, emulsified in the novel adjuvant Raffinose Fatty Acid Sulphate Ester (RFASE), a sulpholipopolysaccharide. Objectives were to determine safety, induction of VEGF‐neutralizing antibodies, and the maximum tolerated dose. Blood was sampled to measure VEGF levels and antibody titers. RESULTS: Eighteen of 27 enrolled patients received three immunizations in six different dose‐levels up to 1,000 μg hVEGF(26–104) and 40 mg RFASE. No dose‐limiting toxicity was observed. Although in four patients an antibody titer against hVEGF(26–104) was induced (highest titer: 2.77 (10)log), neither a reduction in VEGF levels nor neutralizing antibodies against native VEGF(165) were detected. CONCLUSION: Despite having an attractive safety profile, hVEGF(26–104)/RFASE was not able to elicit seroconversions against native VEGF(165) and, consequently, did not decrease circulating VEGF levels. Deficient RFASE adjuvant activity, as well as dominant immunoreactivity toward neoepitopes, may have impeded hVEGF(26–104)/RFASE's efficacy in humans. John Wiley & Sons, Inc. 2020-11-19 2021-02 /pmc/articles/PMC7873342/ /pubmed/33105058 http://dx.doi.org/10.1002/onco.13576 Text en © 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Clinical Trial Results
Goedegebuure, Ruben S.A.
Wentink, Madelon Q.
van der Vliet, Hans J.
Timmerman, Peter
Griffioen, Arjan W.
de Gruijl, Tanja D.
Verheul, Henk M.W.
A Phase I Open‐Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies
title A Phase I Open‐Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies
title_full A Phase I Open‐Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies
title_fullStr A Phase I Open‐Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies
title_full_unstemmed A Phase I Open‐Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies
title_short A Phase I Open‐Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies
title_sort phase i open‐label clinical trial evaluating the therapeutic vaccine hvegf26–104/rfase in patients with advanced solid malignancies
topic Clinical Trial Results
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873342/
https://www.ncbi.nlm.nih.gov/pubmed/33105058
http://dx.doi.org/10.1002/onco.13576
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