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Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients

BACKGROUND: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy. METHODS: AdCD40L is a repli...

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Autores principales: Irenaeus, Sandra, Schiza, Aglaia, Mangsbo, Sara M., Wenthe, Jessica, Eriksson, Emma, Krause, Johan, Sundin, Anders, Ahlström, Håkan, Tötterman, Thomas H., Loskog, Angelica, Ullenhag, Gustav J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667983/
https://www.ncbi.nlm.nih.gov/pubmed/29108250
http://dx.doi.org/10.18632/oncotarget.19750
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author Irenaeus, Sandra
Schiza, Aglaia
Mangsbo, Sara M.
Wenthe, Jessica
Eriksson, Emma
Krause, Johan
Sundin, Anders
Ahlström, Håkan
Tötterman, Thomas H.
Loskog, Angelica
Ullenhag, Gustav J.
author_facet Irenaeus, Sandra
Schiza, Aglaia
Mangsbo, Sara M.
Wenthe, Jessica
Eriksson, Emma
Krause, Johan
Sundin, Anders
Ahlström, Håkan
Tötterman, Thomas H.
Loskog, Angelica
Ullenhag, Gustav J.
author_sort Irenaeus, Sandra
collection PubMed
description BACKGROUND: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy. METHODS: AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival. RESULTS: AdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood. CONCLUSIONS: AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment.
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spelling pubmed-56679832017-11-04 Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients Irenaeus, Sandra Schiza, Aglaia Mangsbo, Sara M. Wenthe, Jessica Eriksson, Emma Krause, Johan Sundin, Anders Ahlström, Håkan Tötterman, Thomas H. Loskog, Angelica Ullenhag, Gustav J. Oncotarget Research Paper BACKGROUND: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy. METHODS: AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival. RESULTS: AdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood. CONCLUSIONS: AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment. Impact Journals LLC 2017-07-31 /pmc/articles/PMC5667983/ /pubmed/29108250 http://dx.doi.org/10.18632/oncotarget.19750 Text en Copyright: © 2017 Irenaeus et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Irenaeus, Sandra
Schiza, Aglaia
Mangsbo, Sara M.
Wenthe, Jessica
Eriksson, Emma
Krause, Johan
Sundin, Anders
Ahlström, Håkan
Tötterman, Thomas H.
Loskog, Angelica
Ullenhag, Gustav J.
Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
title Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
title_full Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
title_fullStr Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
title_full_unstemmed Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
title_short Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
title_sort local irradiation does not enhance the effect of immunostimulatory adcd40l gene therapy combined with low dose cyclophosphamide in melanoma patients
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667983/
https://www.ncbi.nlm.nih.gov/pubmed/29108250
http://dx.doi.org/10.18632/oncotarget.19750
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