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The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model

Glioblastoma (GBM) is an obligatory lethal brain tumor with a median survival, even with the best standard of care therapy, of less than 20 months. In light of this fact, the evaluation of new GBM treatment approaches such as oncolytic virotherapy (OVT) is urgently needed. Based on our preliminary p...

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Autores principales: Klawitter, Moritz, El-Ayoubi, Ali, Buch, Jasmin, Rüttinger, Jakob, Ehrenfeld, Maximilian, Lichtenegger, Eva, Krüger, Marcel A., Mantwill, Klaus, Koll, Florestan J., Kowarik, Markus C., Holm, Per Sonne, Naumann, Ulrike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456411/
https://www.ncbi.nlm.nih.gov/pubmed/36077380
http://dx.doi.org/10.3390/ijms23179965
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author Klawitter, Moritz
El-Ayoubi, Ali
Buch, Jasmin
Rüttinger, Jakob
Ehrenfeld, Maximilian
Lichtenegger, Eva
Krüger, Marcel A.
Mantwill, Klaus
Koll, Florestan J.
Kowarik, Markus C.
Holm, Per Sonne
Naumann, Ulrike
author_facet Klawitter, Moritz
El-Ayoubi, Ali
Buch, Jasmin
Rüttinger, Jakob
Ehrenfeld, Maximilian
Lichtenegger, Eva
Krüger, Marcel A.
Mantwill, Klaus
Koll, Florestan J.
Kowarik, Markus C.
Holm, Per Sonne
Naumann, Ulrike
author_sort Klawitter, Moritz
collection PubMed
description Glioblastoma (GBM) is an obligatory lethal brain tumor with a median survival, even with the best standard of care therapy, of less than 20 months. In light of this fact, the evaluation of new GBM treatment approaches such as oncolytic virotherapy (OVT) is urgently needed. Based on our preliminary preclinical data, the YB-1 dependent oncolytic adenovirus (OAV) XVir-N-31 represents a promising therapeutic agent to treat, in particular, therapy resistant GBM. Preclinical studies have shown that XVir-N-31 prolonged the survival of GBM bearing mice. Now using an immunohumanized mouse model, we examined the immunostimulatory effects of XVir-N-31 in comparison to the wildtype adenovirus (Ad-WT). Additionally, we combined OVT with the inhibition of immune checkpoint proteins by using XVir-N-31 in combination with nivolumab, or by using a derivate of XVir-N-31 that expresses a PD-L1 neutralizing antibody. Although in vitro cell killing was higher for Ad-WT, XVir-N-31 induced a much stronger immunogenic cell death that was further elevated by blocking PD-1 or PD-L1. In vivo, an intratumoral injection of XVir-N-31 increased tumor infiltrating lymphocytes (TILs) and NK cells significantly more than Ad-WT not only in the virus-injected tumors, but also in the untreated tumors growing in the contralateral hemisphere. This suggests that for an effective treatment of GBM, immune activating properties by OAVs seem to be of greater importance than their oncolytic capacity. Furthermore, the addition of immune checkpoint inhibition (ICI) to OVT further induced lymphocyte infiltration. Consequently, a significant reduction in contralateral non-virus-injected tumors was only visible if OVT was combined with ICI. This strongly indicates that for an effective eradication of GBM cells that cannot be directly targeted by an intratumoral OV injection, additional ICI therapy is required.
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spelling pubmed-94564112022-09-09 The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model Klawitter, Moritz El-Ayoubi, Ali Buch, Jasmin Rüttinger, Jakob Ehrenfeld, Maximilian Lichtenegger, Eva Krüger, Marcel A. Mantwill, Klaus Koll, Florestan J. Kowarik, Markus C. Holm, Per Sonne Naumann, Ulrike Int J Mol Sci Article Glioblastoma (GBM) is an obligatory lethal brain tumor with a median survival, even with the best standard of care therapy, of less than 20 months. In light of this fact, the evaluation of new GBM treatment approaches such as oncolytic virotherapy (OVT) is urgently needed. Based on our preliminary preclinical data, the YB-1 dependent oncolytic adenovirus (OAV) XVir-N-31 represents a promising therapeutic agent to treat, in particular, therapy resistant GBM. Preclinical studies have shown that XVir-N-31 prolonged the survival of GBM bearing mice. Now using an immunohumanized mouse model, we examined the immunostimulatory effects of XVir-N-31 in comparison to the wildtype adenovirus (Ad-WT). Additionally, we combined OVT with the inhibition of immune checkpoint proteins by using XVir-N-31 in combination with nivolumab, or by using a derivate of XVir-N-31 that expresses a PD-L1 neutralizing antibody. Although in vitro cell killing was higher for Ad-WT, XVir-N-31 induced a much stronger immunogenic cell death that was further elevated by blocking PD-1 or PD-L1. In vivo, an intratumoral injection of XVir-N-31 increased tumor infiltrating lymphocytes (TILs) and NK cells significantly more than Ad-WT not only in the virus-injected tumors, but also in the untreated tumors growing in the contralateral hemisphere. This suggests that for an effective treatment of GBM, immune activating properties by OAVs seem to be of greater importance than their oncolytic capacity. Furthermore, the addition of immune checkpoint inhibition (ICI) to OVT further induced lymphocyte infiltration. Consequently, a significant reduction in contralateral non-virus-injected tumors was only visible if OVT was combined with ICI. This strongly indicates that for an effective eradication of GBM cells that cannot be directly targeted by an intratumoral OV injection, additional ICI therapy is required. MDPI 2022-09-01 /pmc/articles/PMC9456411/ /pubmed/36077380 http://dx.doi.org/10.3390/ijms23179965 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Klawitter, Moritz
El-Ayoubi, Ali
Buch, Jasmin
Rüttinger, Jakob
Ehrenfeld, Maximilian
Lichtenegger, Eva
Krüger, Marcel A.
Mantwill, Klaus
Koll, Florestan J.
Kowarik, Markus C.
Holm, Per Sonne
Naumann, Ulrike
The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model
title The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model
title_full The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model
title_fullStr The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model
title_full_unstemmed The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model
title_short The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model
title_sort oncolytic adenovirus xvir-n-31, in combination with the blockade of the pd-1/pd-l1 axis, conveys abscopal effects in a humanized glioblastoma mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456411/
https://www.ncbi.nlm.nih.gov/pubmed/36077380
http://dx.doi.org/10.3390/ijms23179965
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