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Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition
Checkpoint inhibitors have revolutionized cancer therapy and validated immunotherapy as an approach. Unfortunately, responses are seen in a minority of patients. Our objective is to use engineered adenoviruses designed to increase lymphocyte trafficking and cytokine production at the tumor, to asses...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458667/ https://www.ncbi.nlm.nih.gov/pubmed/32923123 http://dx.doi.org/10.1080/2162402X.2020.1761229 |
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author | Cervera-Carrascon, Victor Quixabeira, Dafne C.A. Santos, Joao Manuel Havunen, Riikka Zafar, Sadia Hemminki, Otto Heiniö, Camilla Munaro, Eleonora Siurala, Mikko Sorsa, Suvi Mirtti, Tuomas Järvinen, Petrus Mildh, Markus Nisen, Harry Rannikko, Antti Anttila, Marjukka Kanerva, Anna Hemminki, Akseli |
author_facet | Cervera-Carrascon, Victor Quixabeira, Dafne C.A. Santos, Joao Manuel Havunen, Riikka Zafar, Sadia Hemminki, Otto Heiniö, Camilla Munaro, Eleonora Siurala, Mikko Sorsa, Suvi Mirtti, Tuomas Järvinen, Petrus Mildh, Markus Nisen, Harry Rannikko, Antti Anttila, Marjukka Kanerva, Anna Hemminki, Akseli |
author_sort | Cervera-Carrascon, Victor |
collection | PubMed |
description | Checkpoint inhibitors have revolutionized cancer therapy and validated immunotherapy as an approach. Unfortunately, responses are seen in a minority of patients. Our objective is to use engineered adenoviruses designed to increase lymphocyte trafficking and cytokine production at the tumor, to assess if they increase the response rate to checkpoint inhibition, as these features have been regarded as predictive for the responses. When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding for TNFa and IL-2, also known as TILT-123) and checkpoint inhibitors were used together in fresh urological tumor histocultures, a significant shift toward immune activity (not only tumor necrosis alpha and interleukin-2 but also interferon gamma and granzyme B) and increased T-cell trafficking signals (CXCL10) was observed. In vivo, our viruses enabled an anti-PD-L1 (a checkpoint inhibitor) delivering complete responses in all the treated animals (hazard ratios versus anti-PD-L1 alone 0.057 [0.007; 0.451] or virotherapy alone 0.067 [0.011; 0.415]). To conclude, when an engineered oncolytic adenovirus was utilized to modify the tumor microenvironment towards what meta-analyses have pointed as predictive markers for checkpoint inhibitory therapy, the response to them increased synergistically. Of note, key findings were confirmed in fresh patient-derived tumor explants. |
format | Online Article Text |
id | pubmed-7458667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-74586672020-09-11 Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition Cervera-Carrascon, Victor Quixabeira, Dafne C.A. Santos, Joao Manuel Havunen, Riikka Zafar, Sadia Hemminki, Otto Heiniö, Camilla Munaro, Eleonora Siurala, Mikko Sorsa, Suvi Mirtti, Tuomas Järvinen, Petrus Mildh, Markus Nisen, Harry Rannikko, Antti Anttila, Marjukka Kanerva, Anna Hemminki, Akseli Oncoimmunology Original Research Checkpoint inhibitors have revolutionized cancer therapy and validated immunotherapy as an approach. Unfortunately, responses are seen in a minority of patients. Our objective is to use engineered adenoviruses designed to increase lymphocyte trafficking and cytokine production at the tumor, to assess if they increase the response rate to checkpoint inhibition, as these features have been regarded as predictive for the responses. When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding for TNFa and IL-2, also known as TILT-123) and checkpoint inhibitors were used together in fresh urological tumor histocultures, a significant shift toward immune activity (not only tumor necrosis alpha and interleukin-2 but also interferon gamma and granzyme B) and increased T-cell trafficking signals (CXCL10) was observed. In vivo, our viruses enabled an anti-PD-L1 (a checkpoint inhibitor) delivering complete responses in all the treated animals (hazard ratios versus anti-PD-L1 alone 0.057 [0.007; 0.451] or virotherapy alone 0.067 [0.011; 0.415]). To conclude, when an engineered oncolytic adenovirus was utilized to modify the tumor microenvironment towards what meta-analyses have pointed as predictive markers for checkpoint inhibitory therapy, the response to them increased synergistically. Of note, key findings were confirmed in fresh patient-derived tumor explants. Taylor & Francis 2020-05-22 /pmc/articles/PMC7458667/ /pubmed/32923123 http://dx.doi.org/10.1080/2162402X.2020.1761229 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Cervera-Carrascon, Victor Quixabeira, Dafne C.A. Santos, Joao Manuel Havunen, Riikka Zafar, Sadia Hemminki, Otto Heiniö, Camilla Munaro, Eleonora Siurala, Mikko Sorsa, Suvi Mirtti, Tuomas Järvinen, Petrus Mildh, Markus Nisen, Harry Rannikko, Antti Anttila, Marjukka Kanerva, Anna Hemminki, Akseli Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition |
title | Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition |
title_full | Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition |
title_fullStr | Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition |
title_full_unstemmed | Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition |
title_short | Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition |
title_sort | tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from pd-l1 inhibition |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458667/ https://www.ncbi.nlm.nih.gov/pubmed/32923123 http://dx.doi.org/10.1080/2162402X.2020.1761229 |
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