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Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer

BACKGROUND: Inflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on...

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Autores principales: Alonso-Miguel, Daniel, Valdivia, Guillermo, Guerrera, Diego, Perez-Alenza, Maria Dolores, Pantelyushin, Stanislav, Alonso-Diez, Angela, Beiss, Veronique, Fiering, Steven, Steinmetz, Nicole F, Suarez-Redondo, Maria, vom Berg, Johannes, Peña, Laura, Arias-Pulido, Hugo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919457/
https://www.ncbi.nlm.nih.gov/pubmed/35277459
http://dx.doi.org/10.1136/jitc-2021-004044
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author Alonso-Miguel, Daniel
Valdivia, Guillermo
Guerrera, Diego
Perez-Alenza, Maria Dolores
Pantelyushin, Stanislav
Alonso-Diez, Angela
Beiss, Veronique
Fiering, Steven
Steinmetz, Nicole F
Suarez-Redondo, Maria
vom Berg, Johannes
Peña, Laura
Arias-Pulido, Hugo
author_facet Alonso-Miguel, Daniel
Valdivia, Guillermo
Guerrera, Diego
Perez-Alenza, Maria Dolores
Pantelyushin, Stanislav
Alonso-Diez, Angela
Beiss, Veronique
Fiering, Steven
Steinmetz, Nicole F
Suarez-Redondo, Maria
vom Berg, Johannes
Peña, Laura
Arias-Pulido, Hugo
author_sort Alonso-Miguel, Daniel
collection PubMed
description BACKGROUND: Inflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on survival of neoadjuvant intratumoral (in situ) empty cowpea mosaic virus (eCPMV) immunotherapy in companion dogs diagnosed with IMC. METHODS: Ten IMC-bearing dogs were enrolled in the study. Five dogs received medical therapy, and five received weekly neoadjuvant in situ eCPMV immunotherapy (0.2–0.4 mg per injection) and medical therapy after the second eCPMV injection. Efficacy was evaluated by reduction of tumor growth; safety by hematological and biochemistry changes in blood and plasma; and patient outcome by survival analysis. eCPMV-induced immune changes in blood cells were analyzed by flow cytometry; changes in the tumor microenvironment were evaluated by CD3 (T lymphocytes), CD20 (B lymphocytes), FoxP3 (Treg lymphocytes), myeloperoxidase (MPO; neutrophils), Ki-67 (proliferation index, PI; tumor cell proliferation), and Cleaved Caspase-3 (CC-3; apoptosis) immunohistochemistry. RESULTS: Two neoadjuvant in situ eCPMV injections resulted in tumor shrinkage in all patients by day 14 without systemic adverse events. Although surgery for IMC is generally not an option, reduction in tumor size allowed surgery in two IMC patients. In peripheral blood, in situ eCPMV immunotherapy was associated with a significant decrease of Treg(+)/CD8(+) ratio and changes in CD8(+)Granzyme B(+) T cells, which behave as a lagging predictive biomarker. In the TME, higher neutrophilic infiltration and MPO expression, lower tumor Ki-67 PI, increase in CD3(+) lymphocytes, decrease in FoxP3(+)/CD3(+) ratio (p<0.04 for all comparisons), and no changes in CC-3(+) immunostainings were observed in post-treatment tumor tissues when compared with pretreatment tumor samples. eCPMV-treated IMC patients had a statistically significant (p=0.033) improved overall survival than patients treated with medical therapy. CONCLUSIONS: Neoadjuvant in situ eCPMV immunotherapy demonstrated anti-tumor efficacy and improved survival in IMC patients without systemic adverse effects. eCPMV-induced changes in immune cells point to neutrophils as a driver of immune response. Neoadjuvant in situ eCPMV immunotherapy could be a groundbreaking immunotherapy for canine IMC and a potential future immunotherapy for human IBC patients.
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spelling pubmed-89194572022-03-25 Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer Alonso-Miguel, Daniel Valdivia, Guillermo Guerrera, Diego Perez-Alenza, Maria Dolores Pantelyushin, Stanislav Alonso-Diez, Angela Beiss, Veronique Fiering, Steven Steinmetz, Nicole F Suarez-Redondo, Maria vom Berg, Johannes Peña, Laura Arias-Pulido, Hugo J Immunother Cancer Oncolytic and Local Immunotherapy BACKGROUND: Inflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on survival of neoadjuvant intratumoral (in situ) empty cowpea mosaic virus (eCPMV) immunotherapy in companion dogs diagnosed with IMC. METHODS: Ten IMC-bearing dogs were enrolled in the study. Five dogs received medical therapy, and five received weekly neoadjuvant in situ eCPMV immunotherapy (0.2–0.4 mg per injection) and medical therapy after the second eCPMV injection. Efficacy was evaluated by reduction of tumor growth; safety by hematological and biochemistry changes in blood and plasma; and patient outcome by survival analysis. eCPMV-induced immune changes in blood cells were analyzed by flow cytometry; changes in the tumor microenvironment were evaluated by CD3 (T lymphocytes), CD20 (B lymphocytes), FoxP3 (Treg lymphocytes), myeloperoxidase (MPO; neutrophils), Ki-67 (proliferation index, PI; tumor cell proliferation), and Cleaved Caspase-3 (CC-3; apoptosis) immunohistochemistry. RESULTS: Two neoadjuvant in situ eCPMV injections resulted in tumor shrinkage in all patients by day 14 without systemic adverse events. Although surgery for IMC is generally not an option, reduction in tumor size allowed surgery in two IMC patients. In peripheral blood, in situ eCPMV immunotherapy was associated with a significant decrease of Treg(+)/CD8(+) ratio and changes in CD8(+)Granzyme B(+) T cells, which behave as a lagging predictive biomarker. In the TME, higher neutrophilic infiltration and MPO expression, lower tumor Ki-67 PI, increase in CD3(+) lymphocytes, decrease in FoxP3(+)/CD3(+) ratio (p<0.04 for all comparisons), and no changes in CC-3(+) immunostainings were observed in post-treatment tumor tissues when compared with pretreatment tumor samples. eCPMV-treated IMC patients had a statistically significant (p=0.033) improved overall survival than patients treated with medical therapy. CONCLUSIONS: Neoadjuvant in situ eCPMV immunotherapy demonstrated anti-tumor efficacy and improved survival in IMC patients without systemic adverse effects. eCPMV-induced changes in immune cells point to neutrophils as a driver of immune response. Neoadjuvant in situ eCPMV immunotherapy could be a groundbreaking immunotherapy for canine IMC and a potential future immunotherapy for human IBC patients. BMJ Publishing Group 2022-03-11 /pmc/articles/PMC8919457/ /pubmed/35277459 http://dx.doi.org/10.1136/jitc-2021-004044 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Oncolytic and Local Immunotherapy
Alonso-Miguel, Daniel
Valdivia, Guillermo
Guerrera, Diego
Perez-Alenza, Maria Dolores
Pantelyushin, Stanislav
Alonso-Diez, Angela
Beiss, Veronique
Fiering, Steven
Steinmetz, Nicole F
Suarez-Redondo, Maria
vom Berg, Johannes
Peña, Laura
Arias-Pulido, Hugo
Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
title Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
title_full Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
title_fullStr Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
title_full_unstemmed Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
title_short Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
title_sort neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
topic Oncolytic and Local Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919457/
https://www.ncbi.nlm.nih.gov/pubmed/35277459
http://dx.doi.org/10.1136/jitc-2021-004044
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