RT Journal Article
T1 Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer
A1 Alonso Miguel, Daniel
A1 Valdivia Lara, Edgar Guillermo
A1 Guerrera, Diego
A1 Pérez Alenza, María De Los Dolores
A1 Pantelyushin, Stanislav
A1 Alonso Díez, Ángela
A1 Beiss, Veronique
A1 Fiering, Steven
A1 Steinmetz, Nicole F.
A1 Suárez Redondo, María
A1 Vom Berg, Johannes
A1 Peña Fernández, Laura Luisa
A1 Arias Pulido, Hugo
AB 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.
PB BMJ Publishing Group
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/108214
UL https://hdl.handle.net/20.500.14352/108214
LA eng
NO Alonso-Miguel D, Valdivia G, Guerrera D, et alNeoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancerJournal for ImmunoTherapy of Cancer 2022;10:e004044. doi: 10.1136/jitc-2021-004044
NO National Cancer Institute (NCI)
NO Ministerio de Ciencia, Innovación y Tecnología (España)
NO Universidad Complutense de Madrid
NO Swiss Cancer Research grants
NO Novartis Foundation for Medical-Biological Research
NO Consejo Nacional de Ciencia y Tecnología (México)
DS Docta Complutense
RD 5 abr 2025