Abstract 6663: Innovative CPMV immunotherapy: A canine model for poor-prognosis breast cancer treatment
Authors: Valdivia Guillermo , Pérez-Alenza Dolores , Barreno Lucía , Alonso-Diez Ángela , de Oliveira Jessica Fernanda Affonso , Suárez-Redondo María , Fiering Steven F. , Steinmetz Nicole F. , Peña Laura 
Published: March 2024

Abstract
Cowpea Mosaic Virus (CPMV) is a plant comovirus non-infectious to humans or animals. In mice models, intratumor immunotherapy (ITI) with CPMV devoid of nucleic acids (empty CPMV, eCPMV) and full CPMV results in a highly potent, systemic, antitumor immune response, with full CPMV being much more effective. Dogs with spontaneous mammary (breast) cancer (MC) serve as a valuable model for studying breast cancer (BC), bridging the gap between studies in rodents and human clinical trials. Canine MC develops in the presence of an intact immune system and has a unique advantage of shorter endpoint periods compared to women BC clinical trials. New immunotherapeutic approaches are necessary for poor-prognosis BC, such as triple-negative BC, metastatic BC, and the very aggressive and lethal inflammatory BC (IBC). Previous studies by our group using eCPMV ITI in dogs with MC revealed a substantial reduction in tumor size in both injected and non-injected tumors (abscopal effect), extended survival, and improved quality of life without any adverse effects or toxicity. In this clinical trial, we employed full CPMV nanoparticles ITI in dogs with poor-prognosis (inoperable) MC, comparing them with untreated controls. Regular tumor volume assessments and clinical evaluations have been conducted. Histopathology and immunohistochemistry of immune cell populations were performed to study tumor microenvironment (TME) modifications. Thus far, 5 dogs have been treated: four cases of inflammatory mammary cancer (IMC) and one case of metastatic MC. After at least two weekly CPMV ITI sessions, a significant reduction in tumor volumes was observed. In IMC cases, marked clinical improvement of typical signs (warmth, edema, erythema, and cutaneous pain) was observed in 3 out of 4 cases, and tumor reduction was so remarkable in one dog that surgery was recommended and successfully carried out. In IMC CPMV ITI cases, the survival of 2 dogs exceeded historical IMC records; the dog with metastatic MC maintains stable disease after one year, which is also superior to controls. TME studies showed that eCPMV immunotherapy significantly increased intratumor inflammatory infiltrates, neutrophils, T lymphocytes, and macrophages. Additionally, Treg cells (FOXP3+)/T lymphocytes (CD3+) ratio was significantly reduced. Our results demonstrate that immunotherapy with eCPMV induces a potent immunostimulatory effect on dogs with poor-prognosis MC by recruiting and activating neutrophils as the main drivers of the inflammatory response. This process reduces the immunosuppressive action of regulatory T lymphocytes and produces a breakdown of tumor immune suppression. These findings underscore the therapeutic potential of CPMV nanoparticles ITI in the management of canine IMC and metastatic MC. From a translational point of view, this study lays the groundwork for advancing the treatment of human breast cancer.
Citation Format: Guillermo Valdivia, Dolores Pérez-Alenza, Lucía Barreno, Ángela Alonso-Diez, Jessica Fernanda Affonso de Oliveira, María Suárez-Redondo, Steven F. Fiering, Nicole F. Steinmetz, Laura Peña. Innovative CPMV immunotherapy: A canine model for poor-prognosis breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6663.