Systemic cellular viroimmunotherapy for canine high-grade gliomas

Abstract

BackgroundOncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical tumors and disseminated cancer, such as high-grade gliomas. Companion dogs present malignant gliomas with biological, genetic, phenotypic, immunological, and clinical similarities to human gliomas. These features favor comparative approaches, leading to the treatment of canine oncological patients to achieve translational applications to the human clinic. The systemic administration of oncolytic viruses presents a challenge due to their limitations in effectively targeting tumors and metastases. Therefore, the aim of this study is to evaluate the safety and antitumor activity of a virotherapy used in spontaneous canine tumors.MethodsTen dogs with high-grade rostrotentorial gliomas underwent weekly systemic endovenous cellular virotherapy with dCelyvir (canine mesenchymal stem cells infected with the canine oncolytic adenovirus ICOCAV17) for 8 weeks. Efficacy was determined in seven dogs according to the Response Assessment in Veterinary Neuro-Oncology criteria considering clinical status and MRI measurements. Medical history, physical and neurological examinations, and vaccination status were evaluated prior to and during follow-up. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. Immune populations were analyzed by flow cytometry in peripheral blood and by gene expression and immunohistochemistry in the tumor microenvironment.ResultsThe treatment was well tolerated and major adverse effects were not observed. Two dogs had partial responses (76% and 86% reduction in tumor size), and 3/7 showed stable disease. ICOCAV17 was detected in peripheral blood in nine dogs, and a correlation between the ICOCAV17 particles and anti-canine adenovirus (CAV) antibodies was observed. ICOCAV17 was detected in 3/9 tumor tissues after necropsies. Regarding tumor-infiltrating lymphocytes, the dogs with disease stabilization and partial response tended to have reduced memory B-cell infiltration and increased monocyte/macrophage lineage cells.ConclusionsThese findings indicate that dCelyvir is safe and presents efficacy in canine rostrotentorial high-grade gliomas. These data are relevant to the ongoing phase Ib regulated human clinical trial that is administering this virotherapy to children, adolescents, and young adults with diffuse pontine glioma. Celyvir should be further explored as a treatment in veterinary and human neuro-oncology.

Improved characterization and translation of NK cells for canine immunotherapy

“…To bypass hurdles associated with non-surgical tumors and improve systemic effects, autologous canine mesenchymal stem cells can be infected with a canine oncolytic adenovirus and administered to patients. This was performed on 27 dogs with extracranial cancer and assessed by the same group in 10 subsequent dogs with high-grade gliomas ( 34 , 35 ). In the initial trial, peripheral immune cells including NK cells increased after each dose, although the changes were not statistically significant ( 34 ).…”

“…In the initial trial, peripheral immune cells including NK cells increased after each dose, although the changes were not statistically significant ( 34 ). In the subsequent trial, dogs with gliomas received eight weekly treatments of cellular virotherapy ( 35 ). Using CIBERSORT analysis of bulk-RNAseq on tumor tissue, they found that NK cell fractions were not changed between responders and non-responders post-treatment ( 35 ).…”

“…In the subsequent trial, dogs with gliomas received eight weekly treatments of cellular virotherapy ( 35 ). Using CIBERSORT analysis of bulk-RNAseq on tumor tissue, they found that NK cell fractions were not changed between responders and non-responders post-treatment ( 35 ).…”

The Integration of Community-Dwelling Non-Human Companion Animals in Research Programs

“…(cancerous) (Cloquell et al, 2022;Sayour et al, 2018) Lymphomas (Burton et al, 2018;Gavazza et al, 2013;Sorenmo et al, 2011) Melanomas (Alexander et al, 2006;Barbosa et al, 2023;Forsberg et al, 2023;Riccardo et al, 2019Riccardo et al, , 2022Saellstrom et al, 2021) Sarcomas (Borgatti et al, 2017;Decker et al, 2017;Halpert et al, 2017;Hay et al, 2022;Judge et al, 2020;Ligon et al, 2023;Mason et al, 2016;Sahora et al, 2012;Tierce et al, 2021) General cancer (Frazier et al, 2014;Janku et al, 2016;Mason et al, 2021;Monjazeb et al, 2013;Roberts et al, 2014;Rusk et al, 2006;Saba et al, 2016;Schuh et al, 2017; Spinal cord injury (Granger et al, 2012;Prager et al, 2022) Hemophilia (Callan et al, 2016) Primary corneal endothelial degeneration (Michalak et al, 2022) Epilepsy (Patterson et al, 2020) Antiparasitic agents (Cotreau et al, 2003) Gingivitis (Arzi et al, 2020) Gliomas (non cancerous) (Bentley et al, 2018)…”