Safety, Tumor Reduction, and Clinical Impact of Zika Virus Injection in Dogs with Advanced-Stage Brain Tumors

Abstract

Malignant brain tumors are among the most aggressive cancers with poor prognosis and no effective treatment. Recently, we reported the oncolytic potential of Zika virus infecting and destroying the human central nervous system (CNS) tumors in vitro and in immunodeficient mice model. However, translating this approach to humans requires pre-clinical trials in another immunocompetent animal model. Here, we analyzed the safety of Brazilian Zika virus (ZIKV BR) intrathecal injections in three dogs bearing spontaneous CNS tumors aiming an anti-tumoral therapy. We further assessed some aspects of the innate immune and inflammatory response that triggers the anti-tumoral response observed during the ZIKV BR administration in vivo and in vitro. For the first time, we showed that there were no negative clinical side effects following ZIKV BR CNS injections in dogs, confirming the safety of the procedure. Furthermore, the intrathecal ZIKV BR injections reduced tumor size in immunocompetent dogs bearing spontaneous intracranial tumors, improved their neurological clinical symptoms significantly, and extended their survival by inducing the destruction specifically of tumor cells, sparing normal neurons, and activating an immune response. These results open new perspectives for upcoming virotherapy using ZIKV to destroy and induce an anti-tumoral immune response in CNS tumors for which there are currently no effective treatments.

Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

“…A study using 3 dogs bearing spontaneous CNS tumors to evaluate the safety and therapeutic effect of Brazilian Zika virus (ZIKV BR ) through intrathecal injection showed shrinkage of tumor, extension of survival and improvement of clinical symptoms without negative side effect (161). Further preclinical development of ZIKA OVT is required, including determinants of ZIKA infection in tumor cells, IFN signaling as well as protein expression signatures that enable viral entry and replication (162).…”

Combinatorial Approaches for Cancer Treatment Using Oncolytic Viruses: Projecting the Perspectives through Clinical Trials Outcomes

“…Mostly, we focused on the promising combinations based on the published clinical data, rather than presenting all oncolytic virus variations. Nevertheless, many preclinical and clinical studies using vaccines (e.g., yellow fever 17D strain [ 231 ]), attenuated (Zika virus [ 232 ]) or cancer cell-adapted viruses (e.g., rotavirus [ 233 ]) are currently ongoing and demonstrating encouraging results [ 234 ]. Repurposing the virus vaccines for cancer immunotherapy is of particular interest since the pre-existing viral immunity may increase oncolytic effectiveness.…”

Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment

“…Intrathecal ZIKV injection also led to a reduction of tumor size in an immunocompetent dog model which developed spontaneous intracranial tumors. In these animals, neurological symptoms were improved, and survival was extended, with no clinical virus-related side effects [109]. Moreover, ZIKV modified immune profiling in treated animals, inducing a local immunological response in the tumor mass [109].…”