Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models

Abstract

Oncolytic virotherapy is a potential treatment modality under investigation for various malignancies including malignant brain tumors. Unlike some other natural or modified viruses that show oncolytic activity against cerebral neoplasms, the rodent parvovirus H-1 (H-1PV) is completely apathogenic in humans. H-1PV efficiently kills a number of tumor cells without harm to corresponding normal ones. In this study, the concept of H-1PV-based virotherapy of glioma was tested for rat (RG-2 cell-derived) and for human (U87 cell-derived) gliomas in immunocompetent and immunodeficient rat models, respectively. Large orthotopic rat and human glioma cell-derived tumors were treated with either single stereotactic intratumoral or multiple intravenous (iv) H-1PV injections. Oncolysis was monitored by magnetic resonance imaging and proven by histology. Virus distribution and replication were determined in brain and organs. In immunocompetent rats bearing RG-2-derived tumors, a single stereotactic intratumoral injection of H-1PV and multiple systemic (iv) applications of the virus were sufficient for remission of advanced and even symptomatic intracranial gliomas without damaging normal brain tissue or other organs. H-1PV therapy resulted in significantly improved survival (Kaplan-Meier analysis) in both the rat and human glioma models. Virus replication in tumors indicated a contribution of secondary infection by progeny virus to the efficiency of oncolysis. Virus replication was restricted to tumors, although H-1PV DNA could be detected transiently in adjacent or remote normal brain tissue and in noncerebral tissues. The results presented here and the innocuousness of H-1PV for humans argue for the use of H-1PV as a powerful means to perform oncolytic therapy of malignant gliomas.

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

“…The suppressive activity of PVs against various rodent and human cancers has been documented in both in vitro systems and animal models (4,5). PVs distinguish themselves by their dual oncolytic and immunostimulating activities, broad range of target tumors, ability to circumvent tumor cell resistance to conventional death inducers, and suitability for both local and systemic applications.…”

“…Direct interactions of NS1 with components of the DNA replication (RPA 1-3) and transcription (TBP, TFIIA, and SP1) machineries play a role both in viral DNA replication and transcription and in deregulating DNA/RNA metabolic processes in infected cells [3,4]. Other virus protein-cell protein interactions, such as NS1-CKII [5] and NS2-XPO1 [6], interfere with host cell signaling and nuclear export, respectively. These events affect the host cell dramatically by causing oxidative stress, DNA damage, cell-cycle arrest, cytoskeleton structure rearrangements, mitochondrial membrane depolarization, and/or lysosome permeabilization.…”

Activation of a glioma-specific immune response by oncolytic parvovirus Minute Virus of Mice infection

“…5 The concept of H-1PV-based virotherapy of glioma was successfully tested in vivo, using rat (RG-2) and human (U87) glioma cell implants in immunocompetent and immunodeficient rat models, respectively. 6 It has to be stated that the therapeutic effect of the virus was more pronounced in immunocompetent animals. Pioneering in vitro studies using a melanoma model have demonstrated that tumor cell killing by a wild-type H-1PV can directly stimulate the maturation of human dendritic cells (DCs) and antigen cross-presentation to cytotoxic T lymphocytes.…”

Glioma-Parvovirus Interactions: Molecular Insights and Therapeutic Potential

“…Although a parallel study with the MVM and H-1 viruses has not being carefully addressed, several subsequent reports suggested that H-1 is a more powerful oncolytic agent against human glioblastoma, regarding the levels of both cytotoxicity and virus yield in culture (Herrero et al 2004;Di Piazza et al 2007). Further recent preclinical studies have convincingly supported H-1 as anti-glioblastoma agent for clinical purposes, as its infection synergized with radiation (Geletneky et al 2010a), and moreover it improved survival and remission of advanced intracranial U87MG human glioblastoma in rat models (Geletneky et al 2010b;Kiprianova et al 2011). However, as discussed below for MVM, there are particularly interesting aspects in the non-productive glioma-parvovirus interaction, as they may uncover molecular processes altered in glioma and helping to identify cellular targets for cancer treatments.…”