Single dose GLP toxicity and biodistribution study of a conditionally replicative adenovirus vector, CRAd-S-pk7, administered by intracerebral injection to Syrian hamsters.

Julius Woongki Kim,Jian Qiao,Atique U Ahmed,Drew A Spencer,Maciej S Lesniak,Jill F Mann,Alan L Chang,Jacob S Young,Charles D Hébert,Meijing Wu,Deepak Kanojia,Theresa V Strong,Karen S Aboody,Brenda Auffinger,Joshua Robert Kane,Lingjiao Zhang,Jason Miska

doi:10.1186/s12967-016-0895-8

Abstract

BackgroundCRAd-S-pk7 is a conditionally replicative oncolytic adenoviral vector that contains a survivin promoter and a pk7 fiber modification that confer tumor-specific transcriptional targeting and preferential replication in glioma while sparing the surrounding normal brain parenchyma.MethodsThis IND-enabling study performed under GLP conditions evaluated the toxicity and biodistribution of CRAd-S-pk7 administered as a single intracerebral dose to Syrian hamsters, a permissive model of adenoviral replication. Two hundred and forty animals were stereotactically administered either vehicle (n = 60) or CRAd-S-pk7 at 2.5 × 107, 2.5 × 108, or 2.5 × 109 viral particles (vp)/animal (each n = 60) on day 1. The animals were closely monitored for toxicology evaluation, assessment of viral distribution, and immunogenicity of CRAd-S-pk7.ResultsChanges in hematology, clinical chemistry, and coagulation parameters were minor and transient, and consistent with the inflammatory changes observed microscopically. These changes were considered to be of little toxicological significance. The vector remained localized primarily in the brain and to some degree in the tissues at the incision site. Low levels of vector DNA were detected in other tissues in a few animals suggesting systemic circulation of the virus. Viral DNA was detected in brains of hamsters for up to 62 days. However, microscopic changes and virus-related toxicity to the central nervous system were considered minor and decreased in incidence and severity over time. Such changes are not uncommon in studies using adenoviral vectors.ConclusionThis study provides safety and toxicology data justifying a clinical trial of CRAd-S-pk7 loaded in FDA-approved HB1.F3.CD neural stem cell carriers administered at the tumor resection bed in humans with recurrent malignant glioma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0895-8) contains supplementary material, which is available to authorized users.

Highlights

CRAd-S-pk7 is a conditionally replicative oncolytic adenoviral vector that contains a survivin promoter and a pk7 fiber modification that confer tumor-specific transcriptional targeting and preferential replication in glioma while sparing the surrounding normal brain parenchyma
There was no observable effect on body weights of CRAd-S-pk7-administered hamsters in this study (P > 0.05, one-way analysis of variance (ANOVA), Kruskal–Wallis test when appropriate) (Fig. 2)
Because of the microscopic changes seen in the 2.5 × 107 vp/animal group, a no observed adverse effect level (NOAEL) could not be identified for the CRAd-S-pk7 vector under the conditions of this study. These results provide feasibility data related to the biodistribution, toxicology, and immune response of CRAd-S-pk7 in preparation for a phase 1 clinical trial

Summary

Introduction

CRAd-S-pk is a conditionally replicative oncolytic adenoviral vector that contains a survivin promoter and a pk fiber modification that confer tumor-specific transcriptional targeting and preferential replication in glioma while sparing the surrounding normal brain parenchyma. By taking advantage of these characteristics, a conditionally replicating oncolytic adenovirus, CRAdS-pk, has been generated [5] This viral vector infects cells by binding to anionic cell surface proteins through seven lysine residues (pk7) on the adenoviral fiber [6, 7] and subsequently initiates replication by way of E1 gene expression under the control of the tumor-specific promoter survivin (S) [5]. This glioma selective oncolytic agent, CRAd-S-pk, was shown to efficiently lyse glioma cells while sparing non-neoplastic cells [8, 9]. The biodistribution of oncolytic viruses (OVs) may be limited to the outer borders of a solid tumor mass with robust vascular supply, which often results in inconsistent viral penetration to the center of the tumor mass [8,9,10]

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Conclusion