PreOp JX594- Translational Study
Research type
Research Study
Full title
Pre-Operative JX-594 Study - Translational Sample Analysis
IRAS ID
248783
Contact name
Adel Samson
Contact email
Sponsor organisation
University of Leeds
Clinicaltrials.gov Identifier
N/A, N/A
Duration of Study in the UK
5 years, 0 months, 0 days
Research summary
Summary of Research
The aim of this post-clinical protocol is to explore further scientific questions using the tumour and adjacent normal tissue, as well as the peripheral blood samples obtained from the Pre-operative JX-594 trial (full title: ‘A clinical study to evaluate the biological effects of pre-operative intravenous administration of JX-594 (thymidine kinase-deactivated Vaccinia virus plus GM-CSF) prior to planned surgical resection of locally advanced/poor prognosis or metastatic cancers’; EudraCT number: 2012-000704-15,).
The Pre-operative JX-594 trial, which has now completed patient recruitment, was an open-label, non-randomised study of an oncolytic Vaccinia virus, JX-594, given intravenously (IV) to patients prior to planned surgery of advanced cancers. JX-594 was administered as monotherapy at 1x10^9 plaque forming units, as an IV infusion to all patients approximately 14 days pre-surgery. The primary aim of the study was to assess for the presence of JX-594 in the resected surgical samples by immunohistochemistry (IHC), and for JX-594 in the blood of treated patients. A total of 9 patients were recruited, including 6 with colorectal cancer liver metastases (CRLM), and 3 with malignant melanoma. One recruited patient with CRLM was treated using JX-594, but did not undergo surgery due to disease progression. In addition to the primary objective of the study, which is being assessed under existing ethical permission as part of the clinical trial, numerous other scientific questions remain that can be addressed using the remaining tumour and adjacent normal tissue, as well as the peripheral blood samples obtained from patients recruited to this study. This current protocol therefore seeks to utilise these remaining stored samples towards continued scientific benefit.Summary of Results
The samples of interest were originally obtained from the trial participants receiving one intravenous dose of genetically modified Vaccinia Virus (JX-594) prior to surgical resection of their tumours. The initial results obtained from the trial revealed an invaluable opportunity to explore further questions related to the mechanisms of oncolytic virus therapy in cancer patients with solid tumours, which was the aim of this project.
The additional analysis of tumour/adjacent normal tissue samples was focused on the tumour immune microenvironment and the expression of immune and apoptosis-related genes in tumour. The assessment of peripheral blood samples included testing upregulation of checkpoint proteins on qPCR of PBMCs and plasma for detection of JX-594 DNA.
Pexa-vec therapy showed evidence of clinical efficacy, including pathological tumour response in two patients. Viral protein can be detected within tumour tissue following intravenous infusion, but not in associated background liver. Pexa-vec induces an IFN response leading to immune activation in both the innate and adaptive responses. Furthermore, tumour infiltration by activated CD8 T cells, coupled with an increase in PD-L1 expression in tumours, pave the way forward for a combination approach to therapy using Pexa-vec and anti-PD-L1 therapy.REC name
London - Harrow Research Ethics Committee
REC reference
18/LO/1489
Date of REC Opinion
21 Sep 2018
REC opinion
Further Information Favourable Opinion