Abstract 5791
Background
There is a great demand for improved oncolytic viruses that selectively replicate inside cancer cells while sparing normal tissues. Here we describe a novel oncolytic adenovirus, Ixovex, that obtains a cancer selective replication phenotype by modulating the level of expression of the different alternatively spliced E1B mRNA isoforms.
Methods
In our work to probe the function of the E1B proteins we generated a virus mutant, the Ixovex virus, in which the SA1 3’ splice acceptor site sequence CAG:GA was mutated to CgG:GA. This single nucleotide point mutation (genomic location 3216) changed aa 399 in the E1B-496R protein from an arginine (AGG) to a glycine (gGG). IxoVex was validated for its viral replication (TCID-50 assay) and cytotoxicity (MTS assay) in a panel of normal and cancer cell lines. Animal studies for anti-tumour efficacy studies were performed in nude mice.
Results
Ixovex is a recombinant adenovirus that carries a single point mutation in the E1B-93R 3’ splice acceptor site that results in an overexpression of the E1B-156R splice isoform. Further, the mutation resulted in a loss of E1B-496R (E1B-55K) protein expression and as a consequence a failure of Ixovex to efficiently degrade the p53 tumour suppressor protein. Ixovex significantly inhibited tumour growth and prolonged survival of mice in an immune-deficient lung carcinoma tumour model. In complementation experiments overexpression of E1B-156R was shown to increase the oncolytic index of both Ad5wt and ONYX-015. In contrast to prior art viruses of similar type, Ixovex includes a functional E3B region for better in vivo efficacy. Ixovex virus, throughout this study has been proven to be by far the superior virus in potency compared to ONYX-015.
Conclusions
The decrease in toxicity and the inhibition of replication in normal cells indicate an astounding safety profile of Ixovex. The observation that the ONYX-015 virus replicated better in normal cells compared to Ixovex is intriguing considering that the ONYX-015 virus carries a large deletion that removes the coding sequences and splice signals needed to express the E1B-496R, E1B-93R and E1B-156R proteins. Ixovex significantly inhibit tumour growth in a human lung carcinoma animal model and that ONYX-015 does not.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
IxoGen.
Disclosure
M. Anwar: Shareholder / Stockholder / Stock options: IxoGen. G. Alusi: Shareholder / Stockholder / Stock options: IxoGen. D. Oberg: Shareholder / Stockholder / Stock options: IxoGen.
Resources from the same session
2963 - Analytical performance of the Resolution-HRD plasma assay used to identify mCRPC patients with biallelic disruption of DNA repair genes for treatment with niraparib
Presenter: Ira Pekker
Session: Poster Display session 3
Resources:
Abstract
3523 - Results of a global external quality assessment scheme for EGFR testing on liquid biopsy
Presenter: Nicola Normanno
Session: Poster Display session 3
Resources:
Abstract
3295 - Clinical impact of plasma Next-Generation Sequencing (NGS) in advanced Non-small cell lung cancer (aNSCLC)
Presenter: Laura Bonanno
Session: Poster Display session 3
Resources:
Abstract
5632 - Feasibility study of a ctEGFR prototype assay on the fully automated Idylla™ platform
Presenter: Martin Reijans
Session: Poster Display session 3
Resources:
Abstract
3614 - Enhanced Access to EGFR Molecular Testing in NSCLC using a Cell-Free DNA Tube for Liquid Biopsy
Presenter: Theresa May
Session: Poster Display session 3
Resources:
Abstract
5664 - Analysis of circulating tumor DNA in paired plasma and sputum samples of EGFR-mutated NSCLC patients
Presenter: Christina Grech
Session: Poster Display session 3
Resources:
Abstract
4945 - Liquid biopsy and Array Comparative Genomic Hybridization (aCGH)
Presenter: Panagiotis Apostolou
Session: Poster Display session 3
Resources:
Abstract
5746 - Next-generation sequencing panel verification to detect low frequency single nucleotide and copy number variants from mixing cell line studies
Presenter: Rocio Rosas-Alonso
Session: Poster Display session 3
Resources:
Abstract
5901 - Automated rarefaction analysis for precision B and T cell receptor repertoire profiling from peripheral blood and FFPE-preserved tumor
Presenter: Luca Quagliata
Session: Poster Display session 3
Resources:
Abstract
2027 - A Heptamethine cyanine dye is a potential diagnostic marker for Myeloid-Derived Suppressor Cells
Presenter: Chaeyong Jung
Session: Poster Display session 3
Resources:
Abstract