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
5056 - Phase 2 study of 2 dosing regimens of cemiplimab, a human monoclonal anti–PD-1, in metastatic cutaneous squamous cell carcinoma (mCSCC)
Presenter: Danny Rischin
Session: Poster Display session 3
Resources:
Abstract
5710 - Avelumab for advanced Merkel cell carcinoma in the Netherlands; a nationwide survey
Presenter: Sonja Levy
Session: Poster Display session 3
Resources:
Abstract
3152 - Health-related quality of life in patients with metastatic Merkel cell carcinoma receiving second-line or later avelumab treatment: 36-month follow-up data
Presenter: Sandra D'Angelo
Session: Poster Display session 3
Resources:
Abstract
5715 - A Phase 2, Randomized Study of Nivolumab (NIVO) and Ipilimumab (IPI) versus NIVO, IPI and Stereotactic Body Radiation Therapy (SBRT) for Metastatic Merkel Cell Carcinoma (MCC, NCT03071406) – a preliminary report.
Presenter: Sungjune Kim
Session: Poster Display session 3
Resources:
Abstract
2854 - Real-world impact of immune checkpoint inhibitors in metastatic uveal melanoma
Presenter: Kalijn Bol
Session: Poster Display session 3
Resources:
Abstract
2928 - Immune checkpoint inhibitors in a cohort of 206 metastatic uveal melanomas patients
Presenter: Mathilde Saint-Ghislain
Session: Poster Display session 3
Resources:
Abstract
1235 - Incidence and survival of Uveal Melanoma occurring as single cancer versus its occurrence as a first or second primary neoplasm
Presenter: Ahmad Alfaar
Session: Poster Display session 3
Resources:
Abstract
3615 - Validation of a Clinicopathological and Gene Expression Profile (CP-GEP) Model for Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma
Presenter: Evalyn Mulder
Session: Poster Display session 3
Resources:
Abstract
1793 - External validation of the 8th Edition Melanoma Staging System of the American Joint Committee on Cancer (AJCC) using the Surveillance, Epidemiology and End Results (SEER) Program
Presenter: Angelina Tjokrowidjaja
Session: Poster Display session 3
Resources:
Abstract
4278 - Clinical factors and overall survival (OS) associated with patterns of metastases (mets) in melanoma patients (pts).
Presenter: Ines Pires da Silva
Session: Poster Display session 3
Resources:
Abstract