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
1908 - Androgen Receptor (AR) Aberrations in Patients (Pts) With Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Treated With Apalutamide (APA) Plus Androgen Deprivation Therapy (ADT) in TITAN
Presenter: Kim Chi
Session: Poster Display session 3
Resources:
Abstract
4058 - 68Ga-PSMA guided bone biopsies for molecular diagnostics in metastatic castration resistant prostate cancer patients
Presenter: Anouk de Jong
Session: Poster Display session 3
Resources:
Abstract
2226 - Spatial-Temporal Change in Quantitative Total Bone Imaging (QTBI) and Circulating Tumor Cells (CTCs) in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Enzalutamide (ENZA)
Presenter: Glenn Liu
Session: Poster Display session 3
Resources:
Abstract
5795 - Efficacy of Enzalutamide in Hormone-sensitive Metastatic Prostate Cancer: Clinical Utility of 18F-Choline PET and Whole Body MRI.
Presenter: Susanne Osanto
Session: Poster Display session 3
Resources:
Abstract
899 - Urine extracellular vesicle GATA2 mRNA alone and in a multigene test predicts initial prostate biopsy result
Presenter: Jungreem Woo
Session: Poster Display session 3
Resources:
Abstract
3094 - Circulating tumor cell (CTC) genomic landscape in neuroendocrine prostate cancer (NEPC) by single cell copy number analysis
Presenter: Vincenza Conteduca
Session: Poster Display session 3
Resources:
Abstract
2527 - Circulating Tumor Cells (CTC) count and Prostate-Specific Antigen (PSA) response measures in metastatic Castration-Resistant Prostate Cancer (mCRPC) patients (pts) treated with Docetaxel (Doc)
Presenter: Rebeca Lozano Mejorada
Session: Poster Display session 3
Resources:
Abstract
6106 - Assessing the clinical relevance of drug–drug interactions (DDI) with darolutamide (DARO)
Presenter: Christian Zurth
Session: Poster Display session 3
Resources:
Abstract
2237 - KEYNOTE-921: phase 3 study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone (abi)-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Presenter: Daniel Petrylak
Session: Poster Display session 3
Resources:
Abstract
2241 - KEYNOTE-641: Phase 3 Study of Pembrolizumab (pembro) Plus Enzalutamide for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Presenter: Julie Graff
Session: Poster Display session 3
Resources:
Abstract