Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models

Autor: Desmond Pink, Nicole Favis, Krista Vincent, Mary M. Hitt, John D. Lewis, Chad R. Irwin, Kyle Potts, Ronald B. Moore, David H. Evans
Rok vydání: 2017
Předmět:
0301 basic medicine
viruses
medicine.medical_treatment
Virus Replication
chemistry.chemical_compound
0302 clinical medicine
Tumor Cells
Cultured
Research Articles
Cancer
Oncolytic Virotherapy
Mice
Inbred BALB C
3. Good health
Oncolytic Viruses
Cell killing
030220 oncology & carcinogenesis
bladder cancer
Molecular Medicine
Female
immunotherapy
Research Article
Urinary Bladder
Urogenital System
Mice
Nude
Vaccinia virus
Biology
ribonucleotide reductase
Virus
Viral Proteins
03 medical and health sciences
Cell Line
Tumor
Ribonucleotide Reductases
medicine
Animals
Humans
oncolytic virus
Bladder cancer
Immunity
Immunotherapy
medicine.disease
Virology
Rats
Oncolytic virus
030104 developmental biology
Urinary Bladder Neoplasms
chemistry
Cancer cell
Genetics
Gene Therapy & Genetic Disease
Vaccinia
Gene Deletion
Zdroj: EMBO Molecular Medicine
ISSN: 1757-4684
1757-4676
DOI: 10.15252/emmm.201607296
Popis: Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high‐grade disease, Bacillus Calmette–Guerin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating the F4L gene that encodes the virus homolog of the cell‐cycle‐regulated small subunit of ribonucleotide reductase (RRM2). The F4L ‐deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor‐selective replication and cell killing. These F4L ‐deleted VACVs replicated selectively in immune‐competent rat AY‐27 and xenografted human RT112‐luc orthotopic bladder cancer models, causing significant tumor regression or complete ablation with no toxicity. It was also observed that rats cured of AY‐27 tumors by VACV treatment developed anti‐tumor immunity as evidenced by tumor rejection upon challenge and by ex vivo cytotoxic T‐lymphocyte assays. Finally, F4L ‐deleted VACVs replicated in primary human bladder cancer explants. Our findings demonstrate the enhanced safety and selectivity of F4L ‐deleted VACVs, with application as a promising therapy for patients with BCG‐refractory cancers and immune dysregulation. ![][1] Vaccinia virus (VACV) mutated to render it incapable of synthesizing deoxynucleoside triphosphates (dNTPs) is a safe, highly selective, and potentially superior oncolytic agent in animal models for bladder cancer. [1]: /embed/graphic-1.gif
Databáze: OpenAIRE
Externí odkaz: