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Permanent link (DOI): https://doi.org/10.7939/R3N010727

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Deletion of F4L (ribonucleotide reductase) in Vaccinia Virus Produces a Selective Oncolytic Virus and Promotes Anti-tumor Immunity with Superior Safety in Bladder Cancer Open Access

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Other title
Subject/Keyword
Immunotherapy
Ribonucleotide reductase
Vaccinia virus
Virotherapy
Bladder cancer
Oncolytic virus
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Potts, Kyle G
Supervisor and department
Evans, David (Medical Microbiology and Immunology)
Hitt, Mary (Oncology)
Examining committee member and department
Evans, David (Medical Microbiology and Immunology)
Weinfeld, Michael (Oncology)
Hitt, Mary (Oncology)
Mossman, Karnen (Biochemistry)
Moore, Ronald (Surgery)
Department
Department of Oncology
Specialization
Experimental Oncology
Date accepted
2017-09-14T10:02:34Z
Graduation date
2017-11:Fall 2017
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Overall recurrence of non-muscle-invasive bladder cancer (NMIBC) can be as high as 80% within 5 years of initial treatment. High-grade NMIBC has the greatest risk of recurrence and treatment for these patients includes surgery followed by intravesical therapy with the immunotherapeutic agent Bacillus Calmette-Guérin (BCG). BCG however, can be particularly dangerous for immunocompromised patients. Additionally, up to 40% of patients fail BCG therapy and cystectomy remains the standard treatment in these cases. This project examines whether vaccinia virus (VACV) can be used to treat preclinical models of NMIBC and in particular, bladder cancer that is refractory to BCG therapy. Here we have generated a novel oncolytic VACV by mutating the F4L gene that encodes the viral homolog of the stringently cell-cycle-regulated small subunit (RRM2) of ribonucleotide reductase. The F4L-deleted VACVs are highly attenuated in normal tissue and have a tropism that favors cancer cells commonly elevated in RRM2 levels, resulting in selective replication and tumor cell killing. VACVs efficiently replicate in BCGresistant and BCG-susceptible AY-27 cells. F4L-deleted VACVs selectively replicate in both the orthotopic AY-27 immunocompetent rat model and RT112-luc xenograft models, causing significant tumor regression or complete tumor ablation with no toxicity, while the commonly used ΔJ2R VACV causes significant toxicity in immunocompromised mice. Furthermore, rats cured of AY-27 tumors by VACV-treatment develop a protective anti-tumor immunity that is evident by tumor rejection upon challenge, as well as by ex vivo cytotoxic T-lymphocyte assays. Finally, the mutant VACVs replicate in both primary human bladder cancer cultures and tumor explants. Our findings demonstrate the enhanced safety and selectivity of our modified oncolytic VACV, making the F4L-deleted VACV a promising therapy for patients with BCG-refractory cancers and immune dysregulation.
Language
English
DOI
doi:10.7939/R3N010727
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Potts, K.G., Irwin, C.R., Favis, N.A., Pink, D.B., Vincent, K.M., Lewis, J.D., Moore, R.B., Hitt, M.M.* and Evans, D.H.* (2017), 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. EMBO Mol Med. 2017 May; 9(5): 638-654 * These authors contributed equally.Potts, K.G., Hitt, M.M., Moore, R.B. Oncolytic Viruses in the Treatment of Bladder Cancer. Adv Urol. 2012 Jul; 2012(1):404581.

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