ucalgary_2013_lawson_keith.pdf

UNIVERSITY OF CALGARY
Oncolytic Reovirus Combined with Sunitinib as a Novel Multi-Mechanistic Treatment
Strategy for Renal Cell Carcinoma
by
Keith Lawson
A THESIS
SUBMITTED TO THE FACULTY OF GRADUATE STUDIES
IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE
DEGREE OF MASTER OF SCIENCE
DEPARTMENT OF MEDICAL SCIENCE
CALGARY, ALBERTA
MARCH, 2013
© Keith Lawson 2013

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Abstract.
Metastatic renal cell carcinoma (RCC) is an incurable disease resistant to both
radiation and cytotoxic chemotherapy. Although new molecularly targeted agents have
increased the therapeutic options for patients with this disease, 5-year overall survival
rates remain below 10%. The aim of this thesis was to determine the preclinical efficacy
of reovirus as a monotherapy and in combination with sunitinib, a first line mRCC agent
and multi-tyrosine kinase inhibitor, for the treatment of RCC. To assess this, studies
employing a panel of RCC cell lines, as well as a syngeneic immunocompetent murine
model of RCC were utilized. Collectively, these studies demonstrate that reovirus is both
a novel oncolytic and immunotherapeutic agent against RCC. Furthermore, our results
provide the first evidence that sunitinib augments the anti-tumour immune response
generated by an oncolytic virus. As such, this novel treatment paradigm has immediate
clinical applicability for use against multiple tumour histologies, particularly RCC.

III
Acknowledgements.
I must first thank my supervisor and role model Dr. Don Morris for his
unconditional support and belief that I could not only complete this degree but also have
success in becoming a surgeon-scientist. Without this, I do not know if I would have been
able to stay motivated through the trying times of completing this project during medical
school. Additionally, I must my thank my two labmates and friends, Jason Spurrell and
Zhong Qiao Shi, who from the beginning of this project have demonstrated an enormous
amount of patience and dedication to training me to become a good scientist. In this same
regard, I must thank Dr. Frank Jirik for his thoughtful insights into this project as a
member of my graduate committee. I would also like to thank the urology group at the
University of Calgary, in particular Dr. Jun Kawakami, for accommodating and
supporting me in blending my passion for research with my goal of becoming an
academic urologist. I have also had the fortune of having an enormous amount of support
from my family and friends. In particular my fiancé Ambica Parmar and my two friends
Geoff Brin and David Burrowes who have patiently worked to keep me grounded and
ensure I stay balanced for which I cannot thank them enough. Last, but not least, I would
like to thank all members of the Translational Laboratory at the Tom Baker Cancer Center
who always provided a helping hand and made my experience most enjoyable.

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Dedication.
To my grandmother Helen Irene Sorensen for always believing in me.

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Table of Contents.
Abstract................................................................................................................................II
Acknowledgements.............................................................................................................III
Dedication...........................................................................................................................IV
Table of Contents.................................................................................................................V
List of Figures..................................................................................................................VIII
List of Tables……………………………………………………………………………..IX
List of Abbreviations...........................................................................................................X
CHAPTER ONE: Oncolytic virotherapy for renal cell carcinoma (RCC): a novel
therapeutic paradigm?...........................................................................................................2
1.1 RCC epidemiology and background...............................................................................3
1.2 Oncolytic virus background............................................................................................4
1.3 Molecular aberrations in RCC: A candidate malignancy for oncolytic virotherapy......5
1.4 Immunological responsiveness of RCC: A candidate malignancy for oncolytic
virotherapy............................................................................................................................8
1.5 Current evidence to support the use of oncolytic virotherapy against RCC.................11
1.5.1 Adenovirus.....................................................................................................14
1.5.2 Vaccinia virus................................................................................................17
1.5.3 Herpes simplex virus……………………………………………………….18
1.5.4 Sendai virus....................................................................................................19
1.5.5 Measles virus.................................................................................................21
1.5.6 Vesicular stomatitis virus...............................................................................22
1.5.7 Encephalomyocarditis virus...........................................................................23
1.6 Barriers to oncolytic virotherapy in RCC………….....................................................24
1.6.1 Host immune response: viral immune clearance and suppression of anti-
tumour immunity....................................................................................................27