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Dissertation/Thesis Abstract

Evaluation of viral gene expression and E3 immunomodulatory functions of adenovirus serotype 26 to inform vector design for cancer therapy
by Turner, Mallory AnnaMarie, Ph.D., College of Medicine - Mayo Clinic, 2015, 155; 10111527
Abstract (Summary)

To date, species C Ad5 has dominated the field of Ad based therapeutics. However, in recent years limitations to Ad5 have emerged, including pre-existing immunity, blood factor affinity, and off target effects. To combat these issues, a variety of laboratories have explored the other Ad serotypes as potential therapeutics. However, much of our understanding of the biology of adenoviruses (Ads) is extrapolated from human species C Ads 2 and 5. Greater understanding of the biology of alternative Ads as their use expands, will help to avoid pitfalls, and inform their use.

Our laboratory has identified species D Ad 26 as promising oncolytic virus against B cell cancer. This thesis is directed at characterizing the biology and towards making species D virus Ad26 into a useful therapeutic agent against B cell malignancies.

To gain a better understanding of differences in Ad biology between distinct species, the life cycles of Ad26 was compared to Species C Ad6 in human A549 lung cells in vitro. In these cells, both Ad6 and Ad26 infection gave rise to similar genome replication kinetics. However, when evaluating transcriptional output from the cell, Ad6 had greater transcripts accounting for 14-17% of all transcripts compared to 3-13% for Ad26. Specific analysis of viral gene expression by RT-qPCR and NGS revealed unique differences in E1 and E3 regions for the two Ads. Further analysis cellular effects mediated by E3 revealed Ad6 was markedly more effective at suppressing MHC I display on the cell surface and in evading TRAIL-mediated apoptosis than Ad26.

Further analysis of the importance of E3 genes was examined in a murine model of B cell lymphoma (A20). Multiple Ad26 viruses with varying deletions in the E3 region were tested. Studies revealed consistent efficacy, though modest, when tumors were treated with Ad26 viruses with a deletion in E3-14.7k or E3-49k. Importantly, studies on A20 cells in vitro revealed no viral replication, or even transduction of the cells. Thus leaving us to hypothesize that Ad26 efficacy in this model is likely dependent on immune modulation in the tumor microenvironment. As such, follow up studies and further characterization of the immune responses elicited or controlled by the different E3 viruses will be of great importance.

Understanding these differences expands the knowledge of alternative Ad species and informs our development towards a viable Ad26 cancer therapeutic.

Indexing (document details)
Advisor: Barry, Michael A.
Commitee: Ikeda, Yasuhiro, Jelinek, Diane F., Kaufmann, Scott H., Russell, Stephen J.
School: College of Medicine - Mayo Clinic
Department: Virology and Gene Therapy
School Location: United States -- Minnesota
Source: DAI-B 77/10(E), Dissertation Abstracts International
Subjects: Molecular biology, Bioinformatics, Virology
Keywords: Adenovirus, B cell lymphoma, Cancer therapy, Gene expression, Immune modulation, Rna-seq
Publication Number: 10111527
ISBN: 978-1-339-74736-1
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