Reshaping the T-cell landscape and Nr4a3 transcriptional dynamics with oncolytic virotherapy
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Embargo End Date
2025-11-29
ICR Authors
Authors
Appleton, L
Document Type
Thesis or Dissertation
Date
2025-05-29
Date Accepted
Abstract
Oncolytic viruses (OV) are naturally occurring or genetically modified viruses that
selectively infect and replicate within cancer cells, with the potential to induce
oncolysis, immunogenic cell death (ICD) and systemic anti-cancer immunity. Often
described as a “novel therapeutic class”, oncolytic viruses are now decades old, and
while milestone moments for the field include the worldwide approval of oncolytic
herpes simplex virus-1 (HSV-1) Talimogene Laherparepvec in 2015 for the treatment
of advanced melanoma, there have also been notable recent failures of OV in latestage
clinical trials, including in combination with immune checkpoint blockade
despite pre-clinical and early-phase promise.
One advantage of OV is their unmatched flexibility to evolve with the immuneoncology
(IO) landscape. From the ability to encode diverse immune-modulatory
transgenes for expression within tumour tissue, to synergy within complex
combinations, including with immune checkpoint inhibitors (ICI) and adoptive cell
transfer (ACT) therapy. As a result, the number of agents and combinations
undergoing pre-clinical and clinical testing is burgeoning, and the field is challenging
sceptics with persistent, justified optimism. The vast majority of these modifications
and combination strategies target T-cells, as the key effector cells of the immune
system. However, the rate of development has far outstripped our knowledge of Tcell
effects of the viruses themselves, which face a complex juxtaposition of anti-viral
and anti-tumour immunity.
This thesis aims to take a step back, to deeply evaluate the T-cell effects of one of
the lead clinical agents, HSV-1 RP1, to understand what T-cell populations are
induced, and how these
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Targeted Therapy