# Causes and consequences of oncolytic virus infection of non-tumoral cells in cancer immunotherapy

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $46,036

## Abstract

PROJECT SUMMARY
Immunotherapy has changed the way we think about and treat cancer. While some patients experience durable
remissions, the majority however, will not respond. Some known barriers to response are a lack of immune
infiltrate or infiltrate that is suppressed by other cell types in the tumor microenvironment. These patients may
find immunotherapies that induce a de novo immune response, such as oncolytic viruses, more successful than
one that stimulates the existing immune populations. An oncolytic virus selectively replicates in and lyses tumor
cells, stimulating an immune response against viral and tumor antigen, while leaving healthy tissue unharmed.
Currently there is one oncolytic approved for use in the clinic. Despite this recent approval and the rapid
expansion of clinical trials evaluating oncolytics, little is known about the effects of these treatments on tumor
resident immune cells. Many of these trials are currently evaluating oncolytic vaccinia virus as it is an ideal
candidate for immunotherapy. Vaccinia replicates entirely in the cytosol preventing incorporation into host DNA,
has a dsDNA genome that is easily engineered, and stimulates robust immune responses. Using a genetically
engineered strain of oncolytic vaccinia virus (vvDD) with deletions of both viral growth factor and thymidine kinase
to increase its tumor selectivity, we have shown that a single dose of this therapy can dramatically remodel the
tumor infiltrate. Major increases in CD8+ T cell infiltration are observed as expected, however we also observed
surprising phenotypic changes. Seven days post-treatment a loss of regulatory CD4+ T cells (Treg) was seen.
Using a GFP expressing strain of the virus (vvDD-GFP) we found that surprisingly, one day post-treatment Tregs
were selectively infected. As these cells are experiencing hypoxia in the tumor, we hypothesize that hypoxia
leads to infection of these subsets which culminates in their death. The resulting microenvironment, now
depleted of immune regulatory cells, is more supportive of immune infiltration and anti-tumor activity. We will test
this hypothesis by (1) determining if oncolytic viral infection leads to the death of Treg and determine the
contribution of Treg loss to therapeutic efficacy and (2) dissecting the contribution of HIF1α to the ability of vvDD
to infect Tregs. The conclusions from these studies will provide us with a better understanding of the mechanism
of oncolytic vaccinia. With this information it will be possible to design more efficacious oncolytic viruses as well
as determine the patient populations most likely to respond to therapy.

## Key facts

- **NIH application ID:** 10249180
- **Project number:** 5F31CA247129-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kristin Leigh DePeaux
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249180

## Citation

> US National Institutes of Health, RePORTER application 10249180, Causes and consequences of oncolytic virus infection of non-tumoral cells in cancer immunotherapy (5F31CA247129-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10249180. Licensed CC0.

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