# Innate Antiviral Signals for Cancer Immunotherapy

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $350,000

## Abstract

WHO grade IV malignant glioma is emblematic for a majority of cancers, where the efficacy of immune
checkpoint blockade is impeded by a low mutational burden and notorious immunosuppression incited by a
non-engaged tumor microenvironment. To overcome these hurdles and achieve successful immunotherapy of
malignant glioma (or other `non-immunogenic' cancers), novel approaches must be capable of immunologically
engaging the tumor microenvironment (TME) to instigate new antitumor immune repertoire. Our project is
focused on the polio:rhinovirus chimera PVSRIPO, and its capacity to elicit inflammatory responses in the
TME. PVSRIPO yields promising responses after single, convection-enhanced intratumoral infusion in patients
with recurrent WHO grade IV malignant glioma. It targets neoplastic cells for infection and destruction by virtue
of ectopic expression of its receptor, the CD155 tumor antigen, on such cells. We hypothesize, however, that
the key to PVSRIPO's immunotherapy potential is poliovirus' inherent tropism for antigen presenting cells
(APCs), e.g. tumor-associated macrophages, and a peculiar resistance to the innate antiviral interferon (IFN)
response. PVSRIPO infection of APCs elicits sublethal viral propagation that provokes profound, sustained
type I IFN responses and stimulates T cell co-stimulating functions. There is broad agreement that the
unparalleled stimulus of the innate antiviral response in APCs is pivotal for generating tumor antigen-specific
antitumor immunity. As with the role of APCs in natural poliovirus infection, the nature and extent of PVSRIPO
interactions with myeloid host cells in tumors in vivo are unknown. For example, the mechanisms permitting
chronic PVSRIPO replication with subdued cytotoxicity in APCs -necessary preludes to their IFN-dominant
activation- remain obscure. The investigations proposed in this project are of utmost importance for the clinical
development of PVSRIPO immunotherapy in malignant gliomas and beyond. Therefore, we are pursuing the
following Specific Aims: 1) Define the molecular basis for PVSRIPO translation competency, cytotoxicity and
type I IFN induction in macrophages/myeloid cells. We will perform studies in human myeloid-derived
macrophages to mechanistically decipher the unique relationship of PVSRIPO with APCs; 2) Unravel
PVSRIPO's potential for reprogramming macrophages/myeloid cells in the glioma TME in vivo and determine
the role of macrophages in PVSRIPO immunotherapy. We will use transplantable chemically-induced- and
genetically-engineered immunocompetent mouse glioma models to investigate the role of tumor stroma in
PVSRIPO-instigated antitumor immunity; 3) Elucidate PVSRIPO targeting of macrophages/myeloid cells in
primary human glioblastoma explants and examine proinflammatory reprogramming in vitro. We will decipher
the TME response to PVSRIPO infection in fresh, non-dissociated primary tissue explants from glioma patients
and measure its potential in overcoming T cell...

## Key facts

- **NIH application ID:** 9925289
- **Project number:** 5R01NS108773-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthias Gromeier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $350,000
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925289

## Citation

> US National Institutes of Health, RePORTER application 9925289, Innate Antiviral Signals for Cancer Immunotherapy (5R01NS108773-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9925289. Licensed CC0.

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