# Innate Antiviral Signals for Cancer Immunotherapy

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $390,425

## Abstract

Glioblastomas (GBM) feature a profoundly immunosuppressive myeloid infiltrate that constitutes a formidable
barrier to therapy. The infiltrate’s cellular composition, and the tissue context provided by specialized resident
myeloid cells in the CNS (microglia), distinguish GBM from other malignancies. The principal mediators of
immunosuppression in the tumor microenvironment (TME), glioma-associated macrophages/microglia (GAMM),
are exceedingly difficult therapy targets. Their entrenched immune subversive traits, phenotypic heterogeneity
and plasticity pose obstacles to targeted GAMM re-polarization. The goal of this project is to decipher the
mechanisms of GBM immunotherapy with recombinant poliovirus, PVSRIPO, a neurotropic +strand RNA virus
with a deep pro-inflammatory imprint. Poliovirus naturally targets the mononuclear phagocytic system—
macrophages, microglia, dendritic cells (DC)—due to constitutive expression of its receptor CD155 in this
compartment. Wild type poliovirus infection is lytic in DCs/macrophages. In contrast, PVSRIPO, engineered for
attenuation by internal ribosomal entry site (IRES) exchange with human rhinovirus type 2, has a peculiar non-
cytopathogenic host relationship defined by accentuated innate antiviral signaling.
 Infection of the glioma TME with PVSRIPO unleashes multilayered proinflammatory events, including
lingering +strand RNA virus replication within GAMM, activation of diverse innate signaling cascades via multiple
double-stranded RNA sensors, profuse type-I interferon dominant inflammation, polio-specific CD4+T cell
immunologic recall in the tumor, and widespread microglia activation and proliferation in the normal brain.
PVSRIPO has shown promise with single intratumor administration in recurrent GBM, yielding durable
radiographic responses associated with long-term survival in a subset of patients. We uncovered that patients
whose tumors had relatively lower mutational burden and who experienced a short time to 1st recurrence survived
longer after PVSRIPO. These features were associated with enhanced TME inflammatory signatures, indicating
that tumor-intrinsic conditions for GAMM engagement influence immunotherapy outcomes.
 Our central premise is that PVSRIPO generates glioma immune surveillance via proinflammatory
activation of GAMM resulting in stimulation of local tumor antigen cross-presentation, T cell infiltration
of brain parenchyma, and enhanced CD8+T cell effector functions. Realizing this potential in the clinic
for all patients depends on resolving mechanisms that govern antitumor CD8+T cell immunity in the
brain. To achieve this objective, we propose the following Specific Aims: (1) Determine the mechanisms of
microglia/GAMM proinflammatory activation induced by recombinant poliovirus; (2) Elucidate the impact of
microglia cross-presentation on PVSRIPO immunotherapy; (3) Determine if repeat dosing or CD40 ligation
improve the antitumor efficacy of PVSRIPO.

## Key facts

- **NIH application ID:** 10932846
- **Project number:** 5R01NS108773-07
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthias Gromeier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,425
- **Award type:** 5
- **Project period:** 2018-06-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932846

## Citation

> US National Institutes of Health, RePORTER application 10932846, Innate Antiviral Signals for Cancer Immunotherapy (5R01NS108773-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10932846. Licensed CC0.

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