# Project 3: Phase-2 Trial of Oncolytic Poliovirus (PVSRIPO) combined with CCNU (lomustine) against Recurrent Glioblastoma

> **NIH NIH P01** · DUKE UNIVERSITY · 2021 · $497,607

## Abstract

PROJECT SUMMARY – Project 3
The notoriously immunosuppressive tumor microenvironment (TME) is a major detriment to effective cancer
immunotherapy. Pre-clinical evidence in immunocompetent rodent tumor models show that recombinant, non-
pathogenic poliovirus (PVSRIPO) can elicit tumor antigen-specific antitumor immunity, in part through
reversing immunosuppression and generating an immune-engaged TME. PVSRIPO targets tumor cells and
antigen presenting cells (APCs; macrophages/microglia, dendritic cells) via its receptor, the immune
checkpoint molecule CD155. PVSRIPO exhibits potent cytotoxic properties in malignant cells, largely due to
unhinged PKC-Raf-ERK1/2-MNK signals that provide an enormous advantage to viral protein synthesis.
Intriguingly, infection of APCs has a very different outcome. In macrophages or dendritic cells, PVSRIPO
infection leads to chronic, non-cytopathogenic viral propagation that produces durable induction of type 1
interferon-dominant stimulation. PVSRIPO-infected APCs exhibit enhanced antigen-presentation and T cell co-
stimulation capacity. Viral tumor cell lysis, combined with pro-inflammatory APC stimulation occurring in a
context of rampant immune cell invasion into the tumor, set the stage for initiation of antitumor immunity.
PVSRIPO has demonstrated promise in an ongoing Phase 1 clinical trial against recurrent WHO stage IV
malignant glioma (glioblastoma, gliosarcoma) and was granted Breakthrough Therapy Designation in May,
2016. In the course of this trial, we observed intriguing responses to temozolomide or lomustine in patients that
experienced biopsy-proven or imaging-suggested evidence for tumor recurrence post PVSRIPO. We are
pursuing the following Aims: 1) Conduct a Phase 2 randomized clinical trial of PVSRIPO alone or in
combination with lomustine in patients with recurrent WHO Grade IV malignant glioma. We propose a
single-institution, two-arm randomized Phase 2 study that examines the survival of recurrent GBM patients
treated with PVSRIPO alone and PVSRIPO + lomustine chemotherapy. Study objectives are: a) to assess the
efficacy of a single dose of PVSRIPO with or without a single dose of lomustine among adults with recurrent
GBM relative to the survival observed in a (FDA sanctioned) historical control group; b) to assess the safety of
PVSRIPO treatment with lomustine; and c) to define changes visualized on imaging due to intratumoral
inoculation of PVSRIPO alone or in combination with lomustine. 2) Perform immune monitoring to
mechanistically unravel PVSRIPO immunotherapy synergy with lomustine. We will use immune cell
profiling and T Cell Receptor (TCR) sequencing to assess: a) global (whole blood) T cell populations; b)
effector anti-polio memory T cell populations; c) T cells responding to autologous dendritic cell (DC) stimulus
with defined GBM antigens (EGFR, HER2, survivin, hTERT).

## Key facts

- **NIH application ID:** 10246887
- **Project number:** 5P01CA225622-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** DARELL D BIGNER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $497,607
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246887

## Citation

> US National Institutes of Health, RePORTER application 10246887, Project 3: Phase-2 Trial of Oncolytic Poliovirus (PVSRIPO) combined with CCNU (lomustine) against Recurrent Glioblastoma (5P01CA225622-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246887. Licensed CC0.

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