# Retroviral Replicating Vector-mediated Gene Therapy for Ovarian Cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $530,309

## Abstract

Ovarian cancer is the leading cause of death in women with gynecological malignancies in the U.S., with an
overall 5-year survival of <50%. Recurrences are often locoregional, involving peritoneum and abdominal
organs, and especially for platinum-resistant disease which shows reduced response rates to chemotherapy,
improved treatments are needed. We developed a novel strategy using retroviral replicating vectors (RRV) for
highly efficient and tumor-selective delivery of prodrug activator (`suicide') genes such as cytosine deaminase
(CD), and based on our preclinical findings, first-in-human multi-center clinical trials of RRV-CD suicide gene
therapy delivered by local tumor site injection were initiated throughout the U.S. for recurrent high-grade glioma,
and have shown highly promising signs of clinical benefit, radiographic responses, and increased survival, and
a Phase IIB/III registrational trial is now on-going. Furthermore, based on our recent preclinical data showing
that, even with systemic intravenous delivery, RRV is highly restricted to actively dividing tumor cells, without
spread to normal tissues in immunocompetent hosts, and results in prolonged survival upon prodrug
administration without systemic side effects, FDA recently approved a new clinical trial for intravenous delivery
of RRV. Now that there is clinical precedent, it is timely to consider applying systemically or locoregionally
administered RRV also to systemic malignancies such as ovarian cancer. Accordingly, here we propose the
first preclinical studies to evaluate the feasibility, safety, and efficacy of RRV-mediated suicide gene therapy for
treatment-refractory recurrent ovarian cancer. At the cellular level, we will perform gene expression profiling to
evaluate whether primary patient-derived ovarian cancer cells express candidate anti-viral restriction factors
that might impact future clinical application of this strategy, and empirically test whether RRV replication and
suicide gene activity in ovarian cancer cells correlates with gene expression profiling results, using RRV
pseudotyped with different envelopes to enable co-infection (Aim 1). Metastatic ovarian cancer will necessitate
widespread vector delivery via intravenous or intraperitoneal administration, and both routes will be evaluated
for transduction efficiency and biodistribution/safety in ovarian cancer peritoneal carcinomatosis models, using
human xenografts in immunodeficient mice and syngeneic models in immunocompetent mice (Aim 2). Next,
we will evaluate suicide gene therapy with both the clinical RRV-CD (Toca 511) vector and a newly developed
RRV encoding bacterial nitroreductase (NTR), which generates a pro-immunogenic alkylating agent within
infected cancer cells, individually and in combination (Aim 3). As tumor-localized prodrug conversion by RRV
destroys immunosuppressive tumor stroma, while incurring minimal systemic myelotoxicity and maintaining an
intact immune system, we will also test th...

## Key facts

- **NIH application ID:** 10017020
- **Project number:** 5R01CA213119-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** NORIYUKI KASAHARA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,309
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017020

## Citation

> US National Institutes of Health, RePORTER application 10017020, Retroviral Replicating Vector-mediated Gene Therapy for Ovarian Cancer (5R01CA213119-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017020. Licensed CC0.

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