# Engineering stem cell therapies to understand and overcome glioblastoma adaption

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $318,366

## Abstract

Project Summary/Abstract
Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain
cancer Glioblastoma (GBM). Engineered NSCs have unique tumor-homing capacity that allows them to deliver
anti-cancer gene products directly into local and invasive GBM foci. Preclinical studies by our group and others
have shown tumoricidal NSCs routinely reduce orthotopic GBM xenografts between 70-90% and significantly
extend survival of tumor-bearing mice. Yet, these dramatic initial reductions in GBM volumes are not
maintained and treatment durability remains a major challenge for NSC-based therapy. GBM escape occurs
after treatment with NSCs carrying different therapeutic payloads and in pre-clinical models of both solid and
post-surgical GBM. We recently discovered that novel tumor-homing drug delivery vehicles with robust anti-
cancer activity can be developed from “induced neural stem cells” (iNSCs) using cellular reprogramming
technology, referred to as transdifferentiation (TD). Tumoricidal iNSC therapy reduced GBM xenografts 230-
fold in 4 weeks and more than doubled survival. Similar to wild-type NSC therapy, the tumors were not
eradicated and the GBMs re-developed. The events mediating the regrowth of GBMs in response to single-
agent NSC/iNSC therapy are unknown. Our results show that transplanted iNSCs drug carriers are cleared
from the brain, but repeated intracerebroventricular (ICV) infusion restores carrier levels. We also have
evidence that GBM cells become resistant to iNSC-delivered drugs. This allows us to hypothesize that GBM
resistance to iNSC therapy can be overcome by repeat administration to address carrier loss and multi-agent
iNSC delivery to address tumor resistance. With this grant we propose to test this hypothesis, defining the
events that contribute to the dynamic adaption of GBM during NSC treatment and develop strategies to convert
the initial tumor kill into sustained GBM suppression. We will investigate carrier clearance, homing, and tumor
resistance throughout GBM adaption and recurrence. We will then modulate iNSC therapy through repeated
dosing via ICV infusion and delivery of iNSCs carrying multi-drug payloads with the goal of improving treatment
durability by overcoming iNSC loss and the emergence of GBM foci that are resistant to single-agent
treatments. All testing will be done using our novel surgical resection models of murine-derived GBM cells in
immune-competent animals and patient-derived CD133+ human GBM cells to maximize the clinical relevancy
of our finding and understand the impact of the immune system on iNSC treatment durability. The results of
these studies are essential for creating durable NSC-based tumor therapies capable of producing long-lasting
GBM suppression in patient trials.

## Key facts

- **NIH application ID:** 10218274
- **Project number:** 5R01NS099368-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Shawn Hingtgen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $318,366
- **Award type:** 5
- **Project period:** 2017-09-26 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218274

## Citation

> US National Institutes of Health, RePORTER application 10218274, Engineering stem cell therapies to understand and overcome glioblastoma adaption (5R01NS099368-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10218274. Licensed CC0.

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