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Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model
Published on: June 4, 2017
Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies
Karen S Aboody1, Joseph Najbauer, Marianne Z Metz
1Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA. kaboody@coh.org
Abstract:
High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, and are genetically and functionally stable. In vivo biodistribution studies demonstrated NSC retention of tumor tropism, even in mice pretreated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor-bearing and orthotopic glioma-bearing immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was about one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, nontoxic, and effective in mice. These data have led to approval of a first-in-human study of an allogeneic NSC-mediated enzyme/prodrug-targeted cancer therapy in patients with recurrent high-grade glioma.
Insights
This study shows that neural stem cells (NSCs) carrying an enzyme can convert a prodrug into chemotherapy directly within brain tumors. This targeted therapy safely reduced glioma size in mice, paving the way for human trials.
Area of Science:
- Neuro-oncology
- Cancer Gene Therapy
- Stem Cell Therapy
Background:
- High-grade gliomas are challenging to treat due to invasiveness and therapy toxicity.
- Neural stem cells (NSCs) possess tumor-homing abilities, making them potential drug delivery vehicles.
- Enzyme/prodrug therapy offers targeted cancer treatment by converting inactive prodrugs into active chemotherapeutics at the tumor site.
Purpose of the Study:
- To evaluate the safety and efficacy of using a genetically engineered human neural stem cell (NSC) line (HB1.F3.CD) for targeted enzyme/prodrug therapy in gliomas.
- To assess the tumor-homing capabilities and genetic stability of the engineered NSCs.
- To determine the therapeutic effect and toxicity profile of the combined NSC-mediated enzyme/prodrug system in a preclinical glioma model.
Main Methods:
- Developed a clonal human NSC line (HB1.F3.CD) engineered to express cytosine deaminase (CD).
- Administered HB1.F3.CD NSCs intracerebrally into glioma-bearing mice and administered the prodrug 5-fluorocytosine (5-FC).
- Assessed NSC tumor tropism, genetic stability, biodistribution, toxicity, and tumor volume reduction in vivo. In vitro studies confirmed NSC characteristics.
Main Results:
- In vitro and in vivo studies confirmed HB1.F3.CD NSCs possess normal karyotype, tumor tropism, and functional stability.
- Biodistribution studies showed NSCs retained tumor tropism, even with concurrent radiation or dexamethasone treatment.
- No significant toxicity or off-target effects were observed. Tumor volume in treated mice was reduced by approximately two-thirds compared to controls.
Conclusions:
- Combination therapy using HB1.F3.CD NSCs and 5-fluorocytosine is safe, well-tolerated, and effective in reducing glioma volume in mice.
- The engineered NSCs demonstrate potent tumor-targeting capabilities and serve as effective delivery vehicles for localized chemotherapy.
- These promising preclinical results have led to the initiation of a first-in-human clinical trial for recurrent high-grade glioma.
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