Neural Stem Cell-Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients

Area of Science:

• Neuro-oncology
• Stem Cell Therapy
• Cancer Drug Delivery

Background:

• Human neural stem cells (NSCs) exhibit inherent tumor-homing properties, making them promising candidates for targeted cancer therapy.
• Developing effective drug delivery systems for brain tumors remains a significant challenge due to the blood-brain barrier.
• Cytosine deaminase (CD) enzyme can convert the non-toxic prodrug 5-fluorocytosine (5-FC) into the active chemotherapeutic agent 5-fluorouracil (5-FU).

Purpose of the Study:

• To evaluate the safety and feasibility of using retrovirally transduced human neural stem cells (CD-NSCs) expressing cytosine deaminase for brain tumor treatment.
• To assess the ability of CD-NSCs to target brain tumors and locally convert 5-FC to 5-FU in patients with recurrent high-grade glioma.
• To establish a first-in-human proof-of-concept for this novel cell-based chemotherapy delivery system.

Main Methods:

• An immortalized human NSC line (HB1.F3.CD.C21) was engineered to stably express cytosine deaminase (CD-NSCs).
• Recurrent high-grade glioma patients received intracranial administration of CD-NSCs followed by oral 5-FC.
• A 3+3 dose escalation schema was employed for both CD-NSCs and 5-FC; intracerebral microdialysis and blood sampling were used to monitor drug levels and immune responses.

Main Results:

• No dose-limiting toxicity was observed for CD-NSCs; one possible grade 3 transaminitis possibly related to 5-FC was noted.
• No anti-CD-NSC antibodies or replication-competent retrovirus were detected in systemic circulation.
• Intracerebral microdialysis confirmed local production of 5-FU in the brain in a 5-FC dose-dependent manner; autopsy revealed CD-NSC migration to distant tumor sites without evidence of tumorigenicity.

Conclusions:

• This first-in-human study demonstrates the initial safety and proof-of-concept for using engineered neural stem cells as a targeted drug delivery system for brain tumors.
• CD-NSCs successfully migrated to tumor sites and locally generated chemotherapy, supporting their potential as a novel therapeutic strategy for high-grade gliomas.
• The study highlights the potential of cell-based enzyme-prodrug therapy for overcoming challenges in brain tumor treatment.