Modified Neural Stem Cells Feasible For Local Delivery Of Chemotherapy To The Brain

Cytosine deaminase-expressing neural stem cells can convert 5-fluorocytosine to 5-fluorouracil in the brains of patients with high-grade glioma

medwireNews: Results of a first-in-human study among patients with recurrent high-grade gliomas show that intracranially administered cytosine deaminase-expressing neural stem cells (CD-NSCs) migrate to tumour sites in the brain where they locally convert the oral prodrug 5-fluorocytosine (5-FC) to the chemotherapy agent 5-fluorouracil (5-FU) without serious adverse effects.

Collectively, these data “demonstrate initial safety and proof-of-concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy” and “lay the foundation for future studies of neural stem cell-based anti-cancer strategies for the treatment of both primary and metastatic brain tumors”, say Jana Portnow and colleagues from City of Hope in Duarte, California, USA.

The researchers retrovirally transduced an immortalised, clonal NSC line to stably express cytosine deaminase, which converts 5-FC to 5-FU.

The CD-NSCs were administered at a dose of 10 or 50 million, directly into the brains of 15 patients with high-grade glioma who were undergoing tumour resection or biopsy. Four days later, allowing time for the NSCs to stop dividing and distribute among tumour foci, the patients began a 7-day course of oral 5-FC (75 or 150 mg/kg per day in divided doses every 6 hours).

The team reports in Clinical Cancer Research that the treatment was well tolerated with no toxicities associated with intracranial administration of the CD-NSCs and no grade 3 or 4 toxicities related to the CD-NSCs. They did, however, observe one dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC.

Serial blood samples collected during the first 60 days showed no evidence of CD-NSCs, anti-CD-NSC antibodies or replication competent retrovirus in patients' systemic circulation.

Implantation of an intracerebral microdialysis catheter during surgery allowed the researchers to measure 5-FC and 5-FU concentrations in the brain. This showed that the concentration of 5-FU in the brain was significantly higher when patients received 5-FC 150 mg/kg per day versus 75 mg/kg per day, at 81 vs 23 nM.

By contrast, the CD-NSC dose had no apparent impact on 5-FU concentration, but Jana Portnow and co-authors note that inherent inter- and intra-patient variability in NSC biodistribution makes it likely that sample size was too small to detect an NSC-mediated dose effect.

Autopsy data from two participants who died of recurrent or progressive multifocal disease during the study showed that CD-NSCs migrated to tumour foci distant from the primary injection sites, including the opposite hemisphere, and were non-tumourigenic.

Commenting on their findings, Jana Portnow et al say that even if this particular NSC-mediated Enzyme/prodrug combination does not become a new treatment for glioma, the “NSC line can be further modified for tumor-localized delivery of a variety of anti-tumor agents, including other prodrug activating enzymes, oncolytic viruses, apoptotic agents, antibodies, or nanoparticles, which could be given serially or in combination to maximize therapeutic benefit.”

“Thus, this NSC-based approach potentially has widespread applicability, which could lead to improved treatment of both primary and metastatic brain tumors”, they conclude.

Reference

Portnow J, Synold TW, Badie B, et al. Neural stem cell-based anti-cancer gene therapy: a first-in-human study in recurrent high grade glioma patients. Clin Cancer Res; Advance online publication 15 December 2016. doi: 10.1158/1078-0432.CCR-16-1518

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