In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 2018-2018
Abstract:
2018 Background: Human NSCs are inherently tumor-tropic, making them attractive drug delivery vehicles. This pilot-feasibility study assessed the safety of using genetically-modified NSCs for tumor selective enzyme/prodrug therapy. An immortalized, clonal NSC line was retrovirally-transduced to stably express CD, which converts the prodrug 5-FC to 5-fluorouracil (5-FU), producing chemotherapy locally at sites of tumor in the brain. Methods: Patients 18 years or older with recurrent high-grade glioma underwent intracranial administration of NSCs during tumor resection or biopsy. Four days later, 5-FC was administered orally every 6 hours for 7 days. Study treatment was given only once. A standard 3+3 dose escalation schema was used to increase doses of NSCs from 1 x 10 7 to 5 x 10 7 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU; serial blood samples were obtained to assess systemic drug concentrations. Three patients received iron-labeled NSCs for MRI tracking. Brain autopsies were done on 2 patients. Results: Fifteen patients received study treatment. Three were inevaluable for toxicity and replaced. All patients tolerated the NSCs well. There was 1 dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC. At the highest dose level of NSCs, the average steady-state concentration of 5-FU in the brain was 63.9±7.9 nM. The average maximum 5-FU level in brain was 104±88 nM compared to 24±36 nM in plasma, indicating local production of 5-FU in the brain by the NSCs. MR imaging of iron-labeled NSCs showed preliminary evidence of NSC migration. Autopsy data documented (by IHC, FISH, and PCR) NSCs at distant sites of tumor in the brain and no development of secondary tumors. Conclusions: This first-in-human study has demonstrated safety and proof-of-concept regarding NSC-mediated conversion of 5-FC to 5-FU and NSC tumor-tropism. NSCs have the potential to overcome obstacles of drug delivery that limit current gene therapy strategies. Results of this pilot study will serve as the foundation for future NSC studies. (Supported by NCI 1R21 CA137639-01A1, CIRM DR-01421). Clinical trial information: NCT01172964.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.2018
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
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