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  • Neural stem cell (NSC)-mediated conversion of 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) in recurrent glioma patients: A proof of concept.

    Final Number:
    492

    Authors:
    Jana Portnow MD; Timothy W Synold PhD; Simon F Lacey; Massimo D'Apuzzo; Paul H Frankel; Mike Yue Chen MD; Karen S Aboody MD; Behnam Badie MD

    Study Design:
    Clinical Trial

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2012 Annual Meeting

    Introduction: Human NSCs are inherently tumor-tropic, making them an attractive drug delivery vehicle. This first-in-human Human NSCs are inherently tumor-tropic, making them an attractive drug delivery vehicle. This first-in-human phase I study is assessing the safety and feasibility of using genetically-modified NSCs for tumor selective enzyme/prodrug therapy. An immortalized, clonal NSC line was retrovirally-transduced to stably express cytosine deaminase (CD), which converts the prodrug 5-FC to 5-FU, producing chemotherapy locally at sites of tumor in the brain while minimizing systemic toxicities.

    Methods: Patients with recurrent high-grade gliomas undergo intracranial administration of NSCs during resection or biopsy of tumor. Four days later, 5-FC is administered orally every 6 hours for 7 days. Patients receive only 1 round of NSCs and 5-FC. This study uses a standard 3 +3 dose escalation schema for increasing the doses of NSCs and 5-FC. A microdialysis catheter is placed at the time of surgery to measure intracerebral levels of 5-FC and 5-FU, and serial blood samples are obtained to measure systemic concentrations of these drugs. Peripheral blood mononuclear cells are collected on days 4, 10, 32, and 60 for analysis by flow cytometry-based antibody binding assays and CD4/CD8 degranulation assays to assess NSC immunogenicity.

    Results: Accrual to dose levels 1 and 2 has been completed. Thus far, there have been no DLTs. Microdialysis data demonstrate the presence of 5-FU in the brain throughout the entire 5-FC dosing interval. Average steady state concentrations of 5-FU and 5-FC in brain are 23.4 nM and 24.5 mM, respectively in cohort 1 (n=4) and 106.7 nM and 153.3 mM, respectively in cohort 2 (n=2). Analysis of plasma samples to date have shown high levels of 5-FC, but no detectable 5-FU in circulation. Anti-NSC antibody and T-cell responses have not been detected.

    Conclusions: Although accrual is ongoing, dialysate and plasma data from the first 2 patient cohorts demonstrate the proof-of-concept that the NSCs are converting 5-FC to 5-FU locally in the brain. Furthermore, levels of 5-FU in the brain increase in a 5-FC dose-dependent manner. No immune responses to these allogeneic NSCs have occurred after first exposure.

    Patient Care: This is the first-in-human clinical trial demonstrating the feasibility and potential application of neural stem cells for glioblastoma therapy.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the rationale for the application of stem cell therapy for malignant glioma, 2) Discuss the value of cerebral microdialyis in clinical trials, and 3) Identify potential challenges of cellular therapies for brain tumors.

    References:

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