title: Neural Stem Cell-Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients.
abstract: Purpose:Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).Experimental Design:Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC 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 CD-NSCs from 1 × 107to 5 × 107and 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 as well as to perform immunologic correlative studies.Results:Fifteen patients underwent study treatment. We saw no dose-limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD-NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.Conclusions:Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy.Clin Cancer Res; 23(12); 2951-60. ©2016 AACR.
authors.affiliation: Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, California. jportow@coh.org.
authors.forename: Jana
authors.initials: J
authors.lastname: Portnow
authors.affiliation: Department of Cancer Biology, City of Hope, Duarte, California.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.affiliation: Division of Neurosurgery, City of Hope, Duarte, California.
authors.forename: Behnam
authors.initials: B
authors.lastname: Badie
authors.affiliation: Department of Developmental & Stem Cell Biology, City of Hope, Duarte, California.
authors.forename: Revathiswari
authors.initials: R
authors.lastname: Tirughana
authors.affiliation: Clinical Immunobiology Correlative Studies Laboratory, City of Hope, Duarte, California.
authors.forename: Simon F
authors.initials: SF
authors.lastname: Lacey
authors.affiliation: Department of Pathology, City of Hope, Duarte, California.
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Apuzzo
authors.affiliation: Department of Developmental & Stem Cell Biology, City of Hope, Duarte, California.
authors.forename: Marianne Z
authors.initials: MZ
authors.lastname: Metz
authors.affiliation: Department of Developmental & Stem Cell Biology, City of Hope, Duarte, California.
authors.forename: Joseph
authors.initials: J
authors.lastname: Najbauer
authors.affiliation: Cytogenetics Laboratory, City of Hope, Duarte, California.
authors.forename: Victoria
authors.initials: V
authors.lastname: Bedell
authors.affiliation: Department of Developmental & Stem Cell Biology, City of Hope, Duarte, California.
authors.forename: Tien
authors.initials: T
authors.lastname: Vo
authors.affiliation: Department of Developmental & Stem Cell Biology, City of Hope, Duarte, California.
authors.forename: Margarita
authors.initials: M
authors.lastname: Gutova
authors.affiliation: Division of Biostatistics, City of Hope, Duarte, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Frankel
authors.affiliation: Division of Neurosurgery, City of Hope, Duarte, California.
authors.forename: Mike
authors.initials: M
authors.lastname: Chen
authors.affiliation: Division of Neurosurgery, City of Hope, Duarte, California.|Department of Developmental & Stem Cell Biology, City of Hope, Duarte, California.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Aboody
mesh_terms: D000293:Adolescent; D000328:Adult; D043525:Cytosine Deaminase / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D058953:Neural Stem Cells / Q000637:transplantation*
chemical_list: D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil