Feasibility of intracerebrally administering multiple doses of genetically modified neural stem cells to locally produce chemotherapy in glioma patients


Neural stem cells (NSCs) are tumor tropic and can be genetically modified to produce anti-cancer therapies locally in the brain. In a prior first-in-human study we demonstrated that a single dose of intracerebrally administered allogeneic NSCs, which were retrovirally transduced to express cytosine deaminase (CD), tracked to glioma sites and converted oral 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). The next step in the clinical development of this NSC-based anti-cancer strategy was to assess the feasibility of administering multiple intracerebral doses of CD-expressing NSCs (CD-NSCs) in patients with recurrent high-grade gliomas. CD-NSCs were given every 2 weeks using an indwelling brain catheter, followed each time by a 7-d course of oral 5-FC (and leucovorin in the final patient cohort). Fifteen evaluable patients received a median of 4 (range 2–10) intracerebral CD-NSC doses; doses were escalated from 50 × 106 to 150 × 106 CD-NSCs. Neuropharmacokinetic data confirmed that CD-NSCs continuously produced 5-FU in the brain during the course of 5-FC. There were no clinical signs of immunogenicity, and only three patients developed anti-NSC antibodies. Our results suggest intracerebral administration of serial doses of CD-NSCs is safe and feasible and identified a recommended dose for phase II testing of 150 × 106 CD-NSCs.

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Fig. 1: Study schema.
Fig. 2: Intracerebral microdialysis data: CD-NSC-mediated conversion of 5-FC to 5-FU.
Fig. 3: Assessment of antibody responses to multiple doses of NSCs.
Fig. 4: Serial brain MRIs from Patient 14 who had stable disease for 5 months.


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We thank Narine Arabyan, PhD, Keely Walker, PhD, and Alice Tuan, BS, for their editing and/or technical assistance with preparing this manuscript. We also thank Shiny Wu, BS, for her technical support in providing the PK data.


This research was supported by grants from the United States Food and Drug Administration R01 FD004816 (co-principal investigators: J. Portnow and K.S. Aboody), Phase One Foundation (PI: J. Portnow), The Rosalinde and Arthur Gilbert Foundation, and City of Hope. In addition, research reported in this publication included work performed in the Analytical Pharmacology and Biostatistics and Mathematical Modeling Cores supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Jana Portnow.

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K.S. Aboody is a shareholder and board member of TheraBiologics, Inc.

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Portnow, J., Badie, B., Suzette Blanchard, M. et al. Feasibility of intracerebrally administering multiple doses of genetically modified neural stem cells to locally produce chemotherapy in glioma patients. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-00219-y

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