A PHASE I STUDY OF CYTOSINE DEAMINASE-EXPRESSING NEURAL STEM CELLS (CD-NSCs) ADMINISTERED INTRACRANIALLY AND IN COMBINATION WITH ORAL 5-FLUOROCYTOSINE (5-FC) AND LEUCOVORIN IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

Human NSCs are tumor tropic, making them attractive vehicles for delivery of therapeutics. An immortalized, clonal NSC line was retrovirally transduced to express CD, which converts 5-FC to 5-fluorouracil (5-FU). The primary objectives of this study were to assess the feasibility of serially administering CD-NSCs intracranially via a Rickham catheter and determine the recommended doses for phase II testing (RP2D). Adult patients with recurrent high grade gliomas underwent tumor resection or biopsy and placement of a Rickham. CD-NSCs were injected during surgery and thereafter infused through the Rickham every 2 weeks. Three days after each dose of CD-NSCs, patients took 5-FC (and leucovorin—dose level 3 patients only) orally every 6 hours for 7 days. The dose of CD-NSCs was escalated from 50 x 106 to 150 x 106 using a standard 3 + 3 design. 5-FC and leucovorin doses were 37.5 mg/kg and 25 mg, respectively. A treatment cycle was 28 days, with CD-NSCs administered on days 1 and 15, followed by 5-FC (and leucovorin) on days 4–10 and 18–24. Blood samples were drawn to assess for possible anti-NSC antibody and T cell responses. Fifteen evaluable patients received a median of 2 (range 1–5) cycles of study treatment. One dose-limiting toxicity occurred: grade 3 wound infection. Three patients developed anti-NSC antibodies after receiving 3 doses of NSCs. There was no correlation between these results and use of dexamethasone or number of cycles. Analyses of PK and possible anti-NSC T cell responses are ongoing. Three patients had stable disease for 5 months. Use of a Rickham to serially administer CD-NSCs intracranially is safe and feasible. Study treatment was well tolerated. There were no clinical signs of immunogenicity to these allogeneic CD-NSCs. The RP2D is 150 million CD-NSCs, 37.5 mg/kg of 5-FC, and 25 mg of leucovorin per dose.