20. Carboxylesterase-Secreting Neural Stem Cells Increase Efficacy of Irinotecan in Orthotopic Glioma Models: Translation Toward the Clinic

Human neural stem cells (NSCs) are serving as vehicles for targeted delivery of cytosine deaminase/5-flucytosine enzyme/prodrug therapy to recurrent glioma patients in first in human Phase 1 clinical trials (IND 14041). The initial safety/feasibility clinical study demonstrated safety, non-tumorigenicity, non-immunogenicity with 1 round of treatment, and proof of concept for localized conversion of 5-Flucytosine to the active chemotherapeutic agent, 5-Fluorouracil. We have now developed a second generation NSC brain tumor therapy, engineering NSCs to secrete a modified human carboxylesterase (hCE1m6) that converts irinotecan (IRN) to the potent topoisomerase inhibitor SN-38. Biodistribution, efficacy, and safety/toxicity studies have been completed and an Investigational New Drug application has been filed with the Food and Drug Administration (IND 16265).Early studies on the CE-expressing human NSCs was described in Metz, et al., Stem Cells Transl Med. 2013 Dec;2(12):983), demonstrating tumor tropism in orthotopic human glioma models and tumor localized conversion of IRN to SN-38 in a time-dependent manner. The current preclinical studies show in vivo biodistribution of varying doses of intracranially delivered CE-NSCs and optimization of a clinically relevant adult IRN treatment regimen based on pharmacokinetic and long term survival studies. These studies demonstrated a statistically significant increase in long-term survival distributions with the addition of CE-NSCs + IRN as compared to IRN alone (see figure). These data, together with our preclinical safety/toxicity data, support clinical translation of this schema to phase I clinical trials for patients with recurrent glioma. View Large Image | Download PowerPoint Slide