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STEM-32. PRE-CLINICAL SAFETY AND EFFICACY STUDIES OF NEURAL STEM CELL MEDIATED CARBOXYLESTERASE/IRINOTECAN ENZYME/PRODRUG GENE THERAPY FOR RECURRENT GLIOMA LEADING TO FIRST-IN-HUMAN PHASE I CLINICAL TRIAL

ABSTRACT: Abstract Human neural stem cells (NSCs) are inherently tumor-tropic, localizing to invasive brain tumor foci following intracerebral administration in preclinical models of primary and secondary brain tumors, thus overcoming obstacles limiting current therapeutic modalities. These NSCs can be engineered to express numerous anti-cancer agents, making them attractive drug delivery vehicles. By concentrating therapy selectively at the tumor sites, toxicity to normal tissues and associated side effects are minimized, improving quality of life. A first-in-human pilot safety/feasibility clinical trial for recurrent glioma patients using a clonal, allogeneic NSC line (HB1.F3.CD21) for cytosine deaminase/5-fluorocytosine (5-FC) enzyme/prodrug gene therapy demonstrated safety, proof of concept for brain tumor localized NSC-mediated conversion of prodrug to active chemotherapeutic agent, non-tumorigenicity, and non-immunogenicity with a single round of treatment (Portnow et al, 2016). HB1.F3.CD21 NSCs were further engineered to secrete a modified human carboxylesterase (hCE1m6) that converts irinotecan (IRN) to the potent topoisomerase-1 inhibitor SN-38. Presented are the preclinical in vitro and in vivo pharmacokinetic studies optimizing dose and scheduling of hCE1m6-NSCs and a clinically equivalent bolus dose of IRN. Efficacy studies in orthotopic glioma models with multiple treatment cycles demonstrated a highly significant increase in the long-term survival distribution in mice treated with hCE1m6-NSCs + IRN as compared to IRN alone (Holm-Bonferroni adjusted p-value <0.0001). Results of IND-enabling safety/toxicity studies showed no significant increase in toxicity, as determined by daily clinical observations, blood chemistries, CBCs, and histopathology, in mice treated with hCE1m6-NSCs + IRN as compared to IRN alone. These results led to FDA approval for a recently initiated first-in-human phase I dose escalation, multiple treatment cycle study of intracranially administered carboxylesterase expressing NSCs in combination with intravenous irinotecan for the treatment of recurrent high grade gliomas (IND 16265; clincialtrial.gov ID NCT02192359).

SUBMITTER: Ghoda L

PROVIDER: S-EPMC5693135 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Project description:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Association of UDP-glucuronosyltransferase 1A1 (UGT1A1) genetic polymorphisms *6 and *28 with reduced clearance of SN-38 and severe neutropenia in irinotecan therapy was demonstrated in Japanese cancer patients. * The detailed gene structure of CES1 has been characterized. * Possible functional SNPs in the promoter region have been reported. WHAT THIS STUDY ADDS * Association of functional CES1 gene number with AUC ratio [(SN-38 + SN-38G)/irinotecan], an in vivo index of CES activity, was observed in patients with irinotecan monotherapy. * No significant effects of major CES1 SNPs on irinotecan PK were detected. AIMS Human carboxylesterase 1 (CES1) hydrolyzes irinotecan to produce an active metabolite SN-38 in the liver. The human CES1 gene family consists of two functional genes, CES1A1 (1A1) and CES1A2 (1A2), which are located tail-to-tail on chromosome 16q13-q22.1 (CES1A2-1A1). The pseudogene CES1A3 (1A3) and a chimeric CES1A1 variant (var1A1) are also found as polymorphic isoforms of 1A2 and 1A1, respectively. In this study, roles of CES1 genotypes and major SNPs in irinotecan pharmacokinetics were investigated in Japanese cancer patients. METHODS CES1A diplotypes [combinations of haplotypes A (1A3-1A1), B (1A2-1A1), C (1A3-var1A1) and D (1A2-var1A1)] and the major SNPs (-75T>G and -30G>A in 1A1, and -816A>C in 1A2 and 1A3) were determined in 177 Japanese cancer patients. Associations of CES1 genotypes, number of functional CES1 genes (1A1, 1A2 and var1A1) and major SNPs, with the AUC ratio of (SN-38 + SN-38G)/irinotecan, a parameter of in vivo CES activity, were analyzed for 58 patients treated with irinotecan monotherapy. RESULTS The median AUC ratio of patients having three or four functional CES1 genes (diplotypes A/B, A/D or B/C, C/D, B/B and B/D; n= 35) was 1.24-fold of that in patients with two functional CES1 genes (diplotypes A/A, A/C and C/C; n= 23) [median (25th-75th percentiles): 0.31 (0.25-0.38) vs. 0.25 (0.20-0.32), P= 0.0134]. No significant effects of var1A1 and the major SNPs examined were observed. CONCLUSION This study suggests a gene-dose effect of functional CES1A genes on SN-38 formation in irinotecan-treated Japanese cancer patients.

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STEM-32. PRE-CLINICAL SAFETY AND EFFICACY STUDIES OF NEURAL STEM CELL MEDIATED CARBOXYLESTERASE/IRINOTECAN ENZYME/PRODRUG GENE THERAPY FOR RECURRENT GLIOMA LEADING TO FIRST-IN-HUMAN PHASE I CLINICAL TRIAL

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