Dataset Information

Bcl-2 Overexpression Improves Survival and Efficacy of Neural Stem Cell-Mediated Enzyme Prodrug Therapy.

ABSTRACT: Tumor-tropic neural stem cells (NSCs) can be engineered to localize gene therapies to invasive brain tumors. However, like other stem cell-based therapies, survival of therapeutic NSCs after transplantation is currently suboptimal. One approach to prolonging cell survival is to transiently overexpress an antiapoptotic protein within the cells prior to transplantation. Here, we investigate the utility and safety of this approach using a clinically tested, v-myc immortalized, human NSC line engineered to contain the suicide gene, cytosine deaminase (CD-NSCs). We demonstrate that both adenoviral- and minicircle-driven expression of the antiapoptotic protein Bcl-2 can partially rescue CD-NSCs from transplant-associated insults. We further demonstrate that the improved CD-NSC survival afforded by transient Bcl-2 overexpression results in decreased tumor burden in an orthotopic xenograft glioma mouse model following administrations of intracerebral CD-NSCs and systemic prodrug. Importantly, no evidence of CD-NSC transformation was observed upon transient overexpression of Bcl-2. This research highlights a critical need to develop clinically relevant strategies to improve survival of therapeutic stem cell posttransplantation. We demonstrate for the first time in this disease setting that improving CD-NSC survival using Bcl-2 overexpression can significantly improve therapeutic outcomes.

SUBMITTER: Mooney R

PROVIDER: S-EPMC6031202 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Bcl-2 Overexpression Improves Survival and Efficacy of Neural Stem Cell-Mediated Enzyme Prodrug Therapy.

Mooney Rachael R Majid Asma Abdul AA Mota Daniel D He Adam A Aramburo Soraya S Flores Linda L Covello-Batalla Jennifer J Machado Diana D Gonzaga Joanna J Aboody Karen S KS

Stem cells international 20180620

Tumor-tropic neural stem cells (NSCs) can be engineered to localize gene therapies to invasive brain tumors. However, like other stem cell-based therapies, survival of therapeutic NSCs after transplantation is currently suboptimal. One approach to prolonging cell survival is to transiently overexpress an antiapoptotic protein within the cells prior to transplantation. Here, we investigate the utility and safety of this approach using a clinically tested, v-myc immortalized, human N ...[more]

PMID: 30026762

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Project description: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).

Dataset Information

Bcl-2 Overexpression Improves Survival and Efficacy of Neural Stem Cell-Mediated Enzyme Prodrug Therapy.

Publications

<i>Bcl-2</i> Overexpression Improves Survival and Efficacy of Neural Stem Cell-Mediated Enzyme Prodrug Therapy.

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