Bcl-2Overexpression 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.

Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications

“…Robey et al [ 25 ] indicated that most cell death occurs in the first week post-transplantation. In NSC transplantation for neurological disorders in the brain, less than 4%-10% of primary NSCs survived within the first few days[ 96 ]. Similarly, Yasuda and Hayashi’s groups showed that 15% of transplanted cells survived at 1 wk and 9% at 4 wk in a rat infarction model[ 97 ].…”

Blood–Brain Barrier in Brain Tumors: Biology and Clinical Relevance

“…Lastly, a wide range of stem cell-based systems have been tested against brain malignancies, using the ability of neural stem cells (NSCs) and mesenchymal stem cells (MSCs) to cross the BBB/BTB by rolling on and adhere to endothelium with subsequent transmigration. The reason for the high tumor tropism of NSCs and MSCs are not yet fully elucidated: probably chemokines and cytokines released by the tumor may play a central role [ 97 , 98 , 99 ].…”

Engineered cells as glioblastoma therapeutics

“…The clinical trial of engineered neural stem cells in glioblastoma described above made use of the HB1.F3 cell line, which was originally derived from human fetal brain tissue by v-myc immortalization [ 49 ]. This line has been characterized in detail in preclinical models with respect to tumor-homing ability [ 50 ], persistence [ 51 , 52 ], and lack of tumorigenicity [ 53 ]. Additional therapeutic payloads beyond cytosine deaminase have also been explored using HB1.F3 [ 54 ].…”