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  • 1
    Online Resource
    Online Resource
    Use of FLOSEAL ® as a scaffold and its impact on induced neural stem cell phenotype, persistence, and efficacy
    Wiley ; 2022
    In:  Bioengineering & Translational Medicine Vol. 7, No. 2 ( 2022-05)
    Details
    In: Bioengineering & Translational Medicine, Wiley, Vol. 7, No. 2 ( 2022-05)
    Abstract: Induced neural stem cells (iNSCs) have emerged as a promising therapeutic platform for glioblastoma (GBM). iNSCs have the innate ability to home to tumor foci, making them ideal carriers for antitumor payloads. However, the in vivo persistence of iNSCs limits their therapeutic potential. We hypothesized that by encapsulating iNSCs in the FDA‐approved, hemostatic matrix FLOSEAL®, we could increase their persistence and, as a result, therapeutic durability. Encapsulated iNSCs persisted for 95 days, whereas iNSCs injected into the brain parenchyma persisted only 2 weeks in mice. Two orthotopic GBM tumor models were used to test the efficacy of encapsulated iNSCs. In the GBM8 tumor model, mice that received therapeutic iNSCs encapsulated in FLOSEAL® survived 30 to 60 days longer than mice that received nonencapsulated cells. However, the U87 tumor model showed no significant differences in survival between these two groups, likely due to the more solid and dense nature of the tumor. Interestingly, the interaction of iNSCs with FLOSEAL® appears to downregulate some markers of proliferation, anti‐apoptosis, migration, and therapy which could also play a role in treatment efficacy and durability. Our results demonstrate that while FLOSEAL® significantly improves iNSC persistence, this alone is insufficient to enhance therapeutic durability.
    Type of Medium: Online Resource
    ISSN: 2380-6761 , 2380-6761
    URL: Issue
    URL: Article
    DOI: 10.1002/btm2.v7.2
    DOI: 10.1002/btm2.10283
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2865162-5
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  • 2
    Online Resource
    Online Resource
    SCIDOT-24. INCREASING INDUCED NEURAL STEM CELL PERSISTENCE IN THE TUMOR RESECTION CAVITY
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi276-vi276
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi276-vi276
    Abstract: Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Afflicted patients have a median survival rate of only 15 months, and patient survival statistics have remained stagnant for over three decades. Current standard of care includes maximal safe tumor resection, chemotherapy, and radiation. Nevertheless, GBM is aggressive, making recurrence and deeper tumor infiltration inevitable. Neural stem cells transdifferentiated from a skin biopsy, i.e. induced neural stem cells (iNSCs), have the innate ability to home to tumors, and, when engineered with cytotoxic proteins, can actively kill cancer cells. However, direct injection of these cells into the hostile immune environment of the tumor resection cavity results in an accelerated clearance rate and therefore a shortened therapeutic window. To combat this clearance issue, we investigated the FDA-approved hemostatic matrix, Floseal, as a cell delivery platform to increase iNSC persistence. In vitro, SEM imaging showed homogeneous iNSC distribution throughout Floseal. Using our surgical resection model of GBM in mice, we delivered iNSCs into the post-surgical cavity in Floseal and by direct injection to model current clinical delivery strategies. Serial kinetic imaging showed that human iNSC persistence delivered into the cavity in Floseal persisted over 90 days, while cells directly injected into the brain parenchyma persist less than 20 days. When we investigated the impact on tumor kill, we found the increase in persistence increased survival of GBM-bearing mice more than 30 days compared to control cells. Light-sheet microscopy showed wild-type neural stem cells migrate into invasive GBM-8 tumors in the contralateral hemisphere, and we are now using this approach to validate the homing of iNSCs delivered via Floseal. Administration of iNSCs encapsulated in the biocompatible Floseal matrix offers a promising, clinically-translatable therapeutic strategy for GBM.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz175.1160
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2094060-9
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  • 3
    Online Resource
    Online Resource
    STEM-12. INCREASING INDUCED NEURAL STEM CELL PERSISTENCE IN THE TUMOR RESECTION CAVITY
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi236-vi236
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi236-vi236
    Abstract: Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Afflicted patients have a median survival rate of only 15 months, and patient survival statistics have remained stagnant for over three decades. Current standard of care includes maximal safe tumor resection, chemotherapy, and radiation. Nevertheless, GBM is aggressive, making recurrence and deeper tumor infiltration inevitable. Neural stem cells transdifferentiated from a skin biopsy, i.e. induced neural stem cells (iNSCs), have the innate ability to home to tumors, and, when engineered with cytotoxic proteins, can actively kill cancer cells. However, direct injection of these cells into the hostile immune environment of the tumor resection cavity results in an accelerated clearance rate and therefore a shortened therapeutic window. To combat this clearance issue, we investigated the FDA-approved hemostatic matrix, Floseal, as a cell delivery platform to increase iNSC persistence. In vitro, SEM imaging showed homogeneous iNSC distribution throughout Floseal. Using our surgical resection model of GBM in mice, we delivered iNSCs into the post-surgical cavity in Floseal and by direct injection to model current clinical delivery strategies. Serial kinetic imaging showed that human iNSC persistence delivered into the cavity in Floseal persisted over 90 days, while cells directly injected into the brain parenchyma persist less than 20 days. When we investigated the impact on tumor kill, we found the increase in persistence increased survival of GBM-bearing mice more than 30 days compared to control cells. Light-sheet microscopy showed wild-type neural stem cells migrate into invasive GBM-8 tumors in the contralateral hemisphere, and we are now using this approach to validate the homing of iNSCs delivered via Floseal. Administration of iNSCs encapsulated in the biocompatible Floseal matrix offers a promising, clinically-translatable therapeutic strategy for GBM.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz175.986
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2094060-9
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  • 4
    Online Resource
    Online Resource
    DDEL-04. BIOMATERIAL SCAFFOLDS FOR THE DELIVERY OF NEURAL STEM CELL THERAPIES INTO THE GLIOBLASTOMA RESECTION CAVITY
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii94-vii95
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii94-vii95
    Abstract: Therapeutic neural stem cells (tNSCs) are a promising new platform for the treatment of glioblastoma (GBM). tNSCs exhibit a characteristic known as tumor tropism, in which they can migrate towards distant GBM foci via cytokine signaling. Complementarily, genetic engineering of NSCs may be performed to turn the cells into drug-producing therapeutics. Together, this results in NSCs that act as targeted drug delivery vehicles that can seek out and kill invasive GBM lesions post-resection. However, one limitation of this cell therapy platform is that tNSCs delivered directly into the GBM resection cavity are rapidly cleared. We hypothesized that the commercially available, FDA-approved hemostat FLOSEAL® may be used as a drug delivery system for improving cell persistence in the brain, thus resulting in improved therapeutic efficacy. It was found that tNSCs encapsulated in FLOSEAL® were detectable in the brain for over 95 days in mice, a drastic improvement compared to directly injected cells and cells encapsulated in other existing hemostat systems, which persisted 2 weeks or less. However, two in vivo efficacy studies of tNSCs encapsulated in FLOSEAL® yielded contrasting results. While the FLOSEAL®-tNSC system was significantly more efficacious against a GBM8 tumor model in mice compared to directly injected tNSCs, it was not significantly more effective against a U87 tumor model. This could be due to a variety of factors, including the tumor type (diffuse vs. solid for GBM8 and U87, respectively) and negative impacts of FLOSEAL® on tNSC markers of proliferation, migration, drug production, and anti-apoptosis. While FLOSEAL® is a promising material for the delivery of tNSCs in the treatment of post-operative GBM, alternative systems that allow for improved persistence while maintaining the therapeutic activity of the cells would be optimal for long-term treatment with tNSCs.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.350
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 5
    Online Resource
    Online Resource
    EXTH-35. INCREASING THERAPEUTIC INDUCED NEURAL STEM CELL PERSISTENCE IN THE GLIOBLASTOMA TUMOR RESECTION CAVITY
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi171-vi171
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi171-vi171
    Abstract: Induced neural stem cells (iNSCs) have emerged as a promising therapeutic platform for glioblastoma (GBM). iNSCs have the innate ability to home to tumor foci, making them ideal carriers for anti-tumor payloads. However, iNSC persist for only two weeks in the murine GBM tumor resection cavity. We hypothesized that by encapsulating iNSCs in a scaffold matrix, we could increase both the persistence of the cells the therapeutic durability. METHODS iNSCs expressing TRAIL were encapsulated in a gelatin-thrombin matrix; fibrinogen was used to polymerize the matrix. SEM was used to explore interactions between iNSCs and the scaffold matrix. To evaluate persistence, iNSCs encapsulated in the matrix were implanted into mock resection cavities of athymic nude mice and followed via BLI. To study the impacts of encapsulation on iNSC efficacy, athymic nude mice were implanted with U87 or GBM8 tumors. Tumors were then resected, and iNSCs encapsulated in the matrix were implanted; tumor volume was monitored via BLI. RESULTS SEM images showed homogeneous distribution of iNSCs throughout the matrix; iNSCs were completed encased in the fibrin clot component of the matrix and did not adhere to gelatin. In vivo, encapsulated iNSCs persisted for nearly 100 days whereas iNSCs directly injected into the brain parenchyma persisted & lt; 20 days. Using mice bearing GBM8 tumors, animals treated with a high dose of therapeutic encapsulated iNSCs survived ~60 days longer than animals treated with non-therapeutic cells. A similar trend was observed in animals inoculated with U87 tumors. While not statistically significant, 25% of mice treated with iNSCs encapsulated in the gelatin-thrombin matrix survived longer than those treated with iNSCs encapsulated in a fibrin-only matrix, suggesting additional benefit due to the gelatin component. FUTURE DIRECTIONS: Prospective experiments will explore the impact of the scaffold on iNSC phenotype, including proliferation, differentiation, and migration markers.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.674
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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