A Preclinical Evaluation of Neural Stem Cell–Based Cell Carrier for Targeted Antiglioma Oncolytic Virotherapy

Ahmed, Atique U.; Thaçi, Bart; Tobias, Alex L.; Auffinger, Brenda; Zhang, Lingjiao; Cheng, Yu; Kim, Chung Kwon; Yunis, Catherine; Han, Yu; Alexiades, Nikita G.; Fan, Xiaobing; Aboody, Karen S.; Lesniak, Maciej S.

doi:10.1093/jnci/djt141

Cited by 87 publications

(113 citation statements)

References 29 publications

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“…Six-to eight-week-old athymic nude male or female mice were obtained from Envigo Research Models and Services and from Charles River Laboratories and were maintained in a pathogen-free facility. Mice were anesthetized with a ketamine HCl (25 mg/mL)/xylazine (2.5 mg/mL) solution, and patient-derived GBM43 or MGG8 cells (without or with TF siRNA knockdown; 1 × 10 5 or 2 × 10 5 cells in 2.5 μL sterile saline) were injected in the mouse brain at 2.5 mm depth through a transcranial burr hole created at coordinates 2 mm lateral and 1.5 mm caudal relative to bregma using an established procedure (78). Standard postsurgery care was given following the IACUC-approved protocol.…”

Section: Methodsmentioning

confidence: 99%

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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104

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Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTICtargeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.siRNA | lipopolymeric nanoparticle | glioblastoma transcription factor | brain tumor-initiating cells | convection-enhanced delivery G lioblastoma (GBM) is one of the most challenging tumors to treat (1, 2). Despite decades of research and maximal clinical combination therapy encompassing surgical resection, chemotherapy, and radiation, the median life expectancy of patients has not been extended beyond 2 y after diagnosis (2). Increasing evidence suggests that the genetic, epigenetic, and signaling heterogeneity of GBM underlies the ineffectiveness of currently available therapeutics (1, 2). Additionally, therapeutic schemes devised to challenge brain tumor cells are frequently thwarted by insufficient delivery caused by pharmacokinetics, the blood-brain barrier (BBB), and an altered tumor microenvironment in which tumor-derived signaling recruits immunomodulatory cells and induces extracellular matrix remodeling to build safe harbors of tumorigenic niches (3-5). These obstacles call for tailored therapeutic strategies to counter tumor heterogeneity and overcome roadblocks in delivery. RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Pro...

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Section: Methodsmentioning

confidence: 99%

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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104

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“…The establishment and maintenance via implantation on the flank side of nude mice was previously described. 18 …”

Section: Cell Linesmentioning

confidence: 99%

“…U87MG-Luc (2.5 · 10 5 cells) or GBM43 (1 · 10 5 cells) glioma cells were implanted via cranial guide screws as described previously. 18 The mice were anesthetized with a ketamine-xylazine mixture (115/ 17 mg/kg). A burr hole was made to facilitate stereotactic injection that was performed with a 10-ll Hamilton syringe (Hamilton, Reno, NV) with a 30-gauge needle.…”

Section: Animal Studymentioning

confidence: 99%

A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma

et al. 2015

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The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as ''GliomaFF.'' We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy.

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“…In particular, human fetal stem cells loaded with oncolytic viruses (OVs) have demonstrated improved survival in mouse animal models when compared with controls involving OVs without fetal stem cells [89]. Fetal stem cells loaded with mesoporous silica nanoparticles (MSNs) also remained viable longer than fetal stem cells without MSNs once implanted into the mouse [90].…”

Section: Blood Brain Barrier -Therapeutic Deliverymentioning

confidence: 99%

Stem Cell Therapy for Brain Tumors

Aleynik

Rameshwar

2015

IJTS

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Glioblastoma multiforme (GBM), the most common and lethal brain cancer, prognosis remains bleak with a median survival of about 15 months despite maximal surgical resection, radiotherapy, and temozolomide treatment. The difficulty associated with safely and effectively delivering therapeutics across the blood brain barrier (BBB) is a major challenge towards GBM treatment. Ongoing research and clinical trials, including attempts to deliver therapeutics within stem cells present possible solutions. The relationships between brain cancer pathology, stem cell properties, therapeutic advantages and disadvantages of various stem cell types, drug delivery methods, cancer stem cells, gene therapy, anti-cancer vaccines, chimeric antigen receptor therapies, and combination therapies are discussed.

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A Preclinical Evaluation of Neural Stem Cell–Based Cell Carrier for Targeted Antiglioma Oncolytic Virotherapy

Abstract: HB1.F3.CD NSCs loaded with CRAd-Survivin-pk7 overcome major limitations of OV in vivo and warrant translation in a phase I human clinical trial for patients with GBM.

Cited by 87 publications

References 29 publications

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma

Stem Cell Therapy for Brain Tumors

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