Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas

Abstract

Therapeutically engineered stem cells have shown promise for glioblastoma multiforme (GBM) therapy; however, key preclinical studies are urgently needed for their clinical translation. In this study, we investigated a new approach to GBM treatment using therapeutic stem cells encapsulated in biodegradable, synthetic extracellular matrix (sECM) in mouse models of human GBM resection. Using multimodal imaging, we first showed quantitative surgical debulking of human GBM tumors in mice, which resulted in increased survival. Next, sECM encapsulation of engineered stem cells increased their retention in the tumor resection cavity, permitted tumor-selective migration and release of diagnostic and therapeutic proteins in vivo. Simulating the clinical scenario of GBM treatment, the release of tumor-selective S-TRAIL (secretable tumor necrosis factor apoptosis inducing ligand) from sECM-encapsulated stem cells in the resection cavity eradicated residual tumor cells by inducing caspase-mediated apoptosis, delayed tumor regrowth and significantly increased survival of mice. This study demonstrates the efficacy of encapsulated therapeutic stem cells in mouse models of GBM resection and may have implications for developing effective therapies for GBM.

Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery

“…Such a lack of tumor tropism with the use of systemic delivery is likely a result of the blood-brain barrier. Consistent with our finding, previous studies using NSCs for targeting brain tumors have also chosen a local delivery route inside the brain to achieve targeting efficacy (1)(2)(3)(4)(5). Although the method reported here is efficient only through intracranial delivery, but not systemic delivery, it is very compatible with the current modalities of cancer therapies and can be combined with current clinical treatment plan without additional surgery.…”

“…Nonviral engineered hADSCs can be injected during the same surgery of bulk tumor removal to target and eradicate the infiltrating tumor microsatellites that cannot be surgically removed. The promise of such an approach has been demonstrated recently by injecting viral engineered NSCs and bone marrow-derived MSCs into brain cavity after bulk tumor resection (1,2). Together, our results suggest that local intracranial delivery of nonviral modified hADSCs is more effective than systemic delivery for targeting infiltrating microsatellite cells to prevent brain tumor recurrence.…”

“…Recent research shows that transplanted human neural stem cells (NSCs; hNSCs) possess remarkable tumortropic migratory capacity in vitro and in vivo; hNSCs have been used for the delivery of cytotoxic and immunomodulatory therapies (1)(2)(3)(4)(5) and were recently approved for clinical trials. However, the clinical translational potential of hNSCs may be hindered by ethical concerns associated with their isolation, expansion, and associated immune response (6,7).…”

Validation of an imageable surgical resection animal model of Glioblastoma (GBM)

“…The first investigated encapsulated stem cell migration in combination with intravital microscopy 8 . In this paper the authors successfully used a "cranial window" to perform surgical resection and deliver encapsulated stem cells.…”

Molecular imaging in the development of a novel treatment paradigm for glioblastoma (GBM): an integrated multidisciplinary commentary

“…SPIO nanoparticles used with clinical 1.5-T MRI system revealed that mesenchymal stem cells used as delivery vehicles for therapeutic agents are able to migrate toward GBM in vivo being a promising strategy in anti-GBM treatment [90]. In order to visualise stem cell-based therapeutic interventions in a mouse model of GBM, optical imaging has also been used [91,92]. …”