Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma

Abstract

Neural stem cells (NSCs) are inherently tumor-tropic, which allows them to migrate through normal tissue and selectively localize to invasive tumor sites in the brain. We have engineered a clonal, immortalized allogeneic NSC line (HB1.F3.CD21; CD-NSCs) that maintains its stem-like properties, a normal karyotype and is HLA Class II negative. It is genetically and functionally stable over time and multiple passages, and has demonstrated safety in phase I glioma trials. These properties enable the production of an “off-the-shelf” therapy that can be readily available for patient treatment. There are multiple factors contributing to stem cell tumor-tropism, and much remains to be elucidated. The route of NSC delivery and the distribution of NSCs at tumor sites are key factors in the development of effective cell-based therapies. Stem cells can be engineered to deliver and/or produce many different therapeutic agents, including prodrug activating enzymes (which locally convert systemically administered prodrugs to active chemotherapeutic agents); oncolytic viruses; tumor-targeted antibodies; therapeutic nanoparticles; and extracellular vesicles that contain therapeutic oligonucleotides. By targeting these therapeutics selectively to tumor foci, we aim to minimize toxicity to normal tissues and maximize therapeutic benefits. In this manuscript, we demonstrate that NSCs administered via intracerebral/ventricular (IVEN) routes can migrate efficiently toward single or multiple tumor foci. IVEN delivery will enable repeat administrations for patients through an Ommaya reservoir, potentially resulting in improved therapeutic outcomes. In our preclinical studies using various glioma lines, we have quantified NSC migration and distribution in mouse brains and have found robust migration of our clinically relevant HB1.F3.CD21 NSC line toward invasive tumor foci, irrespective of their origin. These results establish proof-of-concept and demonstrate the potential of developing a multitude of therapeutic options using modified NSCs.

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials

“…Stem cells have been proposed in recent years for glioma therapy [168,169,170,171]. These cells have a tropism for brain tumoral tissue, a minimum tropism for normal neural cells, and the capability to cross the BBB [172,173,174,175,176].…”

Stem cells for the treatment of glioblastoma: a 20-year perspective

“…Intraventricular administration has also been proven to result in good intratumoral distribution of stem cells [ 58 ]. Quantitative analysis and 3D reconstructions of the distribution of NSCs following intraventricular administration in mice demonstrated that these cells migrated efficiently toward tumors, even in the case of multifocal tumors located in different hemispheres [ 83 ]. NSCs tended to locate around the tumor margin but were also found within the tumor core.…”

Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors

“…There are other case reports that have combined trastuzumab with other cytotoxic agents like methotrexate and/or cytarabine, resulting in prolongation of disease control in HER2+ brain tumor patients [ 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. In the preclinical setting, prophylactic IT administration of adeno-associated virus serotype 9 (AAV9) gene therapy vectors and tumor tropic neural stem cells (NSCs) loaded with chemotherapeutic agents shows that IT administration has the potential for efficient drug delivery of large molecules and biological vectors to the subarachnoid space [ 48 , 67 , 68 , 69 ].…”