Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma
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 norm...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.00068/full |
| _version_ | 1811275359008587776 |
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| author | Margarita Gutova Linda Flores Vikram Adhikarla Lusine Tsaturyan Revathiswari Tirughana Soraya Aramburo Marianne Metz Joanna Gonzaga Alexander Annala Timothy W. Synold Jana Portnow Russell C. Rockne Karen S. Aboody |
| author_facet | Margarita Gutova Linda Flores Vikram Adhikarla Lusine Tsaturyan Revathiswari Tirughana Soraya Aramburo Marianne Metz Joanna Gonzaga Alexander Annala Timothy W. Synold Jana Portnow Russell C. Rockne Karen S. Aboody |
| author_sort | Margarita Gutova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T23:36:28Z |
| format | Article |
| id | doaj.art-e2940e7905ce47aeacc9f5e793103521 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T23:36:28Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e2940e7905ce47aeacc9f5e7931035212022-12-22T03:12:07ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-02-01910.3389/fonc.2019.00068428582Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic GliomaMargarita Gutova0Linda Flores1Vikram Adhikarla2Lusine Tsaturyan3Revathiswari Tirughana4Soraya Aramburo5Marianne Metz6Joanna Gonzaga7Alexander Annala8Timothy W. Synold9Jana Portnow10Russell C. Rockne11Karen S. Aboody12Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDivision of Mathematical Oncology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Medical Oncology & Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDivision of Mathematical Oncology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesNeural 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.https://www.frontiersin.org/article/10.3389/fonc.2019.00068/fullgliomaneural stem cellsNSCsintraventricular administrationtherapeuticdrug delivery |
| spellingShingle | Margarita Gutova Linda Flores Vikram Adhikarla Lusine Tsaturyan Revathiswari Tirughana Soraya Aramburo Marianne Metz Joanna Gonzaga Alexander Annala Timothy W. Synold Jana Portnow Russell C. Rockne Karen S. Aboody Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma Frontiers in Oncology glioma neural stem cells NSCs intraventricular administration therapeutic drug delivery |
| title | Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma |
| title_full | Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma |
| title_fullStr | Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma |
| title_full_unstemmed | Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma |
| title_short | Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma |
| title_sort | quantitative evaluation of intraventricular delivery of therapeutic neural stem cells to orthotopic glioma |
| topic | glioma neural stem cells NSCs intraventricular administration therapeutic drug delivery |
| url | https://www.frontiersin.org/article/10.3389/fonc.2019.00068/full |
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