Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers
Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as ne...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-03-01
|
| Series: | Molecular Therapy: Oncolytics |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770518300366 |
| _version_ | 1818452483009150976 |
|---|---|
| author | Michael Karl Melzer Lisa Zeitlinger Sabine Mall Katja Steiger Roland M. Schmid Oliver Ebert Angela Krackhardt Jennifer Altomonte |
| author_facet | Michael Karl Melzer Lisa Zeitlinger Sabine Mall Katja Steiger Roland M. Schmid Oliver Ebert Angela Krackhardt Jennifer Altomonte |
| author_sort | Michael Karl Melzer |
| collection | DOAJ |
| description | Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells. We show that CD8+ T central memory cells (CD8+ T cm) can be efficiently loaded with VSV, they support intracellular virus production, and they can efficiently transfer VSV to tumor cells without compromising their own viability or antitumor reactivity. Loading VSV onto CD8+ T cm not only improves the safety compared with systemic administration of naked virus, but this approach also allows for an effective delivery of virus to its tumor target, resulting in an effective combination therapy in NSG mice bearing subcutaneous human acute myeloid leukemia (AML) tumors. We conclude that the combination of potent tumor debulking provided by the oncolytic VSV with the added effector functions afforded by the cytotoxic immune carrier cells results in a potent and safer immunotherapeutic, which can be further developed for clinical translation. Keywords: adoptive T cell therapy, vesicular stomatitis virus, oncolytic virotherapy, immunotherapy, acute myeloid leukemia |
| first_indexed | 2024-12-14T21:23:48Z |
| format | Article |
| id | doaj.art-583fed58d5614b318c8f82a711d6010d |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-14T21:23:48Z |
| publishDate | 2019-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-583fed58d5614b318c8f82a711d6010d2022-12-21T22:46:51ZengElsevierMolecular Therapy: Oncolytics2372-77052019-03-01122640Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as CarriersMichael Karl Melzer0Lisa Zeitlinger1Sabine Mall2Katja Steiger3Roland M. Schmid4Oliver Ebert5Angela Krackhardt6Jennifer Altomonte7Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, GermanyKlinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, GermanyKlinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany; German Cancer Consortium of Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyInstitut für Pathologie, Klinikum rechts der Isar, Technical University, 81675 Munich, GermanyKlinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, GermanyKlinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, GermanyKlinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany; German Cancer Consortium of Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyKlinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, 81675 Munich, Germany; Corresponding author: Jennifer Altomonte, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University, Ismaningerstrasse 22, 81675 Munich, Germany.Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells. We show that CD8+ T central memory cells (CD8+ T cm) can be efficiently loaded with VSV, they support intracellular virus production, and they can efficiently transfer VSV to tumor cells without compromising their own viability or antitumor reactivity. Loading VSV onto CD8+ T cm not only improves the safety compared with systemic administration of naked virus, but this approach also allows for an effective delivery of virus to its tumor target, resulting in an effective combination therapy in NSG mice bearing subcutaneous human acute myeloid leukemia (AML) tumors. We conclude that the combination of potent tumor debulking provided by the oncolytic VSV with the added effector functions afforded by the cytotoxic immune carrier cells results in a potent and safer immunotherapeutic, which can be further developed for clinical translation. Keywords: adoptive T cell therapy, vesicular stomatitis virus, oncolytic virotherapy, immunotherapy, acute myeloid leukemiahttp://www.sciencedirect.com/science/article/pii/S2372770518300366 |
| spellingShingle | Michael Karl Melzer Lisa Zeitlinger Sabine Mall Katja Steiger Roland M. Schmid Oliver Ebert Angela Krackhardt Jennifer Altomonte Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers Molecular Therapy: Oncolytics |
| title | Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers |
| title_full | Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers |
| title_fullStr | Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers |
| title_full_unstemmed | Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers |
| title_short | Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers |
| title_sort | enhanced safety and efficacy of oncolytic vsv therapy by combination with t cell receptor transgenic t cells as carriers |
| url | http://www.sciencedirect.com/science/article/pii/S2372770518300366 |
| work_keys_str_mv | AT michaelkarlmelzer enhancedsafetyandefficacyofoncolyticvsvtherapybycombinationwithtcellreceptortransgenictcellsascarriers AT lisazeitlinger enhancedsafetyandefficacyofoncolyticvsvtherapybycombinationwithtcellreceptortransgenictcellsascarriers AT sabinemall enhancedsafetyandefficacyofoncolyticvsvtherapybycombinationwithtcellreceptortransgenictcellsascarriers AT katjasteiger enhancedsafetyandefficacyofoncolyticvsvtherapybycombinationwithtcellreceptortransgenictcellsascarriers AT rolandmschmid enhancedsafetyandefficacyofoncolyticvsvtherapybycombinationwithtcellreceptortransgenictcellsascarriers AT oliverebert enhancedsafetyandefficacyofoncolyticvsvtherapybycombinationwithtcellreceptortransgenictcellsascarriers AT angelakrackhardt enhancedsafetyandefficacyofoncolyticvsvtherapybycombinationwithtcellreceptortransgenictcellsascarriers AT jenniferaltomonte enhancedsafetyandefficacyofoncolyticvsvtherapybycombinationwithtcellreceptortransgenictcellsascarriers |