Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model
Recent advances in novel immune strategies, particularly chimeric antigen receptor (CAR)-bearing T-cells, have shown limited efficacy against glioblastoma (GBM) in clinical trials. We currently have an incomplete understanding of how these emerging therapies integrate with the current standard of ca...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2020.1757360 |
| _version_ | 1819133895368507392 |
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| author | Surya Murty Samuel T. Haile Corinne Beinat Amin Aalipour Israt S. Alam Tara Murty Travis M. Shaffer Chirag B. Patel Edward E. Graves Crystal L. Mackall Sanjiv S. Gambhir |
| author_facet | Surya Murty Samuel T. Haile Corinne Beinat Amin Aalipour Israt S. Alam Tara Murty Travis M. Shaffer Chirag B. Patel Edward E. Graves Crystal L. Mackall Sanjiv S. Gambhir |
| author_sort | Surya Murty |
| collection | DOAJ |
| description | Recent advances in novel immune strategies, particularly chimeric antigen receptor (CAR)-bearing T-cells, have shown limited efficacy against glioblastoma (GBM) in clinical trials. We currently have an incomplete understanding of how these emerging therapies integrate with the current standard of care, specifically radiation therapy (RT). Additionally, there is an insufficient number of preclinical studies monitoring these therapies with high spatiotemporal resolution. To address these limitations, we report the first longitudinal fluorescence-based intravital microscopy imaging of CAR T-cells within an orthotopic GBM preclinical model to illustrate the necessity of RT for complete therapeutic response. Additionally, we detail the first usage of murine-derived CAR T-cells targeting the disialoganglioside GD2 in an immunocompetent tumor model. Cell culture assays demonstrated substantial GD2 CAR T-cell-mediated killing of murine GBM cell lines SB28 and GL26 induced to overexpress GD2. Complete antitumor response in advanced syngeneic orthotopic models of GBM was achieved only when a single intravenous dose of GD2 CAR T-cells was following either sub-lethal whole-body irradiation or focal RT. Intravital microscopy imaging successfully visualized CAR T-cell homing and T-cell mediated apoptosis of tumor cells in real-time within the tumor stroma. Findings indicate that RT allows for rapid CAR T-cell extravasation from the vasculature and expansion within the tumor microenvironment, leading to a more robust and lasting immunologic response. These exciting results highlight potential opportunities to improve intravenous adoptive T-cell administration in the treatment of GBM through concurrent RT. Additionally, they emphasize the need for advancements in immunotherapeutic homing to and extravasation through the tumor microenvironment. |
| first_indexed | 2024-12-22T09:54:34Z |
| format | Article |
| id | doaj.art-a7e4daafe1b94a41b5da9f3711edf6f3 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-22T09:54:34Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-a7e4daafe1b94a41b5da9f3711edf6f32022-12-21T18:30:18ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2020.17573601757360Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma modelSurya Murty0Samuel T. Haile1Corinne Beinat2Amin Aalipour3Israt S. Alam4Tara Murty5Travis M. Shaffer6Chirag B. Patel7Edward E. Graves8Crystal L. Mackall9Sanjiv S. Gambhir10Stanford University School of MedicineStanford University School of MedicineStanford University School of MedicineStanford University School of MedicineStanford University School of MedicineStanford University School of MedicineStanford University School of MedicineStanford University School of MedicineStanford University School of MedicineStanford University School of MedicineStanford University School of MedicineRecent advances in novel immune strategies, particularly chimeric antigen receptor (CAR)-bearing T-cells, have shown limited efficacy against glioblastoma (GBM) in clinical trials. We currently have an incomplete understanding of how these emerging therapies integrate with the current standard of care, specifically radiation therapy (RT). Additionally, there is an insufficient number of preclinical studies monitoring these therapies with high spatiotemporal resolution. To address these limitations, we report the first longitudinal fluorescence-based intravital microscopy imaging of CAR T-cells within an orthotopic GBM preclinical model to illustrate the necessity of RT for complete therapeutic response. Additionally, we detail the first usage of murine-derived CAR T-cells targeting the disialoganglioside GD2 in an immunocompetent tumor model. Cell culture assays demonstrated substantial GD2 CAR T-cell-mediated killing of murine GBM cell lines SB28 and GL26 induced to overexpress GD2. Complete antitumor response in advanced syngeneic orthotopic models of GBM was achieved only when a single intravenous dose of GD2 CAR T-cells was following either sub-lethal whole-body irradiation or focal RT. Intravital microscopy imaging successfully visualized CAR T-cell homing and T-cell mediated apoptosis of tumor cells in real-time within the tumor stroma. Findings indicate that RT allows for rapid CAR T-cell extravasation from the vasculature and expansion within the tumor microenvironment, leading to a more robust and lasting immunologic response. These exciting results highlight potential opportunities to improve intravenous adoptive T-cell administration in the treatment of GBM through concurrent RT. Additionally, they emphasize the need for advancements in immunotherapeutic homing to and extravasation through the tumor microenvironment.http://dx.doi.org/10.1080/2162402X.2020.1757360chimeric antigen receptor (car)glioblastomaintravital microscopyimagingimmunotherapy |
| spellingShingle | Surya Murty Samuel T. Haile Corinne Beinat Amin Aalipour Israt S. Alam Tara Murty Travis M. Shaffer Chirag B. Patel Edward E. Graves Crystal L. Mackall Sanjiv S. Gambhir Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model OncoImmunology chimeric antigen receptor (car) glioblastoma intravital microscopy imaging immunotherapy |
| title | Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model |
| title_full | Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model |
| title_fullStr | Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model |
| title_full_unstemmed | Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model |
| title_short | Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model |
| title_sort | intravital imaging reveals synergistic effect of car t cells and radiation therapy in a preclinical immunocompetent glioblastoma model |
| topic | chimeric antigen receptor (car) glioblastoma intravital microscopy imaging immunotherapy |
| url | http://dx.doi.org/10.1080/2162402X.2020.1757360 |
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