Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice
Chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of multiple types of hematological malignancies, but have shown limited efficacy in patients with glioblastoma (GBM) or other solid tumors. This may be largely due to the immunosuppressive tumor microenvironment (TME) that com...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/3/e005583.full |
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| author | Dai Fukumura Rakesh K Jain Jun Ren Xinyue Dong Zohreh Amoozgar Somin Lee Meenal Datta Sylvie Roberge Mark Duquette |
| author_facet | Dai Fukumura Rakesh K Jain Jun Ren Xinyue Dong Zohreh Amoozgar Somin Lee Meenal Datta Sylvie Roberge Mark Duquette |
| author_sort | Dai Fukumura |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of multiple types of hematological malignancies, but have shown limited efficacy in patients with glioblastoma (GBM) or other solid tumors. This may be largely due to the immunosuppressive tumor microenvironment (TME) that compromises CAR-T cells’ delivery and antitumor activity. We previously showed that blocking vascular endothelial growth factor (VEGF) signaling can normalize tumor vessels in murine and human tumors, including GBM, breast, liver, and rectal carcinomas. Moreover, we demonstrated that vascular normalization can improve the delivery of CD8+ T cells and the efficacy of immunotherapy in breast cancer models in mice. In fact, the US FDA (Food and drug administration) has approved seven different combinations of anti-VEGF drugs and immune checkpoint blockers for liver, kidney, lung and endometrial cancers in the past 3 years. Here, we tested the hypothesis that anti-VEGF therapy can improve the delivery and efficacy of CAR-T cells in immunocompetent mice bearing orthotopic GBM tumors. We engineered two syngeneic mouse GBM cell lines (CT2A and GSC005) to express EGFRvIII—one of the most common neoantigens in human GBM—and CAR T cells to recognize EGFRvIII. We found that treatment with the anti-mouse VEGF antibody (B20) improved CAR-T cell infiltration and distribution throughout the GBM TME, delayed tumor growth, and prolonged survival of GBM-bearing mice compared with EGFRvIII-CAR-T cell therapy alone. Our findings provide compelling data and a rationale for clinical evaluation of anti-VEGF agents with CAR T cells for GBM patients. |
| format | Article |
| id | doaj-art-596a942a981e432ca363975cf37ae1e0 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-596a942a981e432ca363975cf37ae1e02025-02-09T14:30:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-03-0111310.1136/jitc-2022-005583Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in miceDai Fukumura0Rakesh K Jain1Jun Ren2Xinyue Dong3Zohreh Amoozgar4Somin Lee5Meenal Datta6Sylvie Roberge7Mark Duquette8Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA1Massachusetts General Hospital and Harvard Medical School, Boston, MA, USADepartment of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA1Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA1Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA1Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA1Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA1Massachusetts General Hospital and Harvard Medical School, Boston, MA, USAChimeric antigen receptor (CAR)-T cells have revolutionized the treatment of multiple types of hematological malignancies, but have shown limited efficacy in patients with glioblastoma (GBM) or other solid tumors. This may be largely due to the immunosuppressive tumor microenvironment (TME) that compromises CAR-T cells’ delivery and antitumor activity. We previously showed that blocking vascular endothelial growth factor (VEGF) signaling can normalize tumor vessels in murine and human tumors, including GBM, breast, liver, and rectal carcinomas. Moreover, we demonstrated that vascular normalization can improve the delivery of CD8+ T cells and the efficacy of immunotherapy in breast cancer models in mice. In fact, the US FDA (Food and drug administration) has approved seven different combinations of anti-VEGF drugs and immune checkpoint blockers for liver, kidney, lung and endometrial cancers in the past 3 years. Here, we tested the hypothesis that anti-VEGF therapy can improve the delivery and efficacy of CAR-T cells in immunocompetent mice bearing orthotopic GBM tumors. We engineered two syngeneic mouse GBM cell lines (CT2A and GSC005) to express EGFRvIII—one of the most common neoantigens in human GBM—and CAR T cells to recognize EGFRvIII. We found that treatment with the anti-mouse VEGF antibody (B20) improved CAR-T cell infiltration and distribution throughout the GBM TME, delayed tumor growth, and prolonged survival of GBM-bearing mice compared with EGFRvIII-CAR-T cell therapy alone. Our findings provide compelling data and a rationale for clinical evaluation of anti-VEGF agents with CAR T cells for GBM patients.https://jitc.bmj.com/content/11/3/e005583.full |
| spellingShingle | Dai Fukumura Rakesh K Jain Jun Ren Xinyue Dong Zohreh Amoozgar Somin Lee Meenal Datta Sylvie Roberge Mark Duquette Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice Journal for ImmunoTherapy of Cancer |
| title | Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice |
| title_full | Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice |
| title_fullStr | Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice |
| title_full_unstemmed | Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice |
| title_short | Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice |
| title_sort | anti vegf therapy improves egfr viii car t cell delivery and efficacy in syngeneic glioblastoma models in mice |
| url | https://jitc.bmj.com/content/11/3/e005583.full |
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