Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors
The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combin...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2014-09, Vol.74 (18), p.5195-5205 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | Nishio, Nobuhiro Diaconu, Iulia Liu, Hao Cerullo, Vincenzo Caruana, Ignazio Hoyos, Valentina Bouchier-Hayes, Lisa Savoldo, Barbara Dotti, Gianpietro |
| description | The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors. Cancer Res; 74(18); 5195-205. ©2014 AACR. |
| doi_str_mv | 10.1158/0008-5472.CAN-14-0697 |
| format | Article |
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Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors. 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Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors. Cancer Res; 74(18); 5195-205. ©2014 AACR.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Cytokines - immunology</subject><subject>Disease Models, Animal</subject><subject>Immunotherapy - methods</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Microscopy, Confocal</subject><subject>Neuroblastoma - immunology</subject><subject>Neuroblastoma - therapy</subject><subject>Neuroblastoma - virology</subject><subject>Oncolytic Virotherapy - methods</subject><subject>Oncolytic Viruses - immunology</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>T-Lymphocytes - immunology</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9P3DAQxa0KBFvgI7TykUuoJ8k49qXSakX_SKhc4Gx5HYd1FduLnSDtt68j6IqeepoZ-b0nP_0I-QTsBgDFF8aYqLDt6pvN-lcFbcW47D6QFWAjqq5t8YSsjppz8jHn3-VEYHhGzmtkvOxyRfw6edvTGEwcD5Mz9MWlOVMbdjoYm6nzfg6WDnMwk4sh0zhQs3PepqLVYXJPNtBkjd1PMVU-9m5wJe-BGjuOxR5ojqPr6TT7mPIlOR30mO3V27wgj99uHzY_qrv77z8367vKtJJPFfadFFYC1gyQg5CGgdA9k3LgyKXhotP9FtmwBdk2oDteCyZxwKZn5a6bC_L1NXc_b0s9Y8OU9Kj2yXmdDipqp_59CW6nnuKLaoF3iLwEXL8FpPg82zwp7_JSSQcb56xAMMFrEFz8X4q85hxkg0WKr1KTYs7JDscfAVMLVbUQUwsxVagqaNVCtfg-v69zdP3F2PwBKEmeyA</recordid><startdate>20140915</startdate><enddate>20140915</enddate><creator>Nishio, Nobuhiro</creator><creator>Diaconu, Iulia</creator><creator>Liu, Hao</creator><creator>Cerullo, Vincenzo</creator><creator>Caruana, Ignazio</creator><creator>Hoyos, Valentina</creator><creator>Bouchier-Hayes, Lisa</creator><creator>Savoldo, Barbara</creator><creator>Dotti, Gianpietro</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>7U9</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20140915</creationdate><title>Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors</title><author>Nishio, Nobuhiro ; 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Cell Line, Tumor Cytokines - immunology Disease Models, Animal Immunotherapy - methods Mice Mice, Inbred NOD Microscopy, Confocal Neuroblastoma - immunology Neuroblastoma - therapy Neuroblastoma - virology Oncolytic Virotherapy - methods Oncolytic Viruses - immunology Receptors, Antigen, T-Cell - immunology T-Lymphocytes - immunology Xenograft Model Antitumor Assays |
| title | Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors |
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