Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants
Background Adoptive T-cell therapy has demonstrated clinical activity in B-cell malignancies, offering hope for its application to a broad spectrum of cancers. However, a significant portion of patients with solid tumors experience primary or secondary resistance to this treatment modality. Target a...
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e009868.full |
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| author | James L Gulley Ling Zhang Christian S Hinrichs John S Davies Andrew Sinkoe Wiem Lassoued Farrah Karimipour Philip Homan Daniel Burnett Scott M Norberg Alex Kuznetsov Margaret Cam Ping Xue |
| author_facet | James L Gulley Ling Zhang Christian S Hinrichs John S Davies Andrew Sinkoe Wiem Lassoued Farrah Karimipour Philip Homan Daniel Burnett Scott M Norberg Alex Kuznetsov Margaret Cam Ping Xue |
| author_sort | James L Gulley |
| collection | DOAJ |
| description | Background Adoptive T-cell therapy has demonstrated clinical activity in B-cell malignancies, offering hope for its application to a broad spectrum of cancers. However, a significant portion of patients with solid tumors experience primary or secondary resistance to this treatment modality. Target antigen loss resulting either from non-uniform antigen expression or defects in antigen processing and presentation machinery is one well-characterized resistance mechanism. Constitutively expressed membrane-anchored interleukin-12 (caIL-12) has demonstrated enhanced antitumor activity and low systemic exposure in multiple preclinical adoptive T-cell treatment models with homogeneous tumor antigen expression. In this study, we assess the therapeutic impact of caIL-12 on target antigen-negative variants in syngeneic mouse models.Methods Target antigen-positive tumors were generated by transducing B16F10 melanoma cells (B16) or Lewis Lung Carcinoma cells (LLC) with a construct expressing the OVA antigen, SIINFEKL, tagged to ubiquitin (B16-U-OVA, LLC-U-OVA), while B16 or LLC tumors served as antigen-negative variants. C57BL/6J mice were subcutaneously injected with heterogeneous tumors composed of 80% B16-U-OVA and 20% B16. Bilateral tumors were established by injecting the left flank with B16-U-OVA or LLC-U-OVA tumors and the right flank injected with B16 or LLC tumors. The tumor-bearing mice then underwent 5.5 Gy total body irradiation, followed by adoptive transfer of OT-I TCR-T cells engineered with or without caIL-12.Results TCR-T cells (OT-I) delivered caIL-12 to the B16-U-OVA tumor sites and induced robust tumor control and survival benefits in mice bearing a heterogeneous tumor with OVA-negative variants. caIL-12 exerted its effect on OVA-negative B16 variants primarily by priming and activating endogenous antitumor CD8 T cells via antigen spreading. In addition, antigen spreading induced by OT-I-caIL-12 resulted in controlling OVA-negative tumors implanted at distant sites. This therapeutic effect required antigen-specific TCR-T cells and caIL-12 to colocalize at the tumor site, along with endogenous CD8 T cells capable of recognizing shared tumor antigens.Conclusion Expression of caIL-12 by tumor-targeting T cells demonstrated therapeutic effect against target-antigen-negative tumor variants, primarily through the induction of antigen spreading. These findings highlight the potential of caIL-12 to address challenges of antigen escape and tumor heterogeneity that may limit the efficacy of T-cell therapy against solid tumors. |
| format | Article |
| id | doaj-art-e3020d262804492f80c241d2d2ce5dc4 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e3020d262804492f80c241d2d2ce5dc42025-08-20T02:32:41ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-009868Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variantsJames L Gulley0Ling Zhang1Christian S Hinrichs2John S Davies3Andrew Sinkoe4Wiem Lassoued5Farrah Karimipour6Philip Homan7Daniel Burnett8Scott M Norberg9Alex Kuznetsov10Margaret Cam11Ping Xue12Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USADuncan and Nancy MacMillan Cancer Immunology and Metabolism Center of Excellence, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USADepartment of Safety Assessment, Genentech Inc, South San Francisco, California, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAAdvanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACCR Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USABackground Adoptive T-cell therapy has demonstrated clinical activity in B-cell malignancies, offering hope for its application to a broad spectrum of cancers. However, a significant portion of patients with solid tumors experience primary or secondary resistance to this treatment modality. Target antigen loss resulting either from non-uniform antigen expression or defects in antigen processing and presentation machinery is one well-characterized resistance mechanism. Constitutively expressed membrane-anchored interleukin-12 (caIL-12) has demonstrated enhanced antitumor activity and low systemic exposure in multiple preclinical adoptive T-cell treatment models with homogeneous tumor antigen expression. In this study, we assess the therapeutic impact of caIL-12 on target antigen-negative variants in syngeneic mouse models.Methods Target antigen-positive tumors were generated by transducing B16F10 melanoma cells (B16) or Lewis Lung Carcinoma cells (LLC) with a construct expressing the OVA antigen, SIINFEKL, tagged to ubiquitin (B16-U-OVA, LLC-U-OVA), while B16 or LLC tumors served as antigen-negative variants. C57BL/6J mice were subcutaneously injected with heterogeneous tumors composed of 80% B16-U-OVA and 20% B16. Bilateral tumors were established by injecting the left flank with B16-U-OVA or LLC-U-OVA tumors and the right flank injected with B16 or LLC tumors. The tumor-bearing mice then underwent 5.5 Gy total body irradiation, followed by adoptive transfer of OT-I TCR-T cells engineered with or without caIL-12.Results TCR-T cells (OT-I) delivered caIL-12 to the B16-U-OVA tumor sites and induced robust tumor control and survival benefits in mice bearing a heterogeneous tumor with OVA-negative variants. caIL-12 exerted its effect on OVA-negative B16 variants primarily by priming and activating endogenous antitumor CD8 T cells via antigen spreading. In addition, antigen spreading induced by OT-I-caIL-12 resulted in controlling OVA-negative tumors implanted at distant sites. This therapeutic effect required antigen-specific TCR-T cells and caIL-12 to colocalize at the tumor site, along with endogenous CD8 T cells capable of recognizing shared tumor antigens.Conclusion Expression of caIL-12 by tumor-targeting T cells demonstrated therapeutic effect against target-antigen-negative tumor variants, primarily through the induction of antigen spreading. These findings highlight the potential of caIL-12 to address challenges of antigen escape and tumor heterogeneity that may limit the efficacy of T-cell therapy against solid tumors.https://jitc.bmj.com/content/12/11/e009868.full |
| spellingShingle | James L Gulley Ling Zhang Christian S Hinrichs John S Davies Andrew Sinkoe Wiem Lassoued Farrah Karimipour Philip Homan Daniel Burnett Scott M Norberg Alex Kuznetsov Margaret Cam Ping Xue Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants Journal for ImmunoTherapy of Cancer |
| title | Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants |
| title_full | Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants |
| title_fullStr | Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants |
| title_full_unstemmed | Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants |
| title_short | Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants |
| title_sort | adoptive transfer of membrane restricted il 12 tcr t cells promotes antigen spreading and elimination of antigen negative tumor variants |
| url | https://jitc.bmj.com/content/12/11/e009868.full |
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