Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma
Background Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB fail...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/5/e006436.full |
| _version_ | 1827944019611615232 |
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| author | Christian Klein Daria Briukhovetska Michael von Bergwelt-Baildon Sebastian Kobold Mitchell P Levesque Bruno L Cadilha Stefan Endres Mohamed-Reda Benmebarek Hannah Obeck Sophia Stock Florian Märkl Julius Keyl Martina Geiger Clara Karches Melanie Schwerdtfeger Stefanos Michaelides Jakob Jobst Philipp Jie Müller Lina Majed Matthias Seifert Anna-Kristina Klüver Theo Lorenzini Ruth Grünmeier Moritz Thomas Adrian Gottschlich Richard Klaus Carsten Marr Simon Rothenfusser Markus Vincent Heppt |
| author_facet | Christian Klein Daria Briukhovetska Michael von Bergwelt-Baildon Sebastian Kobold Mitchell P Levesque Bruno L Cadilha Stefan Endres Mohamed-Reda Benmebarek Hannah Obeck Sophia Stock Florian Märkl Julius Keyl Martina Geiger Clara Karches Melanie Schwerdtfeger Stefanos Michaelides Jakob Jobst Philipp Jie Müller Lina Majed Matthias Seifert Anna-Kristina Klüver Theo Lorenzini Ruth Grünmeier Moritz Thomas Adrian Gottschlich Richard Klaus Carsten Marr Simon Rothenfusser Markus Vincent Heppt |
| author_sort | Christian Klein |
| collection | DOAJ |
| description | Background Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens.Methods Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo.Results MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model.Conclusion The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients. |
| first_indexed | 2024-03-13T10:24:04Z |
| format | Article |
| id | doaj.art-b199e93aa3494d549053b8485d6551d1 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-13T10:24:04Z |
| publishDate | 2023-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-b199e93aa3494d549053b8485d6551d12023-05-19T22:00:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-05-0111510.1136/jitc-2022-006436Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanomaChristian Klein0Daria Briukhovetska1Michael von Bergwelt-Baildon2Sebastian Kobold3Mitchell P Levesque4Bruno L Cadilha5Stefan Endres6Mohamed-Reda Benmebarek7Hannah Obeck8Sophia Stock9Florian Märkl10Julius Keyl11Martina Geiger12Clara Karches13Melanie Schwerdtfeger14Stefanos Michaelides15Jakob Jobst16Philipp Jie Müller17Lina Majed18Matthias Seifert19Anna-Kristina Klüver20Theo Lorenzini21Ruth Grünmeier22Moritz Thomas23Adrian Gottschlich24Richard Klaus25Carsten Marr26Simon Rothenfusser27Markus Vincent Heppt28Roche Pharma Research and Early Development, Discovery Oncology, Roche Innovation Center Zurich, Schlieren, SwitzerlandCenter of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Klinikum der Ludwig-Maximilians-Universitat Munchen, Munich, GermanyDepartment of Internal Medicine III, University Hospital, Ludwig Maximilians University Munich, München, GermanyEinheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, GermanyDepartment of Dermatology, University Hospital Zurich, Zurich, SwitzerlandCenter of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Munich, GermanyEinheit für Klinische Pharmakologie (EKLiP), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, GermanyDepartment of Medicine IV, Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, GermanyDepartment of Medicine IV, Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, GermanyGerman Cancer Consortium (DKTK), Partner Site Munich, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyRoche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, SwitzerlandDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyInstitute of AI for Health, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDivision of Pediatric Nephrology, Department of Pediatrics, Dr. v. Haunersches Kinderspital, Klinikum der Universität München, Munich, GermanyInstitute of AI for Health, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, GermanyDepartment of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universität München, Munich, GermanyDepartment of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, GermanyBackground Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens.Methods Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo.Results MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model.Conclusion The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.https://jitc.bmj.com/content/11/5/e006436.full |
| spellingShingle | Christian Klein Daria Briukhovetska Michael von Bergwelt-Baildon Sebastian Kobold Mitchell P Levesque Bruno L Cadilha Stefan Endres Mohamed-Reda Benmebarek Hannah Obeck Sophia Stock Florian Märkl Julius Keyl Martina Geiger Clara Karches Melanie Schwerdtfeger Stefanos Michaelides Jakob Jobst Philipp Jie Müller Lina Majed Matthias Seifert Anna-Kristina Klüver Theo Lorenzini Ruth Grünmeier Moritz Thomas Adrian Gottschlich Richard Klaus Carsten Marr Simon Rothenfusser Markus Vincent Heppt Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma Journal for ImmunoTherapy of Cancer |
| title | Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma |
| title_full | Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma |
| title_fullStr | Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma |
| title_full_unstemmed | Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma |
| title_short | Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma |
| title_sort | bispecific antibodies redirect synthetic agonistic receptor modified t cells against melanoma |
| url | https://jitc.bmj.com/content/11/5/e006436.full |
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