A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer
Abstract Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU)...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2019-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-018-0464-1 |
| _version_ | 1830298251705712640 |
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| author | Lucia D’Amico Ulrike Menzel Michael Prummer Philipp Müller Mélanie Buchi Abhishek Kashyap Ulrike Haessler Alexander Yermanos Rémy Gébleux Manfred Briendl Tamara Hell Fabian I. Wolter Roger R. Beerli Iva Truxova Špíšek Radek Tatjana Vlajnic Ulf Grawunder Sai Reddy Alfred Zippelius |
| author_facet | Lucia D’Amico Ulrike Menzel Michael Prummer Philipp Müller Mélanie Buchi Abhishek Kashyap Ulrike Haessler Alexander Yermanos Rémy Gébleux Manfred Briendl Tamara Hell Fabian I. Wolter Roger R. Beerli Iva Truxova Špíšek Radek Tatjana Vlajnic Ulf Grawunder Sai Reddy Alfred Zippelius |
| author_sort | Lucia D’Amico |
| collection | DOAJ |
| description | Abstract Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU) in a human HER2-expressing syngeneic breast cancer model resistant to trastuzumab and ado-trastuzumab emtansine. Mechanistically, the anthracycline component of the novel ADC induced immunogenic cell death leading to exposure and secretion of danger-associated molecular signals. RNA sequencing derived immunogenomic signatures and TCRβ clonotype analysis of tumor-infiltrating lymphocytes revealed a prominent role of the adaptive immune system in the regulation of T-PNU mediated anti-cancer activity. Depletion of CD8 T cells severely reduced T-PNU efficacy, thus confirming the role of cytotoxic T cells as drivers of the T-PNU mediated anti-tumor immune response. Furthermore, T-PNU therapy promoted immunological memory formation in tumor-bearing animals protecting those from tumor rechallenge. Finally, the combination of T-PNU and checkpoint inhibition, such as α-PD1, significantly enhanced tumor eradication following the treatment. In summary, a novel PNU-armed, HER2-targeting ADC elicited long-lasting immune protection in a murine orthotopic breast cancer model resistant to other HER2-directed therapies. Our findings delineate the therapeutic potential of this novel ADC payload and support its clinical development for breast cancer patients and potentially other HER2 expressing malignancies. |
| first_indexed | 2024-12-19T07:48:13Z |
| format | Article |
| id | doaj.art-fc1ae255093f4779af3f20d721a4f07a |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-19T07:48:13Z |
| publishDate | 2019-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-fc1ae255093f4779af3f20d721a4f07a2022-12-21T20:30:16ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-01-017111510.1186/s40425-018-0464-1A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancerLucia D’Amico0Ulrike Menzel1Michael Prummer2Philipp Müller3Mélanie Buchi4Abhishek Kashyap5Ulrike Haessler6Alexander Yermanos7Rémy Gébleux8Manfred Briendl9Tamara Hell10Fabian I. Wolter11Roger R. Beerli12Iva Truxova13Špíšek Radek14Tatjana Vlajnic15Ulf Grawunder16Sai Reddy17Alfred Zippelius18Cancer Immunology, Department of Biomedicine, University of BaselDepartment of Biosystems Science and Engineering, ETH ZürichNEXUS Personalized Health Technologies, ETH Zürich, Switzerland and Swiss Institute of BioinformaticsCancer Immunology, Department of Biomedicine, University of BaselCancer Immunology, Department of Biomedicine, University of BaselCancer Immunology, Department of Biomedicine, University of BaselDepartment of Biosystems Science and Engineering, ETH ZürichDepartment of Biosystems Science and Engineering, ETH ZürichNBE-Therapeutics LtdNBE-Therapeutics LtdNBE-Therapeutics LtdNBE-Therapeutics LtdNBE-Therapeutics LtdSotio s.aSotio s.aInstitute of Pathology, University Hospital BaselNBE-Therapeutics LtdDepartment of Biosystems Science and Engineering, ETH ZürichCancer Immunology, Department of Biomedicine, University of BaselAbstract Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU) in a human HER2-expressing syngeneic breast cancer model resistant to trastuzumab and ado-trastuzumab emtansine. Mechanistically, the anthracycline component of the novel ADC induced immunogenic cell death leading to exposure and secretion of danger-associated molecular signals. RNA sequencing derived immunogenomic signatures and TCRβ clonotype analysis of tumor-infiltrating lymphocytes revealed a prominent role of the adaptive immune system in the regulation of T-PNU mediated anti-cancer activity. Depletion of CD8 T cells severely reduced T-PNU efficacy, thus confirming the role of cytotoxic T cells as drivers of the T-PNU mediated anti-tumor immune response. Furthermore, T-PNU therapy promoted immunological memory formation in tumor-bearing animals protecting those from tumor rechallenge. Finally, the combination of T-PNU and checkpoint inhibition, such as α-PD1, significantly enhanced tumor eradication following the treatment. In summary, a novel PNU-armed, HER2-targeting ADC elicited long-lasting immune protection in a murine orthotopic breast cancer model resistant to other HER2-directed therapies. Our findings delineate the therapeutic potential of this novel ADC payload and support its clinical development for breast cancer patients and potentially other HER2 expressing malignancies.http://link.springer.com/article/10.1186/s40425-018-0464-1Antibody-drug conjugatesHER2-positive breast cancerAnthracyclineCheckpoint inhibitor combination therapy |
| spellingShingle | Lucia D’Amico Ulrike Menzel Michael Prummer Philipp Müller Mélanie Buchi Abhishek Kashyap Ulrike Haessler Alexander Yermanos Rémy Gébleux Manfred Briendl Tamara Hell Fabian I. Wolter Roger R. Beerli Iva Truxova Špíšek Radek Tatjana Vlajnic Ulf Grawunder Sai Reddy Alfred Zippelius A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer Journal for ImmunoTherapy of Cancer Antibody-drug conjugates HER2-positive breast cancer Anthracycline Checkpoint inhibitor combination therapy |
| title | A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer |
| title_full | A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer |
| title_fullStr | A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer |
| title_full_unstemmed | A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer |
| title_short | A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer |
| title_sort | novel anti her2 anthracycline based antibody drug conjugate induces adaptive anti tumor immunity and potentiates pd 1 blockade in breast cancer |
| topic | Antibody-drug conjugates HER2-positive breast cancer Anthracycline Checkpoint inhibitor combination therapy |
| url | http://link.springer.com/article/10.1186/s40425-018-0464-1 |
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