Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies
Abstract Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrop...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38723-y |
| _version_ | 1827928590492106752 |
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| author | Simona Manni Francesca Del Bufalo Pietro Merli Domenico Alessandro Silvestris Marika Guercio Simona Caruso Sofia Reddel Laura Iaffaldano Michele Pezzella Stefano Di Cecca Matilde Sinibaldi Alessio Ottaviani Maria Cecilia Quadraccia Mariasole Aurigemma Andrea Sarcinelli Roselia Ciccone Zeinab Abbaszadeh Manuela Ceccarelli Rita De Vito Maria Chiara Lodi Maria Giuseppina Cefalo Angela Mastronuzzi Biagio De Angelis Franco Locatelli Concetta Quintarelli |
| author_facet | Simona Manni Francesca Del Bufalo Pietro Merli Domenico Alessandro Silvestris Marika Guercio Simona Caruso Sofia Reddel Laura Iaffaldano Michele Pezzella Stefano Di Cecca Matilde Sinibaldi Alessio Ottaviani Maria Cecilia Quadraccia Mariasole Aurigemma Andrea Sarcinelli Roselia Ciccone Zeinab Abbaszadeh Manuela Ceccarelli Rita De Vito Maria Chiara Lodi Maria Giuseppina Cefalo Angela Mastronuzzi Biagio De Angelis Franco Locatelli Concetta Quintarelli |
| author_sort | Simona Manni |
| collection | DOAJ |
| description | Abstract Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, and the lack of pathophysiological experimental models limit the applicability and development of this form of therapy. Here we present a comprehensive humanized mouse model, by which we show that IFNγ neutralization by the clinically approved monoclonal antibody, emapalumab, mitigates severe toxicity related to CAR-T cell therapy. We demonstrate that emapalumab reduces the pro-inflammatory environment in the model, thus allowing control of severe CRS and preventing brain damage, characterized by multifocal hemorrhages. Importantly, our in vitro and in vivo experiments show that IFNγ inhibition does not affect the ability of CD19-targeting CAR-T (CAR.CD19-T) cells to eradicate CD19+ lymphoma cells. Thus, our study provides evidence that anti-IFNγ treatment might reduce immune related adverse effect without compromising therapeutic success and provides rationale for an emapalumab-CAR.CD19-T cell combination therapy in humans. |
| first_indexed | 2024-03-13T06:10:54Z |
| format | Article |
| id | doaj.art-e13fedf5b3e94ec1a443079d5e0501e7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T06:10:54Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e13fedf5b3e94ec1a443079d5e0501e72023-06-11T11:18:36ZengNature PortfolioNature Communications2041-17232023-06-0114111310.1038/s41467-023-38723-yNeutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignanciesSimona Manni0Francesca Del Bufalo1Pietro Merli2Domenico Alessandro Silvestris3Marika Guercio4Simona Caruso5Sofia Reddel6Laura Iaffaldano7Michele Pezzella8Stefano Di Cecca9Matilde Sinibaldi10Alessio Ottaviani11Maria Cecilia Quadraccia12Mariasole Aurigemma13Andrea Sarcinelli14Roselia Ciccone15Zeinab Abbaszadeh16Manuela Ceccarelli17Rita De Vito18Maria Chiara Lodi19Maria Giuseppina Cefalo20Angela Mastronuzzi21Biagio De Angelis22Franco Locatelli23Concetta Quintarelli24Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Pathological Anatomy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSDepartment of Haematology-Oncology and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCSAbstract Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, and the lack of pathophysiological experimental models limit the applicability and development of this form of therapy. Here we present a comprehensive humanized mouse model, by which we show that IFNγ neutralization by the clinically approved monoclonal antibody, emapalumab, mitigates severe toxicity related to CAR-T cell therapy. We demonstrate that emapalumab reduces the pro-inflammatory environment in the model, thus allowing control of severe CRS and preventing brain damage, characterized by multifocal hemorrhages. Importantly, our in vitro and in vivo experiments show that IFNγ inhibition does not affect the ability of CD19-targeting CAR-T (CAR.CD19-T) cells to eradicate CD19+ lymphoma cells. Thus, our study provides evidence that anti-IFNγ treatment might reduce immune related adverse effect without compromising therapeutic success and provides rationale for an emapalumab-CAR.CD19-T cell combination therapy in humans.https://doi.org/10.1038/s41467-023-38723-y |
| spellingShingle | Simona Manni Francesca Del Bufalo Pietro Merli Domenico Alessandro Silvestris Marika Guercio Simona Caruso Sofia Reddel Laura Iaffaldano Michele Pezzella Stefano Di Cecca Matilde Sinibaldi Alessio Ottaviani Maria Cecilia Quadraccia Mariasole Aurigemma Andrea Sarcinelli Roselia Ciccone Zeinab Abbaszadeh Manuela Ceccarelli Rita De Vito Maria Chiara Lodi Maria Giuseppina Cefalo Angela Mastronuzzi Biagio De Angelis Franco Locatelli Concetta Quintarelli Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies Nature Communications |
| title | Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies |
| title_full | Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies |
| title_fullStr | Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies |
| title_full_unstemmed | Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies |
| title_short | Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies |
| title_sort | neutralizing ifnγ improves safety without compromising efficacy of car t cell therapy in b cell malignancies |
| url | https://doi.org/10.1038/s41467-023-38723-y |
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