Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patients
Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for the treatment of refractory hematopoietic malignancies. Adverse events are common, and neurotoxicity is one of the most important. However, the physiopathology is unknown and neuropathologic information is...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
University of Münster / Open Journals System
2022-01-01
|
| Series: | Free Neuropathology |
| Subjects: | |
| Online Access: | https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/4365 |
| _version_ | 1797952256025296896 |
|---|---|
| author | Núria Vidal Robau Gabriela Caballero Ivan Archilla Andrea Ladino Sara Fernández Valentín Ortiz-Maldonado Montserrat Rovira Marta Gómez-Hernando Julio Delgado María Suárez-Lledó Carlos Fernández de Larrea Olga Balagué Gerard Frigola Abel Muñoz Estrella Ortiz Teresa Ribalta Miguel J. Martinez Maria Angeles-Marcos Marta Español-Rego Azucena González Daniel Benitez-Ribas Eugenia Martinez-Hernandez Pedro Castro Iban Aldecoa |
| author_facet | Núria Vidal Robau Gabriela Caballero Ivan Archilla Andrea Ladino Sara Fernández Valentín Ortiz-Maldonado Montserrat Rovira Marta Gómez-Hernando Julio Delgado María Suárez-Lledó Carlos Fernández de Larrea Olga Balagué Gerard Frigola Abel Muñoz Estrella Ortiz Teresa Ribalta Miguel J. Martinez Maria Angeles-Marcos Marta Español-Rego Azucena González Daniel Benitez-Ribas Eugenia Martinez-Hernandez Pedro Castro Iban Aldecoa |
| author_sort | Núria Vidal Robau |
| collection | DOAJ |
| description | Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for the treatment of refractory hematopoietic malignancies. Adverse events are common, and neurotoxicity is one of the most important. However, the physiopathology is unknown and neuropathologic information is scarce.
Materials and methods: Post-mortem examination of 6 brains from patients that underwent CAR T-cell therapy from 2017 to 2022. In all cases, polymerase chain reaction (PCR) in paraffin blocks for the detection of CAR T cells was performed.
Results: Two patients died of hematologic progression, while the others died of cytokine release syndrome, lung infection, encephalomyelitis, and acute liver failure. Two out of 6 presented neurological symptoms, one with extracranial malignancy progression and the other with encephalomyelitis. The neuropathology of the latter showed severe perivascular and interstitial lymphocytic infiltration, predominantly CD8+, together with a diffuse interstitial histiocytic infiltration, affecting mainly the spinal cord, midbrain, and hippocampus, and a diffuse gliosis of basal ganglia, hippocampus, and brainstem. Microbiological studies were negative for neurotropic viruses, and PCR failed to detect CAR T -cells. Another case without detectable neurological signs showed cortical and subcortical gliosis due to acute hypoxic-ischemic damage. The remaining 4 cases only showed a mild patchy gliosis and microglial activation, and CAR T cells were detected by PCR only in one of them.
Conclusions: In this series of patients that died after CAR T-cell therapy, we predominantly found non-specific or minimal neuropathological changes. CAR T-cell related toxicity may not be the only cause of neurological symptoms, and the autopsy could detect additional pathological findings.
|
| first_indexed | 2024-04-10T22:43:25Z |
| format | Article |
| id | doaj.art-00d9ba14db9a4b1fbb3ea1b2032c2a8c |
| institution | Directory Open Access Journal |
| issn | 2699-4445 |
| language | English |
| last_indexed | 2024-04-10T22:43:25Z |
| publishDate | 2022-01-01 |
| publisher | University of Münster / Open Journals System |
| record_format | Article |
| series | Free Neuropathology |
| spelling | doaj.art-00d9ba14db9a4b1fbb3ea1b2032c2a8c2023-01-15T15:42:04ZengUniversity of Münster / Open Journals SystemFree Neuropathology2699-44452022-01-01310.17879/freeneuropathology-2022-4365Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patientsNúria Vidal Robau0Gabriela Caballero1Ivan Archilla2Andrea Ladino3Sara Fernández4Valentín Ortiz-Maldonado5Montserrat Rovira6Marta Gómez-Hernando7Julio Delgado8María Suárez-Lledó9Carlos Fernández de Larrea10Olga Balagué11Gerard Frigola12Abel Muñoz13Estrella Ortiz14Teresa Ribalta15Miguel J. Martinez16Maria Angeles-Marcos17Marta Español-Rego18Azucena González19Daniel Benitez-Ribas20Eugenia Martinez-Hernandez21Pedro Castro22Iban Aldecoa23Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainPathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainPathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainMedical Intensive Care Unit, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainMedical Intensive Care Unit, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainHaematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainHaematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainHaematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainHaematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainHaematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainHaematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain; August Pi Sunyer Biomedical Research Institute (IDIBAPS) – University of Barcelona, Barcelona, SpainPathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainPathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainPathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainPathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainPathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainMicrobiology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain; Barcelona Institute for Global Health (ISGlobal), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainMicrobiology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainImmunology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainImmunology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainImmunology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainNeurology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainMedical Intensive Care Unit, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain; Microbiology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, SpainPathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain; Neurological Tissue Bank, Biobank of Hospital Clinic of Barcelona – IDIBAPS, Barcelona, SpainIntroduction: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for the treatment of refractory hematopoietic malignancies. Adverse events are common, and neurotoxicity is one of the most important. However, the physiopathology is unknown and neuropathologic information is scarce. Materials and methods: Post-mortem examination of 6 brains from patients that underwent CAR T-cell therapy from 2017 to 2022. In all cases, polymerase chain reaction (PCR) in paraffin blocks for the detection of CAR T cells was performed. Results: Two patients died of hematologic progression, while the others died of cytokine release syndrome, lung infection, encephalomyelitis, and acute liver failure. Two out of 6 presented neurological symptoms, one with extracranial malignancy progression and the other with encephalomyelitis. The neuropathology of the latter showed severe perivascular and interstitial lymphocytic infiltration, predominantly CD8+, together with a diffuse interstitial histiocytic infiltration, affecting mainly the spinal cord, midbrain, and hippocampus, and a diffuse gliosis of basal ganglia, hippocampus, and brainstem. Microbiological studies were negative for neurotropic viruses, and PCR failed to detect CAR T -cells. Another case without detectable neurological signs showed cortical and subcortical gliosis due to acute hypoxic-ischemic damage. The remaining 4 cases only showed a mild patchy gliosis and microglial activation, and CAR T cells were detected by PCR only in one of them. Conclusions: In this series of patients that died after CAR T-cell therapy, we predominantly found non-specific or minimal neuropathological changes. CAR T-cell related toxicity may not be the only cause of neurological symptoms, and the autopsy could detect additional pathological findings. https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/4365hematologic malignancieschimeric antigen receptor (car) t-cellscytokine release syndrome (crs)neurotoxicityneuropathologyimmunohistochemical stains |
| spellingShingle | Núria Vidal Robau Gabriela Caballero Ivan Archilla Andrea Ladino Sara Fernández Valentín Ortiz-Maldonado Montserrat Rovira Marta Gómez-Hernando Julio Delgado María Suárez-Lledó Carlos Fernández de Larrea Olga Balagué Gerard Frigola Abel Muñoz Estrella Ortiz Teresa Ribalta Miguel J. Martinez Maria Angeles-Marcos Marta Español-Rego Azucena González Daniel Benitez-Ribas Eugenia Martinez-Hernandez Pedro Castro Iban Aldecoa Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patients Free Neuropathology hematologic malignancies chimeric antigen receptor (car) t-cells cytokine release syndrome (crs) neurotoxicity neuropathology immunohistochemical stains |
| title | Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patients |
| title_full | Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patients |
| title_fullStr | Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patients |
| title_full_unstemmed | Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patients |
| title_short | Post-mortem neuropathologic examination of a 6-case series of CAR T-cell treated patients |
| title_sort | post mortem neuropathologic examination of a 6 case series of car t cell treated patients |
| topic | hematologic malignancies chimeric antigen receptor (car) t-cells cytokine release syndrome (crs) neurotoxicity neuropathology immunohistochemical stains |
| url | https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/4365 |
| work_keys_str_mv | AT nuriavidalrobau postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT gabrielacaballero postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT ivanarchilla postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT andrealadino postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT sarafernandez postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT valentinortizmaldonado postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT montserratrovira postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT martagomezhernando postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT juliodelgado postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT mariasuarezlledo postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT carlosfernandezdelarrea postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT olgabalague postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT gerardfrigola postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT abelmunoz postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT estrellaortiz postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT teresaribalta postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT migueljmartinez postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT mariaangelesmarcos postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT martaespanolrego postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT azucenagonzalez postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT danielbenitezribas postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT eugeniamartinezhernandez postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT pedrocastro postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients AT ibanaldecoa postmortemneuropathologicexaminationofa6caseseriesofcartcelltreatedpatients |