Post-mortem neuropathologic examination of a 5-case series of CAR T-cell treated patients

Authors

  • Núria Vidal Robau Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Gabriela Caballero Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0002-0739-4896
  • Ivan Archilla Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0002-2142-0608
  • Andrea Ladino Medical Intensive Care Unit, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0003-2769-6004
  • Sara Fernández Medical Intensive Care Unit, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Valentín Ortiz-Maldonado Haematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0003-4699-6862
  • Montserrat Rovira Haematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Marta Gómez-Hernando Haematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Julio Delgado Haematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0002-5157-4376
  • María Suárez-Lledó Haematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Carlos Fernández de Larrea Haematology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain; August Pi Sunyer Biomedical Research Institute (IDIBAPS) – University of Barcelona, Barcelona, Spain
  • Olga Balagué Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0002-5099-3675
  • Gerard Frigola Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0001-6794-6456
  • Abel Muñoz Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Estrella Ortiz Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Teresa Ribalta Pathology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Miguel J. Martinez Microbiology 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, Spain
  • Maria Angeles-Marcos Microbiology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Marta Español-Rego Immunology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Azucena González Immunology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain
  • Daniel Benitez-Ribas Immunology Department, Biomedical Diagnostic Centre (CDB), Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0002-2346-5324
  • Eugenia Martinez-Hernandez Neurology Department, Hospital Clinic of Barcelona – University of Barcelona, Barcelona, Spain https://orcid.org/0000-0002-8317-7068
  • Pedro Castro Medical 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, Spain https://orcid.org/0000-0002-6118-8970
  • Iban Aldecoa Pathology 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, Spain https://orcid.org/0000-0001-5774-7453

DOI:

https://doi.org/10.17879/freeneuropathology-2022-4365

Keywords:

Hematologic malignancies, Chimeric antigen receptor (CAR) T-cells, Cytokine release syndrome (CRS), Neurotoxicity, Neuropathology, Immunohistochemical stains

Abstract

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.

Metrics

Metrics Loading ...

Downloads

Published

2022-10-27

How to Cite

Vidal Robau, N., Caballero, G., Archilla, I., Ladino, A., Fernández, S., Ortiz-Maldonado, V., Rovira, M., Gómez-Hernando, M., Delgado, J., Suárez-Lledó, M., Fernández de Larrea, C., Balagué, O., Frigola, G., Muñoz, A., Ortiz, E. ., Ribalta, T., Martinez, M. J., Angeles-Marcos, M., Español-Rego, M. ., González, A. ., Benitez-Ribas, D. ., Martinez-Hernandez, E., Castro, P., & Aldecoa, I. . (2022). Post-mortem neuropathologic examination of a 5-case series of CAR T-cell treated patients. Free Neuropathology, 3, 23. https://doi.org/10.17879/freeneuropathology-2022-4365

Issue

Section

Original Papers