Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia Journal Article


Authors: Santomasso, B. D.; Park, J. H.; Salloum, D.; Riviere, I.; Flynn, J.; Mead, E.; Halton, E.; Wang, X.; Senechal, B.; Purdon, T.; Cross, J. R.; Liu, H.; Vachha, B.; Chen, X.; Deangelis, L. M.; Li, D.; Bernal, Y.; Gonen, M.; Wendel, H. G.; Sadelain, M.; Brentjens, R. J.
Article Title: Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia
Abstract: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood–cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system–specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity. SIGNIFICANCE: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. © 2018 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 8
Issue: 8
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2018-08-01
Start Page: 958
End Page: 971
Language: English
DOI: 10.1158/2159-8290.cd-17-1319
PROVIDER: scopus
PUBMED: 29880584
PMCID: PMC6385599
DOI/URL:
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
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MSK Authors
  1. Xi Chen
    26 Chen
  2. Renier J Brentjens
    233 Brentjens
  3. Mithat Gonen
    779 Gonen
  4. Jae Hong Park
    178 Park
  5. Elizabeth F Halton
    35 Halton
  6. Michel W J Sadelain
    486 Sadelain
  7. Isabelle C Riviere
    189 Riviere
  8. Xiuyan Wang
    84 Wang
  9. Hans Guido Wendel
    71 Wendel
  10. Justin Robert Cross
    63 Cross
  11. Yvette J Bernal
    29 Bernal
  12. Terence John Purdon
    49 Purdon
  13. Hui   Liu
    8 Liu
  14. Elena   Mead
    26 Mead
  15. Behroze Adi Vachha
    14 Vachha
  16. Jessica Flynn
    40 Flynn