title: Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy.
abstract: Chimeric antigen receptor-modified (CAR) T cells targeting CD19 (CART19) have shown therapeutical activities in CD19+ malignancies. However, the etiological nature of neurologic complications remains a conundrum. In our study, the evidence of blood-brain barrier (BBB)-penetrating CAR T cells as a culprit was revealed. A patient with acute lymphocytic leukemia developed sustained pyrexia with tremors about 6 h after CART19 infusion, followed by a grade 2 cytokine release syndrome (CRS) and neurological symptoms in the next 3 days. Contrast-enhanced magnetic resonance showed signs of intracranial edema. Lumbar puncture on day 5 showed an over 400-mmH2O cerebrospinal pressure. The cerebrospinal fluid (CSF) contained 20 WBCs/μL with predominant CD3+ T cells. qPCR analysis for CAR constructs showed 3,032,265 copies/μg DNA in CSF and 988,747 copies/μg DNA in blood. Cytokine levels including IFN-γ and IL-6 in CSF were extremely higher than those in the serum. Methyprednisone was administrated and the symptoms relieved gradually. The predominance of CART19 in CSF and the huge discrepancies in cytokine distributions indicated the development of a cerebral CRS, presumably featured as CSF cytokines largely in situ produced by BBB-penetrating CAR T cells. For the first time, we reported the development of cerebral CRS triggered by BBB-penetrating CAR T cells.
  
  
  
  ChiCTR-OCC-15007008 .
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yongxian
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Shanghai SiDanSai Biotechnology Limited Company, Shanghai, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Qu
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Shanghai SiDanSai Biotechnology Limited Company, Shanghai, China.
authors.forename: Chengfei
authors.initials: C
authors.lastname: Pu
authors.affiliation: Department of Hematology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liang
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Shi
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Aiyun
authors.initials: A
authors.lastname: Jin
authors.affiliation: Shanghai SiDanSai Biotechnology Limited Company, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. huanghe@zju.edu.cn.
authors.forename: He
authors.initials: H
authors.lastname: Huang
mesh_terms: D000328:Adult; D018941:Antigens, CD19 / Q000134:cerebrospinal fluid / Q000276:immunology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001929:Brain Edema / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology; D016207:Cytokines / Q000134:cerebrospinal fluid / Q000378:metabolism; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects* / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000628:therapy*; D011241:Prednisone / Q000627:therapeutic use; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D018941:Antigens, CD19; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D011241:Prednisone
keywords: Acute lymphocytic leukemia; Blood-brain barrier; CD19; Chimeric antigen receptor-modified T cells; Cytokine release syndrome