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    Home > Active Ingredient News > Antitumor Therapy > CD19 CAR-T causes neurotoxic syndrome, Stanford University et al. found the root cause

    CD19 CAR-T causes neurotoxic syndrome, Stanford University et al. found the root cause

    • Last Update: 2021-03-21
    • Source: Internet
    • Author: User
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    CD19-targeted CAR-T cell therapy has shown great clinical efficacy in patients with B-cell leukemia and lymphoma, including those who have relapsed after receiving traditional chemotherapy.

    However, in addition to the cytokine storm, neurotoxicity is another type of toxic effect that has a high incidence and severely affects the lives of patients due to the related side effects caused by cell therapy.

    CD19 CAR-T Neurotoxicity Syndrome CD19 CAR-T treatment causes Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).
    The patient initially develops tremor, writing difficulties, mild expressive aphasia, and apraxia And impaired attention.

    Expressive aphasia is a special symptom of ICANS.

    In a Phase1 CD19 CAR-T treatment of adult patients with B-ALL in a study, 21 of 22 patients developed expressive aphasia, 19 of which were the initial manifestations of neurotoxicity (Reference 1) .

    In some clinical studies, the incidence of CRS and ICANS of grade 3 and above (Document 4) expressive aphasia develops into global aphasia within a few hours, with difficulties in expression and acceptance; the patient is awake but silent and inactive.

    The patient is awake to distinguish ICANS from other encephalopathy.

    As neurotoxicity progresses, patients may experience subclinical or clinical seizures, and a few will develop diffuse cerebral edema.

    Two potential mechanisms have been proposed to explain the development of ICANS, but the precise pathophysiological basis leading to its development is unclear.

    First, the diffusion of cytokines into the central nervous system may cause neurotoxicity.

    Serum levels of high levels of IL-15, IL-6, IL-10, and IP-10 have been described in patients with high-grade neurotoxicity.

    Second, the entry of CAR-T cells into the central nervous system may lead to the development of neurotoxicity.

    For example, a Phase1 study included 21 children or young people with hematological malignancies who received CD19 CAR-T treatment.
    The report showed that their cerebrospinal fluid CAR-T cell concentration was higher than those of patients without neurotoxicity.
    high.

    Why is CD19 CAR-T attracted to the central nervous system, causing off-tumor toxicity? Pericytes are the target cells of CD19 CAR-T neurotoxicity.
    Stanford University et al.
    published an article on Cell in 2020 (Reference 3).
    Through single-cell sequencing, it was found that the pericytes/Mural Cells of the brain express CD19 (by CD248).
    As a marker to mark pericytes), it is the target cell of CD19 CAR-T to produce off-tumor neurotoxicity.

    Possible mechanism: Pericytes are an important component of the blood-brain barrier.
    The cytokine release syndrome (CRS) caused by CAR-T treatment can destroy the integrity of the blood-brain barrier, and CAR-T cells can break through the blood.
    The brain barrier, and pericytes express CD19, and are attacked by CD19 CAR-T, causing further destruction of the blood-brain barrier.
    A large amount of CAR-T enters the central nervous system, causing more serious neurotoxicity.

    The mechanism of CD19 CAR-T attacking pericytes to cause neurotoxicity (Reference 3) The main research data is that pericytes are highly expressed CD19 and related genes CD19 are specifically expressed in brain pericytes, and CD19 is specifically expressed in brain pericytes, but not in other weeks such as lungs.
    Cells are also not expressed with brain endothelial cells and lung endothelial cells.

    The editor concludes that the immune effector cell neurotoxic syndrome caused by CAR-T cell therapy is a challenge that must be faced in treatment.

    The research results of Stanford University and others found that pericytes are the target cells of CAR-T off-tumor, which provides a scientific basis for finding corresponding prevention strategies and treatment management strategies, and helps to expand the clinical application of CAR-T.

    Reference 1.
    Santomasso BD, Park JH, Salloum D, et al.
    Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia.
    Cancer Discov.
    2018;8:958-971.
    2.
    Gust, J.
    , Hay, et al.
    (2017).
    Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.
    Cancer Discov.
    7, 1404–1419.
    3.
    Parker et al.
    , Single- Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies, Cell (2020), https://doi.
    org/10.
    1016/j.
    cell.
    2020.
    08.
    0224.
    Vipul S Sheth1 and Taming the beast : CRS and ICANS after CAR T-cell therapy for ALLJordan Gauthier1, Bone Marrow Transplantation https://doi.
    org/10.
    1038/s41409-020-01134-4 "Focus on Cell Gene Therapy Clinical Issues Cell Gene Solid Tumors-Blockbuster Clinical PI Big Coffee Comes to TG-Bio in April! More than 500 well-known pharmaceutical companies/CDMO/clinical industry colleagues have already Joining! From April 9-10, Shanghai Longemont Hotel, have you participated?! Clinical topic medical institutions (in-hospitals) carry out clinical trials related to immune cell therapy through clinical case analysis, how to make cell drugs in Clinically, it is more clinically feasible to manipulate humanized anti-BCMA CAR-T cells to treat relapsed/refractory multiple myeloma.
    The preliminary research report on the safety and effectiveness of solid tumor clinical trials.
    Dr.
    Qi Junyuan Chinese Academy of Medical Sciences The chief physician of the GCP ward of the Hematology Hospital has extensive experience in clinical research, design and implementation, and risk control.
    He has undertaken 55 clinical trials, including 24 FIM trials and 5 CAR-T clinical trials.

    CAR-T related work experience: participated in the independent research and development of a number of CAR-T cell products, and successfully transferred them; and achieved significant effects in the treatment of hematological tumors including lymphoma with CAR-T cells, and has treated more than 100 cases of blood so far Tumor patients, rich experience.

    He has published more than 100 research papers in important professional journals at home and abroad, and participated in the compilation of more than 7 monographs.

    Participated in a number of research projects such as the National Natural Science Foundation of China, major international scientific and technological cooperation projects (sub-projects) of the Ministry of Science and Technology, key clinical disciplines of the Ministry of Health, and key scientific and technological support of Tianjin.

    Dr.
    Wu Weizhong, Deputy Director of the Liver Cancer Institute of Fudan University, Doctoral Supervisor of the Deputy Dean of the Zhongshan Clinical Research Institute, Member of the Clinical Stem Cell Group of China Research Hospital, Director of the Shanghai Society for Cell Biology, Member of the Shanghai Society of Immunity, and Liver Cancer Institute of Fudan University Deputy Director, Deputy Director of Zhongshan Clinical Research Institute, Director of Biotherapy Center.

    He has been engaged in basic research and biological treatment of liver cancer metastasis for a long time, and has presided over 5 National Natural Science Foundation projects, 2 Shanghai Science and Technology Commission projects, and participated in the 973 Plan and 2 National Infectious Diseases Major Special Projects.

    He has published more than 40 SCI papers in academic journals such as J Exp Med, Theranostics, j hematol oncol, Nucleic Acids Res, J Clin Oncol, and participated in the editing of 2 books.

    He is the review expert of BMC Cancer, J Transl Med, Mol Biol Rep and other magazines, the National Natural Science Foundation of China, the National Health and Family Planning Commission, and the review expert of the key special projects of "Stem Cell and Transformation Research".

    Dr.
    Zhou Yuhong, chief physician of the Biotherapy Center of Zhongshan Hospital, Fudan University, has a Ph.
    D.
    , has been engaged in solid tumor and lymphoma clinical and basic research for more than 20 years, and has been engaged in lymphoma and myeloma research at the famous MD Anderson Cancer Center in the United States.

    Deputy Chief Physician of the Department of Oncology, Zhongshan Hospital Affiliated to Fudan University, professor, master tutor, director of the Biotherapy Center of Zhongshan Hospital Affiliated to Fudan University, and member of the Standing Committee of the Sarcoma Specialized Committee of the Chinese Anti-Cancer Association.

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