Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia

Li-Yun Chen; Li-Qing Kang; Hai-Xia Zhou; Han-Qing Gao; Xue-Fei Zhu; Nan Xu; Lei Yu; De-Pei Wu; Sheng-Li Xue; Ai-Ning Sun

Translational Oncology (Nov 2020)

Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia

Li-Yun Chen,
Li-Qing Kang,
Hai-Xia Zhou,
Han-Qing Gao,
Xue-Fei Zhu,
Nan Xu,
Lei Yu,
De-Pei Wu,
Sheng-Li Xue,
Ai-Ning Sun

Affiliations

Li-Yun Chen: Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
Li-Qing Kang: Shanghai Unicar-Therapy Bio-medicine Technology Co., Ltd, Shanghai, China; Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
Hai-Xia Zhou: Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
Han-Qing Gao: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China
Xue-Fei Zhu: Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, China
Nan Xu: Shanghai Unicar-Therapy Bio-medicine Technology Co., Ltd, Shanghai, China; Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
Lei Yu: Shanghai Unicar-Therapy Bio-medicine Technology Co., Ltd, Shanghai, China; Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
De-Pei Wu: Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Corresponding authors at: The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Shizi Street 188, Suzhou 215006, China.
Sheng-Li Xue: Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Corresponding authors at: The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Shizi Street 188, Suzhou 215006, China.
Ai-Ning Sun: Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Corresponding authors at: The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Shizi Street 188, Suzhou 215006, China.

Journal volume & issue: Vol. 13, no. 11
p. 100838

Abstract

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Few studies have described chimeric antigen receptor–modified T cell (CAR-T) therapy for central nervous system (CNS) B-cell acute lymphocytic leukemia (B-ALL) patients due to life-threatening CAR-T-related encephalopathy (CRES) safety issues. In this study, CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) were prepared. We conducted a phase 1 clinical trial (ClinicalTrials.gov number, NCT03064269). Three patients with relapsed CNS B-ALL were enrolled, conditioned with the fludarabine and cyclophosphamide for lymphocyte depletion and infused with ssCART-19s for three consecutive days. Clinical symptoms and laboratory examinations were monitored. After ssCART-19 treatment, three patients' symptoms resolved almost entirely. Brain leukemic infiltration reduced significantly based on magnetic resonance imaging (MRI), and there were no leukemic blasts in cerebrospinal fluid (CSF), which was confirmed by cytological and molecular examinations. Additionally, increases in the levels of cytokines and immune cells were observed in the CSF of all patients. Only grade 1 cytokine release syndrome (CRS) manifesting as fever was noted in patients. In conclusion, CAR-Ts with shRNA-IL-6 gene knockdown migrated into the CNS, eradicated leukemic cells and elevated cytokines in CSF with mild, acceptable side effects.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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