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Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients

OBJECTIVE: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biol...

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Autores principales: Taştan, Cihan, Kançağı, Derya Dilek, Turan, Raife Dilek, Yurtsever, Bulut, Çakırsoy, Didem, Abanuz, Selen, Yılancı, Muhammet, Seyis, Utku, Özer, Samed, Mert, Selin, Kayhan, Cavit Kerem, Tokat, Fatma, Açıkel Elmas, Merve, Birdoğan, Selçuk, Arbak, Serap, Yalçın, Koray, Sezgin, Aslıhan, Kızılkılıç, Ebru, Hemşinlioğlu, Cansu, İnce, Ümit, Ratip, Siret, Ovalı, Ercüment
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Galenos Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702660/
https://www.ncbi.nlm.nih.gov/pubmed/32755128
http://dx.doi.org/10.4274/tjh.galenos.2020.2020.0070
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author Taştan, Cihan
Kançağı, Derya Dilek
Turan, Raife Dilek
Yurtsever, Bulut
Çakırsoy, Didem
Abanuz, Selen
Yılancı, Muhammet
Seyis, Utku
Özer, Samed
Mert, Selin
Kayhan, Cavit Kerem
Tokat, Fatma
Açıkel Elmas, Merve
Birdoğan, Selçuk
Arbak, Serap
Yalçın, Koray
Sezgin, Aslıhan
Kızılkılıç, Ebru
Hemşinlioğlu, Cansu
İnce, Ümit
Ratip, Siret
Ovalı, Ercüment
author_facet Taştan, Cihan
Kançağı, Derya Dilek
Turan, Raife Dilek
Yurtsever, Bulut
Çakırsoy, Didem
Abanuz, Selen
Yılancı, Muhammet
Seyis, Utku
Özer, Samed
Mert, Selin
Kayhan, Cavit Kerem
Tokat, Fatma
Açıkel Elmas, Merve
Birdoğan, Selçuk
Arbak, Serap
Yalçın, Koray
Sezgin, Aslıhan
Kızılkılıç, Ebru
Hemşinlioğlu, Cansu
İnce, Ümit
Ratip, Siret
Ovalı, Ercüment
author_sort Taştan, Cihan
collection PubMed
description OBJECTIVE: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey. MATERIALS AND METHODS: We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3ζ sequence as a chimeric antigen receptor (CAR) along with a truncated form of EGFR (EGFRt) on human T-lymphocytes (CAR-T). We preclinically assessed the efficacy and safety of the manufactured CAR-T cells, namely ISIKOK-19, from both healthy donors’ and ALL/NHL patients’ peripheral blood mononuclear cells. RESULTS: We showed significant enhancement of CAR lentivirus transduction efficacy in T-cells using BX-795, an inhibitor of the signaling molecule TBK1/IKKƐ, in order to cut the cost of CAR-T cell production. In addition, ISIKOK-19 cells demonstrated a significantly high level of cytotoxicity specifically against a CD19+ B-lymphocyte cancer model, RAJI cells, in NOD/SCID mice. CONCLUSION: This is the first report of preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.
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spelling pubmed-77026602020-12-05 Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients Taştan, Cihan Kançağı, Derya Dilek Turan, Raife Dilek Yurtsever, Bulut Çakırsoy, Didem Abanuz, Selen Yılancı, Muhammet Seyis, Utku Özer, Samed Mert, Selin Kayhan, Cavit Kerem Tokat, Fatma Açıkel Elmas, Merve Birdoğan, Selçuk Arbak, Serap Yalçın, Koray Sezgin, Aslıhan Kızılkılıç, Ebru Hemşinlioğlu, Cansu İnce, Ümit Ratip, Siret Ovalı, Ercüment Turk J Haematol Research Article OBJECTIVE: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey. MATERIALS AND METHODS: We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3ζ sequence as a chimeric antigen receptor (CAR) along with a truncated form of EGFR (EGFRt) on human T-lymphocytes (CAR-T). We preclinically assessed the efficacy and safety of the manufactured CAR-T cells, namely ISIKOK-19, from both healthy donors’ and ALL/NHL patients’ peripheral blood mononuclear cells. RESULTS: We showed significant enhancement of CAR lentivirus transduction efficacy in T-cells using BX-795, an inhibitor of the signaling molecule TBK1/IKKƐ, in order to cut the cost of CAR-T cell production. In addition, ISIKOK-19 cells demonstrated a significantly high level of cytotoxicity specifically against a CD19+ B-lymphocyte cancer model, RAJI cells, in NOD/SCID mice. CONCLUSION: This is the first report of preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey. Galenos Publishing 2020-12 2020-11-19 /pmc/articles/PMC7702660/ /pubmed/32755128 http://dx.doi.org/10.4274/tjh.galenos.2020.2020.0070 Text en © Copyright 2020 by Turkish Society of Hematology / Turkish Journal of Hematology, Published by Galenos Publishing House. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Taştan, Cihan
Kançağı, Derya Dilek
Turan, Raife Dilek
Yurtsever, Bulut
Çakırsoy, Didem
Abanuz, Selen
Yılancı, Muhammet
Seyis, Utku
Özer, Samed
Mert, Selin
Kayhan, Cavit Kerem
Tokat, Fatma
Açıkel Elmas, Merve
Birdoğan, Selçuk
Arbak, Serap
Yalçın, Koray
Sezgin, Aslıhan
Kızılkılıç, Ebru
Hemşinlioğlu, Cansu
İnce, Ümit
Ratip, Siret
Ovalı, Ercüment
Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients
title Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients
title_full Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients
title_fullStr Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients
title_full_unstemmed Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients
title_short Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients
title_sort preclinical assessment of efficacy and safety analysis of car-t cells (isikok-19) targeting cd19-expressing b-cells for the first turkish academic clinical trial with relapsed/refractory all and nhl patients
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702660/
https://www.ncbi.nlm.nih.gov/pubmed/32755128
http://dx.doi.org/10.4274/tjh.galenos.2020.2020.0070
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