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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| Format: | Article |
| Language: | English |
| Published: |
Galenos Publishing House
2020-11-01
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| Series: | Turkish Journal of Hematology |
| Subjects: | |
| Online Access: | https://jag.journalagent.com/z4/download_fulltext.asp?pdir=tjh&un=TJH-31391 |
| _version_ | 1797909165868318720 |
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| author | Cihan Taştan Derya Dilek Kançağı Raife Dilek Turan Bulut Yurtsever Didem Çakırsoy Selen Abanuz Muhammet Yılancı Utku Seyis Samed Özer Selin Mert Cavit Kerem Kayhan Fatma Tokat Merve Açıkel Elmas Selçuk Birdoğan Serap Arbak Koray Yalçın Aslıhan Sezgin Ebru Kızılkılıç Cansu Hemşinlioğlu Ümit İnce Siret Ratip Ercüment Ovalı |
| author_facet | Cihan Taştan Derya Dilek Kançağı Raife Dilek Turan Bulut Yurtsever Didem Çakırsoy Selen Abanuz Muhammet Yılancı Utku Seyis Samed Özer Selin Mert Cavit Kerem Kayhan Fatma Tokat Merve Açıkel Elmas Selçuk Birdoğan Serap Arbak Koray Yalçın Aslıhan Sezgin Ebru Kızılkılıç Cansu Hemşinlioğlu Ümit İnce Siret Ratip Ercüment Ovalı |
| author_sort | Cihan Taştan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T11:04:08Z |
| format | Article |
| id | doaj.art-23ae462105714cc7b49d3f11c108d506 |
| institution | Directory Open Access Journal |
| issn | 1308-5263 |
| language | English |
| last_indexed | 2024-04-10T11:04:08Z |
| publishDate | 2020-11-01 |
| publisher | Galenos Publishing House |
| record_format | Article |
| series | Turkish Journal of Hematology |
| spelling | doaj.art-23ae462105714cc7b49d3f11c108d5062023-02-15T16:19:31ZengGalenos Publishing HouseTurkish Journal of Hematology1308-52632020-11-0137423424710.4274/tjh.galenos.2020.2020.0070TJH-31391Preclinical 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 PatientsCihan Taştan0Derya Dilek Kançağı1Raife Dilek Turan2Bulut Yurtsever3Didem Çakırsoy4Selen Abanuz5Muhammet Yılancı6Utku Seyis7Samed Özer8Selin Mert9Cavit Kerem Kayhan10Fatma Tokat11Merve Açıkel Elmas12Selçuk Birdoğan13Serap Arbak14Koray Yalçın15Aslıhan Sezgin16Ebru Kızılkılıç17Cansu Hemşinlioğlu18Ümit İnce19Siret Ratip20Ercüment Ovalı21Acıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Mehmet Ali Aydınlar University, Animal Application and Research Center, İstanbul, TurkeyBoğaziçi University, Center of Life Sciences and Technologies, İstanbul, TurkeyAcıbadem Maslak Hospital, Pathology Laboratory, İstanbul, TurkeyAcıbadem Mehmet Ali Aydınlar University Faculty of Medicine, Department of Pathology, İstanbul, TurkeyAcıbadem Mehmet Ali Aydınlar University Faculty of Medicine, Department of Histology and Embryology, İstanbul, TurkeyAcıbadem Mehmet Ali Aydınlar University, Electron Microscopy Laboratory, İstanbul, TurkeyAcıbadem Mehmet Ali Aydınlar University Faculty of Medicine, Department of Histology and Embryology, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, Turkey; Medical Park Göztepe Hospital, Pediatric Hematopoetic Stem Cell Transplantation Unit, İstanbul, TurkeyAcıbadem Altunizade Hospital, İstanbul, TurkeyAcıbadem Altunizade Hospital, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyAcıbadem Mehmet Ali Aydınlar University Faculty of Medicine, Department of Pathology, İstanbul, TurkeyAcıbadem Mehmet Ali Aydınlar University Faculty of Medicine, Department of Hematology, İstanbul, TurkeyAcıbadem Labcell Cellular Therapy Laboratory, İstanbul, TurkeyObjective: 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.https://jag.journalagent.com/z4/download_fulltext.asp?pdir=tjh&un=TJH-31391chimeric antigen receptorcd19car-timmunotherapy |
| spellingShingle | Cihan Taştan Derya Dilek Kançağı Raife Dilek Turan Bulut Yurtsever Didem Çakırsoy Selen Abanuz Muhammet Yılancı Utku Seyis Samed Özer Selin Mert Cavit Kerem Kayhan Fatma Tokat Merve Açıkel Elmas Selçuk Birdoğan Serap Arbak Koray Yalçın Aslıhan Sezgin Ebru Kızılkılıç Cansu Hemşinlioğlu Ümit İnce Siret Ratip Ercüment Ovalı 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 Turkish Journal of Hematology chimeric antigen receptor cd19 car-t immunotherapy |
| 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 | chimeric antigen receptor cd19 car-t immunotherapy |
| url | https://jag.journalagent.com/z4/download_fulltext.asp?pdir=tjh&un=TJH-31391 |
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