First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas
Although chimeric antigen receptor (CAR) T cell therapy has revolutionized type B cancer treatment, efficacy remains limited in various lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategi...
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Elsevier
2024-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253124001951 |
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| author | Pedro Justicia-Lirio María Tristán-Manzano Noelia Maldonado-Pérez Carmen Barbero-Jiménez Marina Cortijo-Gutiérrez Kristina Pavlovic Francisco J. Molina-Estevez Pilar Muñoz Ana Hinckley-Boned Juan R. Rodriguez-Madoz Felipe Prosper Carmen Griñán-Lison Saúl A. Navarro-Marchal Carla Panisello Julia Muñoz-Ballester Pedro A. González-Sierra Concha Herrera Juan A. Marchal Francisco Martín |
| author_facet | Pedro Justicia-Lirio María Tristán-Manzano Noelia Maldonado-Pérez Carmen Barbero-Jiménez Marina Cortijo-Gutiérrez Kristina Pavlovic Francisco J. Molina-Estevez Pilar Muñoz Ana Hinckley-Boned Juan R. Rodriguez-Madoz Felipe Prosper Carmen Griñán-Lison Saúl A. Navarro-Marchal Carla Panisello Julia Muñoz-Ballester Pedro A. González-Sierra Concha Herrera Juan A. Marchal Francisco Martín |
| author_sort | Pedro Justicia-Lirio |
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| description | Although chimeric antigen receptor (CAR) T cell therapy has revolutionized type B cancer treatment, efficacy remains limited in various lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategies have been developed to regulate their secretion using minimal promoters that are controlled by chimeric proteins harboring transactivators. However, these chimeric proteins can disrupt the normal physiology of T cells. Here, we present the first transactivator-free anti-CD19 CAR-T cells able to control IL-18 expression (iTRUCK19.18) under ultra-low doses of doxycycline and without altering cellular fitness. Interestingly, IL-18 secretion requires T cell activation in addition to doxycycline, allowing the external regulation of CAR-T cell potency. This effect was translated into an increased CAR-T cell antitumor activity against aggressive hematologic and solid tumor models. In a clinically relevant context, we generated patient-derived iTRUCK19.18 cells capable of eradicating primary B cells tumors in a doxycycline-dependent manner. Furthermore, IL-18-releasing CAR-T cells polarized pro-tumoral macrophages toward an antitumoral phenotype, suggesting potential for modulating the tumor microenvironment. In summary, we showed that our platform can generate exogenously controlled CAR-T cells with enhanced potency and in the absence of transactivators. |
| format | Article |
| id | doaj-art-bffb79b98bd04d24b3575e2ddc65fa95 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2024-12-01 |
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| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-bffb79b98bd04d24b3575e2ddc65fa952024-11-20T05:06:46ZengElsevierMolecular Therapy: Nucleic Acids2162-25312024-12-01354102308First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomasPedro Justicia-Lirio0María Tristán-Manzano1Noelia Maldonado-Pérez2Carmen Barbero-Jiménez3Marina Cortijo-Gutiérrez4Kristina Pavlovic5Francisco J. Molina-Estevez6Pilar Muñoz7Ana Hinckley-Boned8Juan R. Rodriguez-Madoz9Felipe Prosper10Carmen Griñán-Lison11Saúl A. Navarro-Marchal12Carla Panisello13Julia Muñoz-Ballester14Pedro A. González-Sierra15Concha Herrera16Juan A. Marchal17Francisco Martín18LentiStem Biotech, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, SpainLentiStem Biotech, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, Spain; Corresponding author: María Tristán-Manzano, LentiStem Biotech, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, Spain.Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Av. de la Investigación, 11, 18006 Granada, Spain; Department of Genomic Medicine, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, SpainLentiStem Biotech, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, SpainDepartment of Genomic Medicine, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, SpainDepartment of Genomic Medicine, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, Spain; Maimonides Institute of Biomedical Research in Cordoba (IMIBIC), Cellular Therapy Unit, Reina Sofía University Hospital, University of Cordoba, Av. Menéndez Pidal, 14004 Cordoba, SpainDepartment of Genomic Medicine, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Av. de Madrid 15, 18012 Granada, SpainDepartment of Genomic Medicine, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Av. de Madrid 15, 18012 Granada, Spain; Department of Cellular Biology, Faculty of Sciences, University of Granada, Av. de Fuente Nueva, 18071 Granada, SpainDepartment of Genomic Medicine, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, SpainCentro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain; Hemato-Oncology Program, Cima Universidad de Navarra, IdiSNA, Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, SpainCentro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain; Hemato-Oncology Program, Cima Universidad de Navarra, IdiSNA, Pamplona, Spain; Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain; Hematology and Cell Therapy Department, Clinica Universidad de Navarra, IdiSNA, Pamplona, SpainInstituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Av. de Madrid 15, 18012 Granada, Spain; Excellence Research Unit “Modeling Nature” (MNat), University of Granada, 18016 Granada, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18016 Granada, Spain; Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, 18071 Granada, SpainInstituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Av. de Madrid 15, 18012 Granada, Spain; Excellence Research Unit “Modeling Nature” (MNat), University of Granada, 18016 Granada, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18016 Granada, Spain; Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UKJosep Carreras Leukemia Research Institute, Barcelona, Spain; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain; Red Española de Terapias Avanzadas (TERAV)-Instituto de Salud Carlos III (ISCIII), Madrid, SpainInstituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Av. de Madrid 15, 18012 Granada, Spain; Hematology and Hemotherapy Unit, Virgen de las Nieves University Hospital, Av. de las Fuerzas Armadas 2, 18014 Granada, SpainInstituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Av. de Madrid 15, 18012 Granada, Spain; Hematology and Hemotherapy Unit, Virgen de las Nieves University Hospital, Av. de las Fuerzas Armadas 2, 18014 Granada, SpainMaimonides Institute of Biomedical Research in Cordoba (IMIBIC), Cellular Therapy Unit, Reina Sofía University Hospital, University of Cordoba, Av. Menéndez Pidal, 14004 Cordoba, SpainInstituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Av. de Madrid 15, 18012 Granada, Spain; Excellence Research Unit “Modeling Nature” (MNat), University of Granada, 18016 Granada, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18016 Granada, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Av. de la Investigación 11, 18006 Granada, SpainDepartment of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Av. de la Investigación, 11, 18006 Granada, Spain; Department of Genomic Medicine, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research (GENYO), PTS, Av. de la Ilustración 114, 18016 Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Av. de Madrid 15, 18012 Granada, Spain; Excellence Research Unit “Modeling Nature” (MNat), University of Granada, 18016 Granada, Spain; Corresponding author: Francisco Martín, Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Av. de la Investigación, 11, 18006 Granada, Spain.Although chimeric antigen receptor (CAR) T cell therapy has revolutionized type B cancer treatment, efficacy remains limited in various lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategies have been developed to regulate their secretion using minimal promoters that are controlled by chimeric proteins harboring transactivators. However, these chimeric proteins can disrupt the normal physiology of T cells. Here, we present the first transactivator-free anti-CD19 CAR-T cells able to control IL-18 expression (iTRUCK19.18) under ultra-low doses of doxycycline and without altering cellular fitness. Interestingly, IL-18 secretion requires T cell activation in addition to doxycycline, allowing the external regulation of CAR-T cell potency. This effect was translated into an increased CAR-T cell antitumor activity against aggressive hematologic and solid tumor models. In a clinically relevant context, we generated patient-derived iTRUCK19.18 cells capable of eradicating primary B cells tumors in a doxycycline-dependent manner. Furthermore, IL-18-releasing CAR-T cells polarized pro-tumoral macrophages toward an antitumoral phenotype, suggesting potential for modulating the tumor microenvironment. In summary, we showed that our platform can generate exogenously controlled CAR-T cells with enhanced potency and in the absence of transactivators.http://www.sciencedirect.com/science/article/pii/S2162253124001951MT: Delivery StrategiesCAR-T cellsTRUCKsLent-On-Pluslentiviral vectorsregulation |
| spellingShingle | Pedro Justicia-Lirio María Tristán-Manzano Noelia Maldonado-Pérez Carmen Barbero-Jiménez Marina Cortijo-Gutiérrez Kristina Pavlovic Francisco J. Molina-Estevez Pilar Muñoz Ana Hinckley-Boned Juan R. Rodriguez-Madoz Felipe Prosper Carmen Griñán-Lison Saúl A. Navarro-Marchal Carla Panisello Julia Muñoz-Ballester Pedro A. González-Sierra Concha Herrera Juan A. Marchal Francisco Martín First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas Molecular Therapy: Nucleic Acids MT: Delivery Strategies CAR-T cells TRUCKs Lent-On-Plus lentiviral vectors regulation |
| title | First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas |
| title_full | First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas |
| title_fullStr | First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas |
| title_full_unstemmed | First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas |
| title_short | First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas |
| title_sort | first in class transactivator free doxycycline inducible il 18 engineered car t cells for relapsed refractory b cell lymphomas |
| topic | MT: Delivery Strategies CAR-T cells TRUCKs Lent-On-Plus lentiviral vectors regulation |
| url | http://www.sciencedirect.com/science/article/pii/S2162253124001951 |
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