Induced dendritic cells co-expressing GM-CSF/IFN-α/tWT1 priming T and B cells and automated manufacturing to boost GvL
| Autor: | Julia K. Bialek-Waldmann, Sabine Domning, Agnes Bonifacius, Renata Stripecke, Constanca Figueiredo, Ruth Esser, Sebastian J. Theobald, Lubomir Arseniev, Michael Heuser, Johannes Koenig, Wolfgang Glienke, Steven R. Talbot, Suresh Kumar, Dirk Schaudien, Ulrike Köhl, Farzin Farzaneh, Krasimira Aleksandrova, Rainer Blasczyk, Andreas Schneider, Angela D. A. Cornelius, Britta Eiz-Vesper, Hsin-Chieh Tsay, Caren Clark, Mira Mertens, Arnold Ganser, Constantin von Kaisenberg, André Bleich, Loukia M. Spineli |
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| Přispěvatelé: | Publica |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
immunetherapy CD14 medicine.medical_treatment Priming (immunology) lentiviral vectors Hematopoietic stem cell transplantation QH426-470 stem cell transplantation Leukämie Stammzelle Graft-Versus-Leukemia-Effect 03 medical and health sciences 0302 clinical medicine Antigen Interferon Genetics Medicine dendritic cells Molecular Biology B cell automation Transplantation QH573-671 business.industry GMP leukemia medicine.disease graft-versus-leukemia WT1 Immuntherapie Leukemia 030104 developmental biology medicine.anatomical_structure automated 030220 oncology & carcinogenesis Humanized mouse Cancer research Molecular Medicine Original Article Lentiviral vector business Cytology dendritische Zelle medicine.drug |
| Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 21, Iss, Pp 621-641 (2021) |
| ISSN: | 2329-0501 |
| Popis: | Acute myeloid leukemia (AML) patients with minimal residual disease and receiving allogeneic hematopoietic stem cell transplantation (HCT) have poor survival. Adoptive administration of dendritic cells (DCs) presenting the Wilms tumor protein 1 (WT1) leukemia-associated antigen can potentially stimulate de novo T and B cell development to harness the graft-versus-leukemia (GvL) effect after HCT. We established a simple and fast genetic modification of monocytes for simultaneous lentiviral expression of a truncated WT1 antigen (tWT1), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon (IFN)-α, promoting their self-differentiation into potent “induced DCs” (iDCtWT1). A tricistronic integrase-defective lentiviral vector produced under good manufacturing practice (GMP)-like conditions was validated. Transduction of CD14+ monocytes isolated from peripheral blood, cord blood, and leukapheresis material effectively induced their self-differentiation. CD34+ cell-transplanted Nod.Rag.Gamma (NRG)- and Nod.Scid.Gamma (NSG) mice expressing human leukocyte antigen (HLA)-A∗0201 (NSG-A2)-immunodeficient mice were immunized with autologous iDCtWT1. Both humanized mouse models showed improved development and maturation of human T and B cells in the absence of adverse effects. Toward clinical use, manufacturing of iDCtWT1 was up scaled and streamlined using the automated CliniMACS Prodigy system. Proof-of-concept clinical-scale runs were feasible, and the 38-h process enabled standardized production and high recovery of a cryopreserved cell product with the expected identity characteristics. These results advocate for clinical trials testing iDCtWT1 to boost GvL and eradicate leukemia. Graphical abstract Hematopoietic stem cell transplantation (HCT) is used to treat acute myeloid leukemia (AML). We developed lentivirus-induced dendritic cells expressing immunomodulatory cytokines and truncated WT1 (iDCtWT1). The cells were produced in a GMP-compliant automated process to immunize AML patients after HCT. |
| Databáze: | OpenAIRE |
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