Molecular Therapy: Methods & Clinical Development (Jun 2021)
Induced dendritic cells co-expressing GM-CSF/IFN-α/tWT1 priming T and B cells and automated manufacturing to boost GvL
- Julia K. Bialek-Waldmann,
- Sabine Domning,
- Ruth Esser,
- Wolfgang Glienke,
- Mira Mertens,
- Krasimira Aleksandrova,
- Lubomir Arseniev,
- Suresh Kumar,
- Andreas Schneider,
- Johannes Koenig,
- Sebastian J. Theobald,
- Hsin-Chieh Tsay,
- Angela D.A. Cornelius,
- Agnes Bonifacius,
- Britta Eiz-Vesper,
- Constanca Figueiredo,
- Dirk Schaudien,
- Steven R. Talbot,
- Andre Bleich,
- Loukia M. Spineli,
- Constantin von Kaisenberg,
- Caren Clark,
- Rainer Blasczyk,
- Michael Heuser,
- Arnold Ganser,
- Ulrike Köhl,
- Farzin Farzaneh,
- Renata Stripecke
Affiliations
- Julia K. Bialek-Waldmann
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany; Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Sabine Domning
- Molecular Medicine Group, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, Kings College London, London, UK
- Ruth Esser
- Institute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, Germany
- Wolfgang Glienke
- Institute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, Germany
- Mira Mertens
- Institute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, Germany
- Krasimira Aleksandrova
- Institute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, Germany
- Lubomir Arseniev
- Institute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, Germany
- Suresh Kumar
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany; Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Andreas Schneider
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany; Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Johannes Koenig
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany; Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; German Centre for Infection Research (DZIF), Partner site Hannover, 30625 Hannover, Germany
- Sebastian J. Theobald
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany; Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; German Centre for Infection Research (DZIF), Partner site Hannover, 30625 Hannover, Germany
- Hsin-Chieh Tsay
- Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Angela D.A. Cornelius
- Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Agnes Bonifacius
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany
- Britta Eiz-Vesper
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany
- Constanca Figueiredo
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany
- Dirk Schaudien
- Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
- Steven R. Talbot
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
- Andre Bleich
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
- Loukia M. Spineli
- Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, 30625 Hannover, Germany
- Constantin von Kaisenberg
- Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, 30625 Hannover, Germany
- Caren Clark
- Miltenyi Biotec B.V. & Co. KG, 51429 Bergisch Gladbach, Germany
- Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany
- Michael Heuser
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
- Arnold Ganser
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
- Ulrike Köhl
- Institute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, Germany; Fraunhofer Institute for Cell Therapy and Immunology IZI and University of Leipzig, 04103 Leipzig, Germany
- Farzin Farzaneh
- Molecular Medicine Group, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, Kings College London, London, UK
- Renata Stripecke
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany; Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; German Centre for Infection Research (DZIF), Partner site Hannover, 30625 Hannover, Germany; Corresponding author: Renata Stripecke, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
- Journal volume & issue
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Vol. 21
pp. 621 – 641
Abstract
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.
