Induced dendritic cells co-expressing GM-CSF/IFN-α/tWT1 priming T and B cells and automated manufacturing to boost GvL

Molecular Therapy: Methods & Clinical Development

Dirk Schaudien¹  Loukia M. Spineli¹  Agnes Bonifacius²  Constanca Figueiredo²  Sabine Domning²  Hsin-Chieh Tsay²  Andre Bleich²  Mira Mertens³  Wolfgang Glienke⁴  Julia K. Bialek-Waldmann⁵  Angela D.A. Cornelius⁵  Steven R. Talbot⁵  Britta Eiz-Vesper⁵  Sebastian J. Theobald⁵  Ulrike Köhl⁶  Farzin Farzaneh⁷  Renata Stripecke⁷  Johannes Koenig⁸  Krasimira Aleksandrova⁸  Lubomir Arseniev⁸  Andreas Schneider⁸  Suresh Kumar⁸  Michael Heuser⁹  Arnold Ganser⁹  Rainer Blasczyk⁹  Constantin von Kaisenberg^1,10  Caren Clark^1,10  Ruth Esser^1,11 

[1] German Centre for Infection Research (DZIF), Partner site Hannover, 30625 Hannover, Germany;Laboratory of Regenerative Immune Therapies Applied, REBIRTH−Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany;Medicine, Kings College London, London, UK;;Pharmaceutical Sciences, Faculty of Life Sciences &Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany;Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany;Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany;Institute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, Germany;Institute of Transfusion Medicine and Transplant Engineering, 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;;Molecular Medicine Group, School of Cancer &

关键词: dendritic cells;    lentiviral vectors;    leukemia;    WT1;    stem cell transplantation;    immunetherapy;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown