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. SpineliConstantin von Kaisenberg, Caren Clark, Rainer Blasczyk, Michael Heuser, Arnold Ganser, Ulrike Köhl, Farzin Farzaneh, Renata Stripecke*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)621-641
Number of pages21
JournalMolecular Therapy - Methods and Clinical Development
Volume21
DOIs
Publication statusPublished - 11 Jun 2021

Keywords

  • automated
  • dendritic cells
  • GMP
  • graft-versus-leukemia
  • immunetherapy
  • lentiviral vectors
  • leukemia
  • stem cell transplantation
  • WT1

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