Regenerative Immune Therapies Applied

Objectives

Reconstitution of the immune system requires the regeneration of adaptive immune responses by professional antigen presenting cells such as dendritic cells (DCs). The development and function of DCs is largely affected due to cancer, latent infections or immune suppressive regimens used for transplantation. Our group combines gene therapy and immunotherapy approaches to develop new “vectored vaccines” and cell therapies to harness the immune regeneration. A new generation of induced dendritic cells (“iDCs”) was developed in our group, which is current in development as an advanced therapy medicinal product. We also investigate the mechanisms of human adaptive responses in vivo using humanized mice transplanted with hematopoietic stem cells. Such models are being explored to test novel human vaccines and immune therapies.

Research Focus

1. Novel lentiviral vector modalities for immune therapeutic vaccines (Excellence Cluster Rebirth)

Approximately 20% of the mononuclear cells in in peripheral blood and cord blood are monocytes. Multicistronic integrase-defective lentiviral vectors (IDLVs) have been evaluated in their capacity to reprogram monocytes into highly viable, potent and disease-specific dendritic cells. Through genetic expression of several complementary cytokines and immune-dominant antigens, new IDLV designs and packaging systems can be used for ex vivo or in vivo delivery of the genetic cargo with the purpose of magnifying multipotent immune responses. This technology has been validated for leukemia, melanoma, hepatitis C virus (HCV) and cytomegalovirus (HCMV).

2. Humanized mouse models with adaptive immune responses (Collaborative Research Center 738, German Center for Infectious Research -DZIF).

We demonstrated that iDCs were applied into NOD/Rag1null/IL2Rγnull (NRG) mice after human CD34+ stem cell transplantation, they accelerated de novo immune reconstitution of functional effector T and mature plasma B cells. We showed reconstitution of lymph nodes, which was associated with human pp65-specific T cell immunity and human antibody responses (IgM and IgG). Humanized mice transplanted with CD34+ stem cells from cord blood (CB) receiving iDCs displayed higher human thymic cell development. Remarkably, despite the presence of mature T cells in humanized mice after PB- and CB-HSCT, we did not observe acute xenograft-versus-host-disease (xGVHD). This suggested that iDCs also participate in tolerance. Thus, these humanized endogenously regenerated systems (“HERS”) recapitulated several clinical aspects of HSCT and have thus a broad application for the understanding of human in vivo immune reconstitution.

In collaboration with Dr. Martin Messerle in CRC738, we use these models to recreate HCMV infection. For development of an adaptive immunotherapy against HCMV, donor-derived monocytes were genetically reprogrammed with a tricistronic self-inactivating integrase defective lentiviral vector that co-expresses GM-CSF and IFN-alpha and HCMV antigens (pp65 for T cell responses and gB for antibody responses). In collaboration with Dr. Wolfgang Hammerschmidt and Dr. Reinhold Zeidler (Helmholtz Centre for Infection, Munich) we will evaluate how infection of humanized mice with Epstein Barr virus (EBV) can be controlled with virus-like particles and monoclonal antibodies.

Good manufacturing practices (GMP) and clinical trial developments (Deutsche Krebshilfe, Else Kroener Fresenius Stiftung, Bundesministerium fuer Bildung und Forschung).

A 2-day production of cryopreserved iDCs as immunotherapeutic vaccine against melanoma and HCMV was validated under GMP-compliant conditions. As a first-in-man advanced immune therapeutic medicinal product (ATMP), iDCs are aimed to promote new repertoire of cellular and antibody responses. The Paul-Ehrlich-Institut, that regulates the approval of clinical trials in Germany, provided us with recommendations for production, quality, non-clinical pharm-tox and clinical study design. Currently, we are preparing a multicenter phase I/IIa clinical trial to immunize leukemia and myeloma patients in Hannover, Würzburg and Heidelberg.

Collaborations

  • Dr. Arnold Ganser (Hem/Onc, MHH), Dr. Ulrike Koehl (IFB-TX, MHH), Dr. Rainer Blasczyk (TM, MHH), Dr. Heiko von der Leyen (HCTC, MHH), Dr. Michael Schmitt (Hem/Onc, Heidelberg) and Dr. Ulrich Grigoleit (Hem/Onc, Wuerzburg): Clinical development of iDCs.
  • Dr. Axel Schambach (Exp. Hematol, MHH) and Dr. Manfred Schmidt (NCT, Heidelberg): Development of novel vectors and insertional analyses by NGS.
  • Dr. Katharina Seewald, Dr. Armin Braun and Dr. Henning Weigt: Pharm-tox analyses using humanized mice.
  • Dr. Martin Messerle (Virol., MHH): Models of HCMV infection.
  • Drs. Wolfgang Hammerschmidt and Reinhard Zeidler (HZI, Munich): Models of EBV infection.
  • Dr. Ralf Gutzmer (Dermat. MHH): Melanoma mouse models and immunetherapies.
  • Prof. Ulrike Koehl (MHH, IFB-TX): Q/C analyses of SmyleDCpp65 for clinical development.
  • Dr. Carlos Guzman (HZI, Braunschweig), Dr. Claudia Waskow (CRTD, Dresden), Dr. Christian Muenz (Immunol, Zuerich): Analyses of T cell development and maturation in humanized mice.
  • Dr. Klaus Kuehlke (EUFETS GmbH): GMP production of lentiviral vectors
  • Dr. Malcolm Brenner and Dr. Cliona Rooney (Baylor, Houston, USA): Immune therapies against hematologic malignancies.

Awards

  • R. Stripecke (PI): 2015 DFG award funding for sabbatical at Baylor College of Medicine.
  • S. Theobald (PhD student): 2015 REGSCI PhD fellowship.
  • D. Queiros (PhD student, Portugal): 2015 DAAD fellowship (REGSCI, MHH).
  • V. Volk (PhD student from Belarus): 2014 DAAD fellowship (ZIB, MHH).
  • C. Deves Roth (post-doc, University of Porto Alegre, past alumni): 2014 fellowship from the Science without Borders from the Brazilian government.
  • C. Govayets (visiting PhD student from Free University Belgium): 2014 fellowship from the Fund for Scientific Research, Belgium.
  • M. Pinho (visiting master student University of Sao Paulo): 2014 fellowship from FAPESP, Brazil.
  • G. Salguero: Medizinische Hochschule Hannover, Hilf career award (2011-2012)

Teaching

  • PhD programme ‘Regenerative Sciences’: Antigen Presenting Cells
  • PhD programme ‘Molecular Medicine’: Viral vectors for gene transfer in vitro and in vivo
  • PhD programme ‘Infectious Biology’: Recombinant vaccines
  • Mentoring programme: Mobility in Science

Equipment and Service Facilities

[Please find a list of all available equipment here]

Publications

[Please find the publications of this workgroup here]

Further Information

www.stripecke-mhh.de

Staff

Stripecke, Renata Prof. Dr. Stripecke.Renata(at)mh-hannover.de
Sundarasetty, Bala Sai Sundarasetty.Bala-Sai(at)mh-hannover.de
Gerasch, Laura Gerasch.Laura(at)mh-hannover.de
Schneider, Andreas Schneider.Andreas(at)mh-hannover.de
Schwarzer, Helmut Schwarzer.Helmut(at)mh-hannover.de
Volk, Valery Volk.Valery(at)mh-hannover.de
Queiros, Debora Queiros.Debora(at)mh-hannover.de
Theobald, Sebastian Theobald.Sebastian(at)mh-hannover.de
Wunschel, Eva Wunschel.Eva(at)mh-hannover.de
Marinkovic, Daniela Marinkovic.Daniela(at)mh-hannover.de