• BCRT

Gene Editing for Cell Therapy

Dimitrios L. Wagner

Gene editing and synthetic biology: developing cell therapies for diseases with high unmet medical need.

[Translate to englisch:]

Dimitrios Laurin Wagner

Address:
Charité – Universitätsmedizin Berlin
BIH Center for Regenerative Therapies
Augustenburger Platz 1
13353 Berlin
Telefon:+49 (0)30 450 524 205
E-Mail: [email protected]


Chronic diseases such as cancer and autoimmune diseases place a heavy burden on patients and the healthcare system. Long-term treatment with drugs with unspecific effects can also lead to serious side effects. Novel cell therapies allow us to exploit the potent properties of the body's own cells and to enable long-term and profound treatment successes by means of "living drugs". One example is CAR-T cell therapy, in which the body's own immune cells called T lymphocytes are equipped with artificial cancer-specific recognition receptors (Chimeric Antigen Receptors: CAR) to detect and eliminate blood cancer cells in the patient’s body.

Our junior research group develops platform technologies to design the genetic identity of cells and use it to solve medical problems. Here we focus on improving the latest gene editing technologies from basic research and try to optimize them for clinical application. The goal is to improve the properties of cell products and simplify production to reduce costs and improve access to these promising therapies for patients.

Currently, we are focusing on CRISPR-Cas-based methods that avoid viruses for gene delivery and instead use synthetic nucleic acids and recombinant proteins. By combining synthetic reagents with physical or chemical delivery modalities, we aim to develop safe and efficient techniques for the next generation of novel and effective cell therapies in Berlin.

In addition, we are interested in the immunological aspects that influence the efficiency and safety of cell and gene therapies in the patient's body. Among other things, we want to find out whether and how immune cells from healthy donors can be used for cell therapy of sick people. Our medium-term goal is to develop so-called "off-the-shelf" cell therapies, which are produced from material from healthy people and can thus be used for the rapid and safe treatment of many patients from a single manufacturing run.

-

  • Publications

    Gene editing and immune cell therapies

    • Fast, efficient and virus-free generation of TRAC-replaced CAR T cells. Kath J, Du W, Thommandru B, Turk R, Amini L, Stein M, Zittel T, Martini S, Ostendorf L, Wilhelm A, Akyüz L, Rehm A, Höpken UE, Pruß A, Künkele A, Jacobi AM, Volk HD, Schmueck-Henneresse M, Reinke P, Wagner DL. BioRxiv (preprint) 2021

    We show that virus-free gene editing enables efficient generation of TCR-replaced CAR T cells. Different drug cocktails can be used to improve CAR-T cells yield.

    • CRISPR-Cas-edited Tacrolimus-resistant antiviral T-cells for advanced adoptive immunotherapy in transplant recipients. Amini L, Wagner DL, Rössler U, Vollmer T, Wendering DJ, Wagner LF, Kornak U, Volk HD, Reinke P, Schmueck-Henneresse M. Molecular Therapy 2021, PMID: 32956624
      In this study, we used CRISPR-Cas mediated gene disruption to make virus-specific T cells resistant to the immunosuppressive drug Tacrolimus; thereby giving these T cells an improved chance to clear viruses and persist in patients receiving immunosuppressive drugs after solid organ transplantation.
    • Super-Treg: toward a new era of adoptive Treg therapy enabled by genetic modifications.Amini L, Greig J, Schmueck-Henneresse M, Volk HD, Bézie S, Reinke P Guillonneau, Wagner DL*, Anegon I*. Frontiers in Immunology 2020 (* shared senior authorship)
      Together with our collaborators from Nantes/France, we sketch how regulatory T cells can be genetically engineered to create cutting-edge therapies for autoimmune diseases.
    • CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, Rouce RH, Bao G, Brenner MK, Mamonkin M. Blood 2017, PMID: 28539325
      First demonstration that CRISPR-Cas gene editing can be used to facilitate a novel CAR T cell therapy which may be used to treat T-cell lymphoma/leukemia.
    • Highly Efficient Genome Editing of Murine and Human Hematopoietic Progenitor Cells by CRISPR/Cas9. Gundry MC, Brunetti L, Lin A, ... , Wagner D, … PMID: 27783956
      This study shows that electroporation of CRISPR-Cas ribonucleoproteins allows highly efficient gene editing in blood cells, including T cells. First study to show CRISPR-Cas nucleoproteins can induce off-targets in T cells, therefore calling for careful design and translation for clinical applications.

    Immune responses to cell and gene therapies

    • Immunogenicity of CAR T cells in cancer therapy, Wagner DL, Fritsche E. et al. Nature Reviews Clinical Oncology 2021, PMID: 33633361
      Together with many leading scientists in the CAR-T cell field, we review our current knowledge on anti-CAR immune responses in patients and outline strategies how they can be mitigated to improve autologous/allogeneic CAR T cell therapy.

    High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population Wagner DL, Amini L, Wendering DJ, Burkhardt L-M, Akyüz L, Reinke P, Volk HD, Schmueck-Henneresse M. Nature Medicine 2019; PMID: 30374197
    Our landmark study finds that most humans have T cells which can recognize the Cas9-protein and these anti-Cas9 T cells may impact the efficacy and safety of CRISPR-Cas in vivo gene therapies.

  • Funding

    Horizon Europe project ‘geneTIGA’

    David and Etta Jonas Center for Cellular Therapy

    University of Chicago

    SPARK-BIH project ‘A modular NK cell platform that targets cancer and its suppressive microenvironment’

    Horizon 2020 project 'RESHAPE'

    SPARK-BIH project ‘Next-generation CAR Therapeutics’

    BIH-Regeneration Crossfield Grant ‘Genome Engineering’

    Einstein Center for Regenerative Therapies – Kickbox Grants

  • Team

    Dimitrios L. Wagner, M.D. / Ph.D, group leader

    Lily Jo Becker, undergrad student / research assistant

    Christian Luca Flugel, MD student

    Viktor Glaser, PhD student (assoziiertes Gruppenmitglied)

    Luis Huth, undergrad student / research assistant

    Isabell Kassing, undergrad student  (research assistant)

    Jonas Kath, MD, PhD student

    Ana-Maria Nitulescu, PhD student

    Yaolin Pu, PhD student

    Maik Stein, Dipl. Ing. (assoziiertes Gruppenmitglied)