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Gene and RNA Therapy Center (GRTC)

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Address: Otfried-Müller-Straße 10
72076 Tübingen

Founding Director

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Prof. Dr. Julia Skokowa

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Scientific coordinator

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Dr. Olga Klimenkova

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AG Lengerke

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Prof. Dr. Claudia Lengerke, PI

Internal Medicine II - Haematology, Oncology, Clinical Immunology and Rheumatology

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Improving allogeneic hematopoietic stem cell transplantations and cellular immunotherapies

The lab of Claudia Lengerke is employing genetic engineering to improve allogeneic hematopoietic stem cell transplantation (alloHSCT) outcomes and cellular immunotherapies

  • A major cause of death in acute myeloid leukemia (AML) is progression and relapse emerging from persistent therapy-resistant leukemic cells with stem cell characteristics. These so-called leukemic stem cells (LSC) presumably compete with healthy hematopoietic stem cells (HSCs) for the occupancy of protective bone marrow niches. Wnt signaling is critical during HSC development (Lengerke et al., Cell Stem Cell 2008) and a dominant factor governing stem cell self-renewal and the maintenance of adult HSCs (Luis et al., Cell Stem Cell 2011). Interestingly, dose dependent effects have been shown for canonical Wnt signaling in HSCs, with only mildly increased Wnt signaling levels (2-fold) mediating increased fitness (Luis et al., Cell Stem Cell 2011).
    Funded by an ERC Consolidator Grant to Claudia Lengerke, we seek to explore whether improving healthy HSC fitness and niche affinity can prevent LSCs from occupying niche space and thereby impact their ability to resist therapies and induce relapse. We propose to engineer healthy human HSCs with 2-fold canonical WNT induction by introducing a heterozygous APC knockout using CRISPR/Cas9 technology. We hypothesize that (1) these enhanced WNT levels will improve HSC fitness and transplantation results and that (2) such HSCs can better resist the expansion of AML cells in bone marrow niches, and that thereby their use for transplant therapies will improve therapy responses and outcome in patients with AML. This hypothesis is supported by preliminary data of our group showing that in vivo stimulation of canonical Wnt signaling with LiCl treatment impairs leukemogenesis.
    Major contact persons: Dr. Saskia Rudat
  • Previous data of our group shows that poly-ADP-ribose polymerase 1 (PARP1) represses the expression of NKG2D-ligands (NKG2DL) on the surface of LSCs (Paczulla et al., Nature 2019). Genetic or pharmacologic inhibition of PARP1 induces NKG2DLs specifically on LSCs but not on healthy or pre-leukemic cells. Due to the re-expression of NKG2DL on their surface, LSCs become targetable by the immune system.
    We plan to generate tailored chimeric antigen receptor (CAR) NK cells with an NKG2D-CAR at their surface. The administration of NKG2D-CAR-NK cells, as cellular therapy, combined with the PARP1-inhibition is expected to further enhance the clearance of LSCs.
    Major contact persons: Dr. Saskia Rudat, Dr. Luca Hensen
  • After their infusion, we will follow engineered cells in patients to explore their clonal and phenotypic architecture over time, and to investigate their influence on the cytokine milieu, niches, tumor cell persistence and the endogenous non-transplanted immune system.
    Major contact persons: Dr. Anna Stanger, Dr. Luca Hensen

GRT projects

  1. Increasing the fitness of HSCs by genetic engineering to improve transplant outcome in AML.
  2. Engineering CAR-NK cells for the targeting of NKG2DL cancer cells.
  3. Long-term in vivo follow-up of engineered cells applied as cellular products and analysis of their effects on the endogenous immune system.

 

GRT expertise

  • Clinical trials and GMP-grade production of cell therapy products
  • LSC and HSC biology and function
  • Proof-of-principle preclinical models in syngeneic and patient-derived xenograft (PDX) mouse models

 

Main GRT methods applied in the lab

  • CRISPR/Cas9 technology and screening approaches
  • Retroviral and lentiviral transduction methods
  • Tailored CAR-T/NK cell production


Clinical trials

  • Phase I/II dose finding and efficacy study of MB-CART-CD19/CD22 in patients with advanced lymphatic malignancies (IIT, AKF MF Tübingen)
  • Natural Killer Cell immunotherapy in combination with PARP-inhibition to overcome NKG2D mediated immune evasion in Acute Myeloid Leukemia (NAKIP-AML, NCT Heidelberg)


Funding

  • DKTK Joint Funding Program: Treatment of acute myeloid leukemia by combining azacitidine with non-virally engineered CLEC12A-targeting CAR-NK cells (NoviCARAZA, 2023 - 2026)
  • European Research Council (ERC): Targeting leukemia by modulating hematopoietic stem cell competitiveness (HemStem, 2021 - 2026)
  • DKTK Joint Funding Program: Risk prediction and overcoming therapy resistance in AML (RiskY-AML, 2021 - 2023)
  • Deutsche Krebshilfe: Arming natural killer cells for immunotherapy against acute myeloid leukemia (NK fit against AML, 2021 - 2023)
  • Fortüne Junior Research Group Leader Program to Dr. Anna Stanger: Investigation of anti-BCMA immunotherapy options in multiple myeloma (2022-2024)



Publications

  • Dannenmann B, Klimiankou M, Oswald B, Solovyeva A, Mardan J, Nasri M, Ritter M, Zahabi A, Arreba-Tutusaus P, Mir P, Stein F, Lachmann N, Moritz T, Morishima T, Konantz M, Lengerke C, Ripperger T, Steinemann D, Erlacher M, Niemeyer C, Zeidler K, Welte K, and Skokowa J. Hipsc model of stage-specific leukemogenesis in severe congenital neutropenia reveals baalc as a key oncogene. Cell Stem Cell 2021; 28(5): 906-22.
  • Schürch C, Schaefer T, Müller JS, Hanns P, Arnone M, Dumlin A, Schärer J, Sinning I, Wild K, Skokowa J, Welte K, Carapito R, Bahram S, Konantz M, Lengerke C. SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing. Blood 2020; 137(10): 1340-52.
  • Paczulla AM*, Rothfelder K*, Raffel S*, Konantz M, Steinbacher J, Wang H, Tandler C, Mbarga M, Schaefer T, Falcone M, Nievergall E, Dörfel D, Hanns P, Passweg JR, Lutz C, Schwaller J, Zeiser R, Blazar BR, Caligiuri MA, Dirnhofer S, Lundberg P, Kanz L, Quintanilla-Martínez L, Steinle A, Trumpp A*, Salih HR*, Lengerke C*. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 2019; 572(7768): 254-9.
  • Carapito R, Konantz M, Paillard C, Miao Z, Pichot A, Leduc MS, Yang Y, Bergstrom KL, Mahoney DH, Shardy DL, Alsaleh G, Naegely L, Kolmer A, Paul N, Hanauer A, Rolli V, Müller JS, Alghisi E, Sauteur L, Macquin C, Morlon A, Sancho CS, Amati-Bonneau P, Procaccio V, Mosca-Boidron AL, Marle N, Osmani N, Lefebvre O, Goetz JG, Unal S, Akarsu NA, Radosavljevic M, Chenard MP, Rialland F, Grain A, Béné MC, Eveillard M, Vincent M, Guy J, Faivre L, Thauvin-Robinet C, Thevenon J, Myers K, Fleming MD, Shimamura A, Bottollier-Lemallaz E, Westhof E, Lengerke C*, Isidor B*, Bahram S*. Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features. J Clin Invest 2017; 127(11): 4090-103.
  • Paczulla AM, Dirnhofer S, Konantz M, Medinger M, Salih HR, Rothfelder K, Tsakiris DA, Passweg JR, Lundberg P, Lengerke C. Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice. Haematologica 2017; 102(5): 854-64.
  • Konantz M, Alghisi E, Müller JS, Lenard A, Esain V, Carroll KJ, Kanz L, North TE, Lengerke C. Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence. EMBO J. 2016; 35(21): 2315-31.
  • Paczulla AM*, Bareiss PM*, Wang H, Schairer R, Wiehr S, Kohlhofer U, Rothfuss OC, Fischer A, Perner S, Staebler A, Wallwiener D, Fend F, Fehm T, Pichler B, Kanz L, Quintanilla-Martínez L, Schulze-Osthoff K, Essmann F, Lengerke C. SOX2 expression associates with stem cell state in human ovarian carcinoma. Cancer Res 2013; 73(17): 5544-55.
  • McKinney-Freeman S, Cahan P, Li H, Lacadie SA, Huang HT, Curran M, Loewer S, Naveiras O, Kathrein KL, Konantz M, Langdon EM, Lengerke C, Zon LI, Collins JJ, Daley GQ. The transcriptional landscape of hematopoietic stem cell ontogeny. Cell Stem Cell. 2012; 11(5): 701-14.
  • Lengerke C, Schmitt S, Bowman TV, Jang IH, Maouche-Chretien L, McKinney-Freeman S, Davidson AJ, Hammerschmidt M, Rentzsch F, Green JB, Zon LI, Daley GQ. BMP and Wnt specify hematopoietic stem cell fate by activation of the Cdx-Hox pathway. Cell Stem Cell 2008; 2(1): 72-8
  • Kim K, Lerou P, Yabuuchi A, Lengerke C, Ng K, West J, Kirby A, Daly MJ, Daley GQ. Histocompatible embryonic stem cells by parthenogenesis. Science 2007; 315(5811): 482-6.

*equal contribution

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