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Projects

Projects

The scientific research is structurally divided into two project areas:

Project area A: Strengthening GvL effects

Project area B: Prevention and treatment of GvHD.

This division has proven to be successful and constructive. Collaborative activities between the project areas have transformed the TRR 221 into a tight network in which it is clearly recognized that each GvL-modulating strategy must take into account its influence on GvHD (and vice versa). 

What are A-Projects?

Research projects that focus on the amplification of the graft-versus-leukemia (GvL) effect are grouped as A-projects. Briefly, they explore T cell redirection tools (i.e. T cell receptors (TCRs; A01), chimeric antigen receptors (CARs; A02, A03), tri-specific antibodies (A04) for the enhancement of hematopoiesis-restricted GvL activity and examine the reactivation of silenced GvL responses through improved functional and reproductive „fitness“ of donor immune cells. The latter approaches include the amelioration of metabolic stress (A06), the transfer of T memory stem cells (A07) and the co-activation of innate nucleic acid receptor pathways (A08).

Whats is Project B

Prevention and treatment of GvHD by targeting cell signaling and metabolic pathways, by strengthening immune regulatory networks and by modulating GvHD-promoting co- factors The B-projects focus on the investigation of cell signaling and metabolic pathways (B02-04, B12, B14), immune regulatory/suppressive cells and networks in acute and chronic GvHD (B01, B07- B10, B15) and GvHD-promoting co-factors (B11-B13, B15). Based on their pathophysiological findings, they aim to develop and/or advance novel immunomodulatory strategies for effective prophylaxis and therapy of severe GvHD.  

Taken together, the B-projects tackle the GvHD problem from different angles with the aim to jointly develop innovative complementary or synergistic strategies. The coordinated time- and event-driven biopsy program on gut GvHD in Regensburg provides several B-projects with clinical samples and data of patients for research analyses. All PIs have proven unrestricted willingness to share their expertise, models, technologies and reagents with all other investigators. Promising strategies in GvL projects have been evaluated with respect to their influence on GvHD by the cooperating partners (and vice versa) and all participating institutions supported translational studies evolving from the TRR 221 projects (e.g. B01, B07, B10, B13, MAGIC trial).

Whats is Service Project

Information Infrastructure Project (INF), Service Projects (Z), and Integrated Research Training Group (IRTG) The A/B projects have been strongly supported by the newly established INF project (T. Dandekar, E. Holler, B. Kehr, M. Kunz) that provides the data infrastructure backbone, supporting large-scale omics, imaging, and clinical data. The INF PIs have developed a bioinformatics and data management platform, enabling mechanistic insights into GvHD and GvL immune responses and supporting translational and educational activities. Their broad and diverse expert knowledge was invaluable and contributed significantly to several TRR 221 publications (e.g., INF, refs. 1,10,23). As an outstanding INF achievement the clinical data integration system (DIS) BITCARE has been established at all three sites. Indispensable service was also provided by the pathology project Z01 (M. B¸ttner-Herold, M. Evert, A. Rosenwald), that performs the coordinated sampling and processing of human and murine tissues at each site and employs standardized consensus diagnosis and grading of experimental and human GvHD. The latter has been clearly improved by the TRR 221 owned virtual pathology platform and online CaseCentre (Sysmex/HP), that are both used to jointly evaluate digitized GvHD cases across sites. The project leaders conducted a Round Robin test on human colonic GvHD biopsies to ensure harmonization of the diagnostic approach by the involved pathologists (Z01, ref. 1). A variety of tissue-based histochemical, immunohistochemical, ultrastructural and molecular methods were performed as requested by TRR 221 projects (e.g., refs. 6,7). Service project Z02 by P. Hoffmann, T. Winkler, and A. Beilhack supports the A/B-projects by the generation and cross-breeding of numerous genetically modified mouse strains (e.g. loxP flank in Klf6 gene for conditional deleter mice, IL3 & Csf2 knockout mice, and novel split-cre mice for specific deletion of target genes by a combinatorial expression of the cre recombinase) and assists the projects on-site in the performance of complex mouse ASCT experiments and the conduction of sophisticated in vivo and ex vivo imaging studies. To study the role of the intestinal microbiome in ASCT, Z02 utilizes the proprietary germfree (GF) mouse facility in Regensburg and has performed several ASCT experiments investigating the course of GvHD under GF conditions in coop with B07, B03, B09, and B12. Moreover, a central human biomaterial repository supported by Z03 funds collected samples from hematologic neoplasias, which were provided to A/B-projects as required. To advance ASCT, talented early career researchers (ECRs) require training in their specific field as well as in the basic biology and clinical problems of ASCT. For this purpose, PIs M. Edinger, A. Kremer and F. Berberich-Siebelt further developed and strengthened the cross-site IRTG for doctoral students (PhD, MD) and for MDs (Dr. med.). All IRTG students are enrolled in local graduate programs and the IRTG focuses on complementary ASCT training modules detailed in the IRTG chapter. The joined training of doctoral candidates in medicine (Dr. med.) and natural sciences (Dr. rer. nat./PhD) as well as human biology (Dr. rer. biol. hum./Dr. rer. physiol.) has fostered the 14General information interdisciplinary cooperation and exchange of ideas between scientists and physicians to bridge the gap between laboratory and clinical research. During the 2nd FP, TRR 221 project leaders published 139 peer-reviewed publications on TRR specific topics (w/o reviews and clinical studies; only first and last authorships counted), of which 81 publications list project leaders of at least two different TRR projects as authors (evaluation period: 01/2022 to 04/2025; see also Fig. 3, cooperation array). Of these joint publications, 23 include project leaders from two and 9 from three TRR sites, respectively. Many more joint manuscripts are currently submitted for publication or are in preparation. Notably, joint publications (i.e., from at least two different projects) in the 1st FP (evaluation period: 01/2018 to 07/2021) were 74, of which 12 included project leaders from two and 3 from three TRR 221 sites (as detailed in our last proposal). This strong increase of joint cross-site publications from the 1st to 2nd FP clearly demonstrates that the TRR 221 has evolved into a strongly interacting and intensely collaborating research consortium during the first two FPs.

Project A01

Deciphering the role of HLA-DO in immune responses after allogeneic stem cell transplantation.
Site: Erlangen
Principal Investigator: Dr. rer. nat. Hannah Reimann, PD Dr. Dr. med. Anita Kremer, Ph.D.

Induction of the graft-versus-leukemia (GvL) effect in the absence of graft-versus-host disease (GvHD) by CD4+ T-cells directed against DM-sensitive antigens will be tested in murine models of allogeneic bone marrow transplantation both in a minor and a major mismatch setting. Using H2-O (murine HLA-DO) knock-out and transgenic mice as well as wild type mice as recipient strains will allow us to determine the role of the tissue-specific expression of H2-O for induction of GvL effect and GvHD. In addition, we aim to unravel regulation of HLA-DO expression in human cells. Finally, we will test effects of HLA-DO regulators on GvL effect and GvHD.

1. Kretschmann S, Herda S, Bruns H, Russ J, van der Meijden ED, Schlotzer-Schrehardt U, Griffioen M, Na IK, Mackensen A, Kremer AN. Chaperone protein HSC70 regulates intercellular transfer of Y chromosome antigen DBY. J Clin Invest 2019;129(7):2952-63. doi:10.1172/JCI123105.

2. Kremer AN, van der Meijden ED, Honders MW, Goeman JJ, Wiertz EJ, Falkenburg JH, Griffioen M. Endogenous HLA class II epitopes that are immunogenic in vivo show distinct behavior toward HLA-DM and its natural inhibitor HLA-DO. Blood 2012;120(16):3246-55. doi:10.1182/blood-2011-12-399311.

3. Kremer AN, van der Meijden ED, Honders MW, Pont MJ, Goeman JJ, Falkenburg JH, Griffioen M. Human leukocyte antigen-DO regulates surface presentation of human leukocyte antigen class II-restricted antigens on B cell malignancies. Biol Blood Marrow Transplant 2014; 20(5):742-7. doi:10.1016/j.bbmt.2014.02.005.

4. Bernhardt AL*, Zeun J*, Marecek M*, Reimann H, Kretschmann S, Bausenwein J, van der Meijden ED, Karg MM, Haug T, Meintker L, Lutzny-Geier G, Mackensen A, Kremer AN. Influence of DM-sensitivity on immunogenicity of MHC class II restricted antigens. J Immunother Cancer 2021;9(7):e002401. doi: 10.1136/jitc-2021-002401.

5. Zeun J, Bernhardt AL, Neubeck S, Lang V, Korn K, Nagel L, Kunert T, Brey S, Atreya I, Denzin L, Bäuerle T, Hidner K, Büttner-Herold M, Winkler T, Mackensen A, Reimann H*, Kremer AN*. Selective H2-O tissue expression reduces risk for graft-versus-host disease in an in vivo transplantation model. Transpl Cell Therapy 2025; accepted

6. Mackensen A*, Muller F*, Mougiakakos D*, Boltz S, Wilhelm A, Aigner M, Völkl S, Simon D, Kleyer A, Munoz L, Kretschmann S, Kharboutli S, Gary R, Reimann H, Rosler W, Uderhardt S, Bang H, Herrmann M, Ekici AB, Buettner C, Habenicht KM, Winkler TH, Kronke G*, Schett G*. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 2022;28(10):2124-32. doi:10.1038/s41591-022-02017-5.

7. Müller F*, Taubmann J*, Bucci L, Wilhelm A, Bergmann C, Völkl S, Aigner M, Rothe T, Minopoulou I, Tur C, Knitza J, Kharboutli S, Kretschmann S, Vasova I, Spoerl S, Reimann H, Munoz L, Gerlach RG, Schäfer S, Grieshaber-Bouyer R, Korganow AS, Farge-Bancel D, Mougiakakos D, Bozec A, Winkler T, Krönke G, Mackensen A*, Schett G*. CD19 CAR T-Cell Therapy in Autoimmune Disease – A Case Series with Follow-up. N Engl J Med 2024;390(8):687-700. doi:10.1056/NEJMoa2308917.

8. Kretschmann S*, Völkl S*, Reimann H, Krönke G, Schett G, Achenbach S, Lutzny-Geier G, Müller F, Mougiakakos D, Dingfelder J, Flamann C, Hanssens L, Gary R, Mackensen A, Aigner M. Successful generation of CD19 chimeric antigen receptor (CAR) T cells from patients with advanced Systemic Lupus Erythematosus (SLE). Transplant Cell Ther 2023;29(1):27-33. doi: 10.1016/j.jtct.2022.10.004.

9. Reimann H, Moosmann C, Schober K, Lang V, Verhagen J, Zeun J, Mackensen A, Kremer AN, Völkl S, Aigner M. Identification and characterization of T-cell receptors with therapeutic potential showing conserved specificity against all SARS-CoV 2 strains. Immunobiology 2023;228(5):152720. doi:10.1016/j.imbio.2023.152720.

10. Reimann H*, Nguyen A*, Sanborn JZ, Vaske CJ, Benz SC, Niazi K, Rabizadeh S, Spilman P, Mackensen A, Ruebner M, Hein A, Beckmann MW, van der Meijden ED, Bausenwein J, Kretschmann S, Griffioen M, Schlom J, Gulley JL, Lee KL, Hamilton DH, Soon-Shiong P, Fasching PA*, Kremer AN*. Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy. J Immunother Cancer 2021; 9(6):e002605. doi: 10.1136/jitc-2021-002605.

  • Dr. rer. nat. Hannah Reimann
    Universitätsklinikum Erlangen
    Medizinische Klinik 5
    Hartmannstraße 14
    91052 Erlangen
    T: 09131 85-36287
    hannah.reimann(at)uk-erlangen.de
  • PD Dr. Dr. med. Anita Kremer, Ph.D.
    Universitätsklinikum Erlangen
    Medizinische Klinik 5
    Ulmenweg 18
    91054 Erlangen
    T: 09131 85-43183
    anita.kremer(at)uk-erlangen.de

Project A02

Efficacy and safety of HLA-DPB1-specific T cell receptors as mediators of graft-versus-leukemia effect.
Site: Regensburg
Principal Investigators: Prof. Dr. med. Simone Thomas, Prof. Dr. med. Wolfgang Herr

HLA-DPB1 mismatch antigens occur in allogeneic HSCT from unrelated donors and represent powerful leukemia rejections antigens, which can be efficiently targeted by T cells that have been genetically reprogrammed with allo-HLA-DPB1 specific T-cell receptors (TCR-DP). In this project we will develop an approach that allows for efficient and safe TCR-DP gene therapy in allogeneic HSCT. Special emphasis will be placed on the prevention of treatment-induced HLA-DP-specific alloreactivity to non-hematopoietic tissues (e.g. by „ON-Switch“ TCR or TCR-RNA transfer) and on the development of a novel humanized mouse model that enables the pre-clinical testing of this approach.

  1. Jetani H, Garcia-Cadenas I, Nerreter T, Thomas S, Rydzek J, Meijide JB, Bonig H, Herr W, Sierra J, Einsele H, Hudecek M. CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia 2018;32(5):1168-79. doi:10.1038/s41375-018-0009-0.
  2. Herr W*, Eichinger Y*, Beshay J*, Bloetz A*, Vatter S, Mirbeth C, Distler E, Hartwig UF, Thomas S. HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation. Leukemia 2017;31(2):434-45. doi:10.1038/leu.2016.210.
  3. Klobuch S, Hammon K, Vatter-Leising S, Neidlinger E, Zwerger M, Wandel A, Neuber LM, Heilmeier B, Fichtner R, Mirbeth C, Herr W, Thomas S. HLA-DPB1 Reactive T Cell Receptors for Adoptive Immunotherapy in Allogeneic Stem Cell Transplantation. Cells 2020;9(5):1264. doi:10.3390/cells9051264.
  4. Hammon K*, Renner K*, Althammer M, Voll F, Babl N, Decking S-M, Siska PJ, Matos C, Conejo ZEC, Mendes K, Einwag F, Siegmund H, Iberl S, Berger RS, Dettmer K, Schoenmehl R, Brochhausen C, Herr W, Oefner PJ, Rehli M, Thomas S*, Kreutz M*. D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells. Haematologica 2024;109(8):2500-14. doi:10.3324/haematol.2023.283597.
  5. Seitz CM, Mittelstaet J, Atar D, Hau J, Reiter S, Illi C, Kieble V, Engert F, Drees B, Bender G, Krahl A-C, Knopf P, Schroeder S, Paulsen N, Rokhvarguer A, Scheuermann S, Rapp E, Mast AS, Rabsteyn A, Schleicher S, Grote S, Schilbach K, Kneilling M, Pichler B, Lock D, Kotter B, Dapa S, Miltenyi S, Kaiser A, Lang P, Handgretinger R*, Schlegel P*. Novel adapter CAR-T cell technology for precisely controllable multiplex cancer targeting. Oncoimmunology 2021;10(1):2003532. doi:10.1080/2162402X.2021.2003532.
  6. Atar D, Mast AS, Scheuermann S, Ruoff L, Seitz CM, Schlegel P. Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas. Biomedicines 2022;10(10);2420. doi:10.3390/biomedicines10102420.
  7. Atar D, Ruoff L, Mast AS, Krost S, Moustafa-Oglou M, Scheuermann S, Kristmann B, Feige M, Canak A, Wolsing K, Schlager L, Schilbach K, Zekri L, Ebinger M, Nixdorf D, Subklewe M, Schulte J, Lengerke C, Jeremias I, Werchau N, Mittelstaet J, Lang P, Handgretinger R, Schlegel P, Seitz CM. Rational combinatorial targeting by adapter CAR-T-cells (AdCAR-T) prevents antigen escape in acute myeloid leukemia. Leukemia 2024;38(10):2183-95. doi:10.1038/s41375-024-02351-2.
  8. Wehler TC, Nonn M, Brandt B, Britten CM, Gröne M, Todorova M, Link I, Khan SA, Meyer RG, Huber C, Hartwig UF, Herr W. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 2007;109(1):365-73. doi:10.1182/blood-2006-04-014100.
  9. Distler E, Wölfel C, Köhler S, Nonn M, Kaus N, Schnürer E, Meyer RG, Wehler TC, Huber C, Wölfel T, Hartwig UF, Herr W. Acute myeloid leukemia (AML)-reactive cytotoxic T lymphocyte clones rapidly expanded from CD8(+) CD62L((high)+) T cells of healthy donors prevent AML engraftment in NOD/SCID IL2Rgamma(null) mice. Exp Hematol 2008;36(4):451-63. doi:10.1016/j.exphem.2007.12.011.
  10. Thomas S, Klobuch S, Sommer M, van Ewijk R, Theobald M, Meyer RG, Herr W. Human CD8+ memory and EBV-specific T cells show low alloreactivity in vitro and in CD34+ stem cell-engrafted NOD/SCID/IL-2Rγc null mice. Exp Hematol 2014;42(1):28-38.e1-2. doi:10.1016/j.exphem.2013.09.013.
  • Prof. Dr. med. Simone Thomas
    LIT – Leibniz Institute for Immunotherapy (former RCI)
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5501
    simone.thomas(at)ukr.de
  • Prof. Dr. med. Wolfgang Herr
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5142
    wolfgang.herr(at)ukr.de

Project A03

Advanced CAR T cell engineering to augment the graft-versus-leukemia effect of allogeneic HSCT.
Site: Würzburg
Principal Investigators: Prof. Dr. med. Michael Hudecek, Prof. Dr. med. Hermann Einsele

In this project, we apply the chimeric antigen receptor (CAR) technology to augment the GvL effect of HSCT. CARs are synthetic designer receptors that redirect the specificity of T cells to recognize malignant cells. We will pursue two novel CAR targets, i.e. FLT3 in acute myeloid leukemia and SLAMF7 in multiple myeloma, and apply cutting-edge strategies to increase their efficacy (e.g. through metabolic arming) and safety (e.g. with enhanced suicide genes). To avoid GvHD, we will generate CMV-specific (endogenous TCR) CAR-T cells and employ novel in vivo models to evaluate their ability to concomitantly battle against leukemia/myeloma and CMV infection.

 

  1. Roex MCJ, van Balen P, Germeroth L, Hageman L, van Egmond E, Veld SAJ,

       Hoogstraten C, van Liempt E, Zwaginga JJ, Wreede LC, Meij P, Vossen ACTM, Danhof S, Einsele H, Schaafsma MR, Veelken H, Halkes CJM, Jedema I, Falkenburg JHF. Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation-a phase I/II study. Leukemia 2020;34(3):831-44. doi:10.1038/s41375-019-0600-z. 

  1. San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, Fernández de 

Larrea C, Martínez-López J, Moreau P, Touzeau C, Leleu X, Avivi I, Cavo M, Ishida T, Kim SJ, Roeloffzen W, van de Donk NWCJ, Dytfeld D, Sidana S, Costa LJ, Oriol A, Popat R, Khan AM, Cohen YC, Ho PJ, Griffin J, Lendvai N, Lonardi C, Slaughter A, Schecter JM, Jackson CC, Connors K, Li K, Zudaire E, Chen D, Gilbert J, Yeh TM, Nagle S, Florendo E, Pacaud L, Patel N, Harrison SJ, Einsele H*. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med 2023;389(4):335-47. doi:10.1056/NEJMoa2303379. 

  1. García-Guerrero E, Rodríguez-Lobato LG, Sierro-Martínez B, Danhof S, Bates S, Frenz

       S, Haertle L, Götz R, Sauer M, Rasche L, Kortüm KM, Pérez-Simón JA, Einsele H, Hudecek M, Prommersberger SR. All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells. Haematologica 2023;108(2):568-80. doi:10.3324/haematol.2022.281339. 

  1. Vera-Cruz S, Jornet Culubret M, Konetzki V, Alb M, Friedel SR, Hudecek M, Einsele H,

       Danhof S, Scheller L. Cellular Therapies for Multiple Myeloma: Engineering Hope. Cancers (Basel) 2024;16(22):3867. doi: 10.3390/cancers16223867. 

  1. Gogishvili T, Danhof S, Prommersberger S, Rydzek J, Schreder M, Brede C, Einsele H, Hudecek M*. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes. Blood 2017;130(26):2838-47. doi:10.1182/blood-2017-04-778423.
  2. Jetani H, Garcia-Cadenas I, Nerreter T, Thomas S, Rydzek J, Meijide JB, Bonig H, Herr W, Sierra J, Einsele H, Hudecek M*. CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia 2018;32(5):1168-79. doi:10.1038/s41375-018-0009-0.
  3. Mestermann K, Giavridis T, Weber J, Rydzek J, Frenz S, Nerreter T, Mades A, Sadelain M, Einsele H, Hudecek M*. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med 2019;11(499):eaau5907. doi:10.1126/scitranslmed.aau5907.
  4. Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, Klein M, Wempe A,

  Leister H, Raifer H, Picard F, Muhammad K, Ohl K, Romero R, Fischer F, Bauer CA, Huber M, Gress TM, Lauth M, Danhof S, Bopp T, Nerreter T, Mulder IE, Steinhoff U, Hudecek M, Visekruna A. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun 2021;12(1):4077. doi:10.1038/s41467-021-24331-1. 

  1. Staudt S, Nikolka F, Perl M, Franz J, Leblay N, Yuan XK, Larrayoz M, Lozano T,

       Warmuth L, Fante MA, Skorupskaitė A, Fei T, Bromberg M, Martin-Uriz PS, Rodriguez-Madoz JR, Ziegler-Martin K, Adil-Gholam N,, Benz P, Tran Huu P, Freitag F, Riester Z, Stein-Thoeringer C, Schmitt M, Kleigrewe K, Weber J, Mangold K, Ho P, Einsele H, Prosper F, Ellmeier W, Busch D, Visekruna A, Slingerland J, Shouval R, Hiller K, Lasarte JJ, Martinez-Climent JÁ, Pausch P, Neri P, van den Brink M, Poeck H, Hudecek M, Luu M. Metabolization of microbial postbiotic pentanoate drives anti-cancer CAR T cells. bioRxiv2025:2024.08.19.608538. doi:10.1101/2024.08.19.608538. 

  1. Schauer MP, Weber J, Altieri B, Spieler P, Gehrke L, Sbiera S, Kircher S, Kurlbaum M, Kroiss M, Kiseljak-Vassiliades K, Wierman ME, Nerreter T, Einsele H, Fassnacht M, Landwehr LS, Hudecek M*. Autocrine signaling in hormonally active cancer induces antigen expression for immunotherapy. Published online on bioRxiv January 29, 2025:2025.01.28.632923. doi:10.1101/2025.01.28.632923.
  • Prof. Dr. med. Michael Hudecek
    University Hospital Würzburg
    Department of Medicine III
    Oberdürrbacher Straße 6
    97080 Würzburg
    T: +49 931 201-71091
    hudecek_m(at)ukw.de
  • Prof. Dr. med. Hermann Einsele
    University Hospital Würzburg
    Department of Medicine III
    Oberdürrbacher Straße 6
    97080 Würzburg
    T: +49 931 201-40001
    einsele_h(at)ukw.de

Project A04

Novel tri-specific T-cell activating antibodies for personalized graft-versus-leukemia therapy.
Site: Würzburg
Principal Investigators: Dr. med. Thomas Bumm, Dr. rer. nat. Zeinab Mokhtari, Prof. Dr. med. Gernot Stuhler

We aim to develop novel bi-molecular hemibody constructs that address antigen combinations instead of single target molecules for high precision immunotherapy in the context of allogeneic HSCT. In a first step, we opt to improve the biochemical properties of the constructs focusing on stability, solubility and producibility. In a second step, we will establish humanized NSG mouse models to investigate pharmacokinetics and the specific requisites of dual antigen targeting, mimicking the clinical situation of leukemia patients undergoing allogeneic HSCT.

  1. Banaszek A*, Bumm TGP*, Nowotny B, Geis M, Jacob K, Wölfl M, Trebing J, Kucka K, Kouhestani D, Gogishvili T, Krenz B, Lutz J, Rasche L, Hönemann D, Neuweiler H, Heiby JC, Bargou RC, Wajant H, Einsele H, Riethmüller G, Stuhler G. On-target restoration of a split T cell-engaging antibody for precision immunotherapy. Nat Commun. 2019;10(1):5387. doi: 10.1038/s41467-019-13196-0.
  2. Geis M, Nowotny B, Bohn MD, Kouhestani D, Einsele H, Bumm T, Stuhler G. Combinatorial targeting of multiple myeloma by complementing T cell engaging antibody fragments. Commun Biol. 2021; 4(1):44. doi: 10.1038/s42003-020-01558-0
  3. Kouhestani D, Geis M, Alsouri S, Bumm TGP, Einsele H, Sauer M, Stuhler G. Variant signaling topology at the cancer cell-T-cell interface induced by a two-component T-cell engager. Cell Mol Immunol. 2020;18(6):1568-1570. doi: 10.1038/s41423-020-0507-7.
  4. Goebeler ME, Stuhler G, Bargou R. Bispecific and multispecific antibodies in oncology: opportunities and challenges. Nat Rev Clin Oncol 2024; 21(7):539-60. doi: 10.1038/s41571-024-00905-y. 
  • Dr. med. Thomas Bumm
    University Hospital Würzburg
    Department of Medicine II
    Oberdürrbacher Straße 6
    97080 Würzburg
    T: +49 931 201-44977
    bumm_t(at)ukw.de
  • Dr. rer. nat. Zeinab Mokhtari
    University Hospital Würzburg
    Department of Medicine II
    IZKF Research Laboratory for Experimental Hematopoietic Cell Transplantation
    Zinklesweg 10
    97080 Würzburg
    T: +49 931 201-44051
    Mokhtari_z(at)ukw.de
  • Prof. Dr. med. Gernot Suhler
    University Hospital Würzburg
    Department of Medicine II
    Versbacher Straße 5
    97078 Würzburg
    T: +49 931 201-44423
    Stuhler_g(at)ukw.de

Project A06

Metabolic stress related immune alterations with impact on graft-versus-leukemia effect in allogeneic stem cell transplantation.
Site: Erlangen
Principal Investigators: Prof. Dr. med. Dimitrios Mougiakakos, Prof. Dr. med. Andreas Mackensen

We hypothesize that oxidative stress confers immunological “hits” that predispose for leukemia relapse. The reconstituting donor immune system, which is fundamental for the GvL effect, is negatively impacted by oxidative stress. Our project addresses the importance of redox-balance after allo-HSCT. We will assess oxidative stress and its impact on immune reconstitution and function in allo-HSCT patients. We will test interventions for improving the T-cells’ anti-oxidative capacities together with other key functional properties. Our goal is to identify novel redox biomarkers predicting relapse risk that will allow us the rational design of targeted redox modulation for relapse prevention.

  1. Baur R, Karl F, Böttcher-Loschinski R, Stoll A, Völkl S, Gießl A, Flamann C, Bruns H, Schlötzer-Schrehardt U, Böttcher M, Schewe DM, Fischer T, Jitschin R, Mackensen A, Mougiakakos D. Accumulation of T-cell-suppressive PD-L1high extracellular vesicles is associated with GvHD and might impact GvL efficacy. J Immunother Cancer 2023;11(3):e006362. doi: 10.1136/jitc-2022-006362.

  2. Mougiakakos D, Johansson CC, Kiessling R. Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood 2009;113(15):3542-5. doi: 10.1182/blood-2008-09-181040.
  3. Karl F, Stoll A, Böttcher-Loschinski R, Böttcher M, Baur R, Jacobs B, Völkl S, Jitschin R, Rösler W, Mackensen A, Mougiakakos D. Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients. Leukemia 2021;35(3):910-5. doi:10.1038/s41375-020-0956-0.

  4. Karl F, Liang C, Böttcher-Loschinski R, Stoll A, Flamann C, Richter S, Lischer C, Völkl S, Jacobs B, Böttcher M, Jitschin R, Bruns H, Fischer T, Holler E, Rösler W, Dandekar T, Mackensen A, Mougiakakos D. Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT. Blood 2023;141(13):1626-39. doi: 10.1182/blood.2022017267.

  5. Richter S, Böttcher M, Stoll A, Zeremski V, Völkl S, Mackensen A, Ekici AB, Jacobs B, Mougiakakos D. Increased PD-1 expression on circulating T cells correlates with inferior outcome after autologous stem cell transplantation. Transplant Cell Ther 2024; 30(6):628.e1-628.e9. doi: 10.1016/j.jtct.2024.03.005. 

  6. Jetani H, Navarro-Bailón A, Maucher M, Frenz S, Verbruggen C, Yeguas A, Vidriales MB, González M, Rial Saborido J, Kraus S, Mestermann K, Thomas S, Bonig H, Luu M, Monjezi R, Mougiakakos D, Sauer M, Einsele H, Hudecek M. Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia. Blood 2021;138(19):1830-42. doi: 10.1182/blood.2020009192.

  7. Jitschin R, Saul D, Braun M, Tohumeken S, Völkl S, Kischel R, Lutteropp M, Dos Santos C, Mackensen A, Mougiakakos D. CD33/CD3-bispecific T-cell engaging (BiTE®) antibody construct targets monocytic AML myeloid-derived suppressor cells. J Immunother Cancer 2018;6(1):116. doi: 10.1186/s40425-018-0432-9.

  8. Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, Klein M, Wempe A, Leister H, Raifer H, Picard F, Muhammad K, Ohl K, Romero R, Fischer F, Bauer CA, Huber M, Gress TM, Lauth M, Danhof S, Bopp T, Nerreter T, Mulder IE, Steinhoff U, Hudecek M*, Visekruna A*. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun 2021;12(1):4077. doi: 10.1038/s41467-021-24331

  9. Luu M, Pautz S, Kohl V, Singh R, Romero R, Lucas S, Hofmann J, Raifer H, Vachharajani N, Carrascosa LC, Lamp B, Nist A, Stiewe T, Shaul Y, Adhikary T, Zaiss MM, Lauth M, Steinhoff U, Visekruna A. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun 2019;10(1):760. doi: 10.1038/s41467-019-08711-2. 

  10. Staudt S, Nikolka F, Perl M, Franz J, Leblay N, Yuan X, Larrayoz M, Lozano M, Warmuth L, Fante MA, Skorpskaite A, Fei T, Bromberg Maria, San Martin-Uriz P, Rodriguez-Madoz JR, Ziegler-Martin K, Adil Gholam N, Benz P, Tran Huu P, Freitag F, Riester R, Stein-Thoeringer C, Schmitt M, Kleigrewe K,  Weber J, Mangold K, Ho P, Einsele H, Prosper P, Ellmeier W, Busch D, Visekruna V, Slingerland J, Shouval R, Hiller H, Juan José Lasarte, Jose Angel Martinez-Climent, Pausch P, Neri P, van den Brink M, Poeck H, Hudecek M, Luu M. Metabolization of microbial postbiotic pentanoate drives anti-cancer CAR T cells. bioRxiv  2025; 2024.08.19.608538. doi: 10.1101/2024.08.19.608538. 

Project A07 

Enhancing graft-versus-leukemia responses by donor-derived CAR-modified CD8+ T memory stem cells.
Site: Regensburg
Principal Investigator: Dr. med. Dennis Harrer, Prof. Dr. med. Luca Gattinoni

Relapse after alloHSCT is frequently associated with poor survival in patients with advanced B-cell malignancies. In order to investigate curative options for those patients, we are conducting in collaboration with the US National Cancer Institute (NCI) a first in human trial employing donor-derived CD19-CAR TSCMcells. In this project, we plan to perform a comprehensive and detailed immunomonitoring comparing TSCM-enriched CAR T cell products to conventional donor-derived CAR T cells from a prior NCI study conducted on a similar subset of patients. In particular, we will investigate potential benefits of the TSCM cell platform in terms of CAR T cell expansion, long-term persistence, CAR T cell functionality, safety profile and alloreactivity. Finally, by using retroviral insertion and TCR clonotype analyses, we will assess the differentiation trajectory of CD19-CAR and untransduced TSCMcells to determine how CAR signaling affect their self-renewal and multipotency.

  1. Harrer DC, Schenkel C, Bezler V, Kaljanac M, Hartley J, Barden M, Pan H, Holzinger A, Herr W, Abken H. CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop. Cells 2022;11(23):3839. doi: 10.3390/cells11233839.

  2. Harrer DC, Bezler V, Hartley J, Herr W, Abken H. IRF4 downregulation improves sensitivity and endurance of CAR T cell functional capacities. Front Immunol 2023;14:1185618. doi: 10.3389/fimmu.2023.1185618.

  3. Baldwin JG, Heuser-Loy C, Saha T, Schelker RC, Slavkovic-Lukic D, Strieder N, Hernandez-Lopez I, Rana N, Barden M, Mastrogiovanni F, Martín-Santos A, Raimondi A, Brohawn P, Higgs BW, Gebhard C, Kapoor V, Telford WG, Gautam S, Xydia M, Beckhove P, Frischholz S, Schober K, Kontarakis Z, Corn JE, Iannacone M, Inverso D, Rehli M, Fioravanti J, Sengupta S, Gattinoni L. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell 2024;187(23):6614-30.e21. doi: 10.1016/j.cell.2024.08.029. 

  4. Schelker RC, Fioravanti J, Mastrogiovanni F, Baldwin JG, Rana N, Li P, Chen P, Vadász T, Spolski R, Heuser-Loy C, Slavkovic-Lukic D, Noronha P, Damiano G, Raccosta L, Maggioni D, Pullugula S, Lin JX, Oh J, Grandinetti P, Lecce M, Hesse L, Kocks E, Martín-Santos A, Gebhard C, Telford WG, Ji Y, Restifo NP, Russo V, Rehli M, Herr W, Leonard WJ, Gattinoni L. LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling. Signal Transduct Target Ther 2024;9(1):199. doi: 10.1038/s41392-024-01915-z.

  5. Gattinoni L*, Zhong XS*, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzesinski C, Boni A, Cassard L, Garvin LM, Paulos CM, Muranski P, Restifo NP. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 2009;15(7):808-13. doi: 10.1038/nm.1982.

  6. Gattinoni L*, Lugli E*, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, Restifo NP. A human memory T cell subset with stem cell-like properties. Nat Med 2011;17(10):1290-7. doi: 10.1038/nm.2446.

  7. Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, Roychoudhuri R, Palmer DC, Muranski P, Karoly ED, Mohney RP, Klebanoff CA, Lal A, Finkel T, Restifo NP*, Gattinoni L*. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 2013;123(10):4479-88. doi: 10.1172/JCI69589.

  8. Sabatino M, Hu J, Sommariva M, Gautam S, Fellowes V, Hocker JD, Dougherty S, Qin H, Klebanoff CA, Fry TJ, Gress RE, Kochenderfer JN, Stroncek DF, Ji Y, Gattinoni L. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 2016;128(4):519-28. doi: 10.1182/blood-2015-11-683847. 

  9. Gattinoni L*, Speiser DE*, Lichterfeld M*, Bonini C*. T memory stem cells in health and disease. Nat Med 2017;23(1):18-27. doi: 10.1038/nm.4241. 
  • Dr. med. Dennis Harrer
  • Universitätsklinikum Regensburg
    Klinik und Poliklinik für Innere Medizin III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-15557
    dennis.harrer(at)ukr.de
  • Prof. Dr. med. Luca Gattinoni
    LIT – Leibniz Institute for Immunotherapy (former RCI)
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38131
    luca.gattinoni(at)ukr.de

Project A08

Timed targeting of cGAS / STING to improve tissue-regeneration and anti-tumor responses following allo-HSCT.
Site: Regensburg
Principal investigator(s): Prof. Dr. med. Hendrik Poeck, Dr. rer. nat. Christian Schmidl, PhD

The impact of selective and timed activation or inhibition of the type I interferon inducing cGAS / STING pathway during the course of allo-HSCT and its influence on the GvL effect as well as donor T cell activation and differentiation remains unknown. Using selective receptor ligands and inhibitors, and a combination of advanced in vivo models of leukemia and lymphoma, allogeneic transplantation models, and next-generation sequencing approaches, we aim to unravel the consequences of timed cGAS/STING activation / inhibition during allo-HSCT.

  1. Fischer JC, Bscheider M, Eisenkolb G, Lin CC, 
Wintges A, Otten V, Lindemans CA, Heidegger S, Rudelius M, Monette S, Porosnicu Rodriguez KA, Calafiore M, Liebermann S, Liu C, Lienenklaus S, Weiss S, Kalinke U, Ruland J, Peschel C, Shono Y, Docampo M, Velardi E, Jenq RR, Hanash AM, Dudakov JA, Haas T, van den Brink MRM, Poeck H. RIG-I/MAVS and STING signaling promote gut integrity during irradiation and immune-mediated tissue injury. Sci Transl Med 2017;9(386):eaag2513. doi: 10.1126/scitranslmed.aag2513..

  2. Heidegger S, Stritzke F, Dahl S, Daßler-Plenker J, Joachim L, Buschmann D, Fan K, Sauer CM, Ludwig N, Winter C, Enssle S, Li S, Perl M, Görgens A, Haas T, Orberg ET, Göttert S, Wölfel C, Engleitner T, Cortés-Ciriano I, Rad R, Herr W, Giebel B, Ruland J, Bassermann F, Coch C, Hartmann G, Poeck H. Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy. Cell Rep Med 2023;19;4(9):101171. doi: 10.1016/j.xcrm.2023.101171.

  3. Thiele-Orberg E*, Meedt E*, Hiergeist A*, Xue J, Heinrich P, Ru J, Ghimire S, Miltiadous O, Lindner S, Tiefgraber M, Göldel S, Eismann T, Schwarz A, Göttert S, Jarosch S, Steiger K, Schulz C, Gigl M, Fischer JC, Janssen KP, Quante M, Heidegger S, Herhaus P, Verbeek M, Ruland J, van den Brink MRM, Weber D, Edinger M, Wolff D, Busch DH, Kleigrewe K, Herr W, Bassermann F, Gessner A, Deng L, Holler E, Poeck H. Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation. Nat Cancer 2024;5(1):187-208. doi: 10.1038/s43018-023-00669-x.

  4. Joachim L, Göttert S, Sax A, Steiger K, Neuhaus K, Heinrich P, Fan K, Orberg ET, Kleigrewe K, Ruland J, Bassermann F, Herr W, Posch C, Heidegger S, Poeck H. The microbial metabolite desaminotyrosine enhances T-cell priming and cancer immunotherapy with immune checkpoint inhibitors. EBioMedicine 2023;97:104834. doi: 10.1016/j.ebiom.2023.104834.

  5. Fischer JC, Göttert S, Heinrich P, Walther CN, Fan K, Eisenkolb G, Nefzger SM, Giller M, Khalid O, Ruben T, Jarosch S, Klostermeier L, Engleitner T, Strieder N, Gebhard C, Diederich S, Schmid NA, Lansink Rotgerink L, Joachim L, Ghimire S, Steiger K, Öllinger R, Rad R, Wolff D, Feuerer M, Hoffmann P, Edinger M, Rehli M, Tschurtschenthaler M, Kepp O, Kroemer G, Thiele Orberg E, Combs SE, Herr W, Bassermann F, Busch DH, Holler E, Heidegger S, Poeck H. Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury. bioRxiv 2025; doi: 10.1101/2024.10.21.617518.

  6. Rendeiro AF, Krausgruber T, Fortelny N, Zhao F, Penz T, Farlik M, Schuster LC, Nemc A, Tasnády S, Réti M, Matrái Z, Alpár D, Bödör C, Schmidl C, Bock C. Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL. Nat Commun 2020; 11, 577. doi: 10.1038/s41467-019-14081-6.

  7. Göttert S, Orberg ET, Fan K, Heinrich P, Matthe D, Khalid O, Klostermeier L, Suriano C, Strieder N, Gebhard C, Vonbrunn E, Mamilos A, Hirsch D, Meedt E, Kleigrewe K, Hiergeist A, Ghimire S, Joachim L, Voll F, Neuhaus K, Janssen KP, Perl M, Ruland J, Kreutz M, Weber D, Schmidl C, Köhler N, Tschurtschenthaler M, Hoffmann P, Edinger M, Wolff D, Bassermann F, Rehli M, Haller D, Evert M, Hildner K, Büttner-Herold M, Herr W, Gessner A, Heidegger S, Holler E*, Poeck H*. A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration. bioRxiv 2025. doi: 10.1101/2025.04.08.647747

  8. Riegel D, Romero-Fernández E, Simon M, Adenugba AR, Singer K, Mayr R, Weber F, Kleemann M, Imbusch CD, Kreutz M, Brors B, Ugele I, Werner JM, Siska PJ, Schmidl C. Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells. Mol Cell 2023;83(4):622-36.e10. doi: 10.1016/j.molcel.2022.12.029.

  9. Delacher M, Imbusch CD, Hotz-Wagenblatt A, Mallm JP, Bauer K, Simon M, Riegel D, Rendeiro AF, Bittner S, Sanderink L, Pant A, Schmidleithner L, Braband KL, Echtenachter B, Fischer A, Giunchiglia V, Hoffmann P, Edinger M, Bock C, Rehli M, Brors B, Schmidl C*, Feuerer M*. Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF. Immunity 2020;52(2):295-312 e211. doi: 10.1016/j.immuni.2019.12.002.

  10. Schmidl C*, Rendeiro AF*, Sheffield NC, Bock C. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat Methods 2015;12(10):963-65. doi: 10.1038/nmeth.3542. 
  • Prof. Dr. med. Hendrik Poeck
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5542
    hendrik.poeck(at)ukr.de
  • Dr. rer. nat. Christian Schmidl
    LIT – Leibniz Institute for Immunotherapy (former RCI)
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-18176
    christian.schmidl(at)ukr.de

Spokespersons

Within the Collaborative Research Centre/Transregio (CRC/TRR) 221 innovative immune modulation strategies will be investigated to separate GvHD from GvL effects in order to enhance the safety and efficacy of allo-HSCT in the future.

Andreas Mackensen

Wolfgang Herr

Hermann Einsele

PARTICIPATING INSTITUTIONS

UW
UE
UKR
UKW
UR
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Contact us
Tel: (0049) 0941 944 - 5501
Fax: (0049) 0941 944 - 5502
Mail: wolfgang.herr(at)ukr.de
93053 Regensburg,
Franz-Josef-Strauß-Allee 11
Let's stay in touch