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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 DM-sensitive and DM-resistant antigens in immune responses after allogeneic stem cell transplantation (ASCT)
Site: Erlangen
Principal Investigator: Dr. rer. nat. Hannah Reimann, and Prof. Dr. med. Andreas Mackensen

DM-sensitive antigens are promising targets for selective GvL effects without GvHD. We isolated CD4+ T-cell clones targeting these antigens in mismatched HLA-DP, recognizing primary AML blasts while sparing non-hematopoietic cells. For clinical translation, we aim to develop scalable, GMP-grade T-cell products and assess their GvL and GvHD potential using AML blasts and patient-derived organoids. Preliminary post-ASCT data suggest a link between T-cell responses to DM-resistant antigens and GvHD. To elucidate this relationship, we will longitudinally track T-cell clones targeting DM-sensitive /-resistant antigens in ASCT patients.

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: +49 9131 85 43187
    hannah.reimann(at)uk-erlangen.de

 

Prof. Dr. med. Andreas Mackensen
Universitätsklinikum Erlangen
Medizinische Klinik 5
Hartmannstraße 14
91052 Erlangen

T+49 9131 85-35954

med5-direktion(at)uk-erlangen.de

Project A02

Efficacy and safety of HLA-DPB1-specific chimeric antigen receptors (CAR) as mediators of graft-versus-leukemia (GvL) effect
Site: Regensburg
Principal Investigators: Prof. Dr. med. Simone Thomas, Prof. Dr. med. Wolfgang Herr, PD Dr. Patrick Schlegel

We developed a combinatorial ‘Logic-AND-Gating’ CAR that requires the simultaneous binding to alloHLA-DPB1 of patient origin and to the hematopoiesis-restricted antigen CD45 on leukemia cells for T cell activation. This new approach is thought to prevent HLA-DP-specific alloreactivity toward non-hematopoietic (CD45neg) tissues upon CAR treatment. We will now test this CAR and a novel alloHLA-A2/CD45 CAR for efficacy and toxicity in humanized NSG mouse models to show that this combinatorial ‘Logic-AND-gating’ CAR approach allows the induction of a selective GvL effect in the absence of GvHD.

  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
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5501
    simone.thomas@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@ukr.de
  • PD Dr. Patrick Schlegel
    University Hospital Regensburg
    Department of Pediatric Hematology
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-2101
    patrick.schlegel@ukr.de

Project A03

Advanced CAR T cell engineering to augment the GvL effect of ASCT
Site: Würzburg
Principal Investigators: Prof. Dr. med. Michael Hudecek, Prof. Dr. med. Sophia Danhof, Prof. Dr. med. Hermann Einsele

We have developed CAR-T cells as ‘bridge to transplant’ (pre-ASCT) or as ‘CAR donor lymphocyte infusion’ (post-ASCT) in AML and multiple myeloma. Here, we will investigate the effect of glucocorticoids on CAR-T cells and render them resistant through gene-editing to maintain anti-tumor functionality during GvHD and/or CRS (Aim 1); we will accomplish serial antigen targeting for enhanced GvL effect (Aim 2); and we will analyze how alloreactivity and inflammation may cause AML resistance and/or neurotoxicity during CAR-T cell therapy (Aim 3) to improve the outcome of ASCT and integrate CAR-T therapy into the treatment algorithm.

 

  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.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.
  3. 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@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@ukw.de
  • Prof. Dr. med. Sophia Danhof, MHBA
    University Hospital Würzburg
    Department of Internal Medicine II
    Oberdürrbacher Straße 6
    97080 Würzburg / Germany
    T: +49 931 / 201-44922
    danhof_s@ukw.de

Project A06

Advanced CAR T cell engineering to augment the GvL effect of ASCT
Site: Erlangen
Principal Investigators: Prof. Dr. med. Dimitrios Mougiakakos, Prof. Dr. rer. nat. Maik Luu

Previously, we demonstrated that ASCT patients exhibit increased oxidative stress compared to healthy controls and autologous SCT patients. Oxidative DNA damage in reconstituting T cells correlated with their functional impairment, and an increased relapse risk. Targeting DNA repair mechanisms and mitochondrial health with microbial postbiotics indicates their potential to restore T cell fitness. We aim to: (i) investigate the link between mitochondrial fitness, DNA damage repair, and GvL efficacy, (ii) synergize postbiotics with DNA repair mechanisms to enhance GvL activity, and (iii) translate these insights into a CAR T cell-based approach.

  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. 
  • Prof. Dr. rer. nat. Maik Luu
    University Hospital Würzburg
    Medical Clinic & Polyclinic II
    Versbacher Straße 5
    97078 Würzburg
    T: +49 931 201-71098
    luu_m@ukw.de

Project A07 

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

IL-10 is emerging as a critical Achilles´ heel limiting the functionality of donor-derived CD19-CAR CD8+ T memory stem cells (TSCM) in the treatment of B-cell malignancies relapsing after ASCT. In this project, we seek to elucidate the role of IL-10 in CAR TSCM cell biology and develop strategies to overcome IL-10-mediated immunosuppression. Specifically, we will engineer CAR TSCM with (i) dominant-negative IL-10 receptors, (ii) IL-10 switch receptors converting IL-10 immunosuppressive signaling into T-cell supportive signals, and (iii) synthetic intramembrane proteolysis receptors designed to sustain stemness in response to IL-10.

  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
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38131
    luca.gattinoni(at)ukr.de

Project A09

Identification of T cell receptors and their epitopes mediating GvL responses in acute myeloid leukemia (AML)
Erlangen
Prof. Dr. med. Kilian Schober

This project aims to enhance GvL effects in AML by identifying leukemia-reactive T cell receptors (TCRs) and their target epitopes. Using advanced technologies like single-cell RNA/TCR sequencing and CRISPR-based TCR re-expression, the project screens patient- and donor-derived T cells before and after ASCT. Epitope specificity is mapped using conventional assays and genome-wide peptide-HLA libraries. The goal is to discover over 100 functional TCRs and their epitopes across five common HLA types, paving the way for targeted TCR-based AML immunotherapy after ASCT.

S. Frischholz*, E.-M. Schuster*, M. Grotz*, C. Schülein, J. Benz, K. Kocher, L. Klotz, S. Varga, T. Hiltner, R. Alsalameh, J. Esse, J. Träger, J. Held, F. Graw, J. Pahle, B. Spriewald, L. Gattinoni, V. R. Buchholz, F. Drost, B. Schubert, S. Rothenfußer, D. H. Busch, C. Bogdan & K. Schober. Metabolic quiescence of naïve-like memory T cells precedes and maintains antigen-specific T cell memory. Nature Immunology, in press.

K. Kocher*, F. Drost*, A. M. Tesfaye, C. Moosmann, C. Schuelein, M. Grotz, E. D’Ippolito, F. Graw, B. Spriewald, D. H. Busch, C. Bogdan, M. Tenbusch, B. Schubert*, K. Schober*, Quality of vaccination-induced T cell responses is conveyed by polyclonality and high, but not maximum, antigen receptor avidity. Science Immunology (2025), doi: 10.1126/sciimmunol.adu6730.

K. Kocher*, C. Moosmann*, F. Drost, C. Schülein, P. Irrgang, P. Steininger, J. Zhong, J. Träger, B. Spriewald, C. Bock, D. H. Busch, C. Bogdan, B. Schubert, T. H. Winkler, M. Tenbusch, E. M. Schuster*, K. Schober*, Adaptive immune responses are larger and functionally preserved in a hypervaccinated individual. The Lancet Infectious Diseases (2024), doi:10.1016/S1473-3099(24)00134-8

F. Drost*, E. Dorigatti*, A. Straub*, P. Hilgendorf, K. I. Wagner, K. Heyer, M. López Montes, B. Bischl, D. H. Busch*, K. Schober*, B. Schubert*, Predicting T cell receptor functionality against mutant epitopes. Cell Genomics, (2024), doi: 10.1016/j.xgen.2024.100634

A. Straub, S. Grassmann, S. Jarosch, L. Richter, P. Hilgendorf, M. Hammel, K. I. Wagner, V. R. Buchholz, K. Schober*, D. H. Busch*, Recruitment of epitope-specific T cell clones with a low-avidity threshold supports efficacy against mutational escape upon reinfection, Immunity (2023), doi:10.1016/j.immuni.2023.04.010.

P. Irrgang*, J. Gerling*, K. Kocher*, D. Lapuente, P. Steininger, K. Habenicht, M. Wytopil, S. Beileke, S. Schäfer, J. Zhong, G. Ssebyatika, T. Krey, V. Falcone, C. Schülein, A. S. Peter, K. Nganou-Makamdop, H. Hengel, J. Held, C. Bogdan, K. Überla, K. Schober*, T. H. Winkler*, M. Tenbusch*, Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination, Science Immunology (2023), doi:10.1126/sciimmunol.ade2798.

E. Vogel*, K. Kocher*, A. Priller*, C.-C. Cheng*, P. Steininger, B.-H. Liao, N. Körber, A. Willmann, P. Irrgang, J. Held, C. Moosmann, V. Schmidt, S. Beileke, M. Wytopil, S. Heringer, T. Bauer, R. Brockhoff, S. Jeske, H. Mijocevic, C. Christa, J. Salmanton-García, K. Tinnefeld, C. Bogdan, S. Yazici, P. Knolle, O. A. Cornely, K. Überla, U. Protzer*, K. Schober*, M. Tenbusch*, Dynamics of humoral and cellular immune responses after homologous and heterologous SARS-CoV-2 vaccination with ChAdOx1 nCoV-19 and BNT162b2. eBioMedicine. (2022), doi: 10.1016/j.ebiom.2022.104294

A. Purcarea*, S. Jarosch*, J. Barton, S. Grassmann, L. Pachmayr, E. D’Ippolito, M. Hammel, A. Hochholzer, K. I. Wagner, J. H. van den Berg, V. R. Buchholz, J. B. A. G. Haanen, D. H. Busch*, K. Schober*, Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity. Science Immunology (2022), doi:10.1126/sciimmunol.abm2077 (free access link)

D. S. Fischer*, M. Ansari*, K. I. Wagner*, S. Jarosch, Y. Huang, C. H. Mayr, M. Strunz, N. J. Lang, E. D. Ippolito, M. Hammel, L. Mateyka, S. Weber, L. S. Wolff, K. Witter, I. E. Fernandez, K. Milger, M. Frankenberger, L. Nowak, K. Heinig-Menhard, I. Koch, M. G. Stoleriu, A. Hilgendorff, J. Behr, A. Pichlmair, B. Schubert*, F. J. Theis*, D. H. Busch*, H. B. Schiller*, K. Schober*, Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through “reverse phenotyping.” Nature Communications (2021), doi:10.1038/s41467-021-24730-4

D. S. Fischer*, M. Ansari*, K. I. Wagner*, S. Jarosch, Y. Huang, C. H. Mayr, M. Strunz, N. J. Lang, E. D. Ippolito, M. Hammel, L. Mateyka, S. Weber, L. S. Wolff, K. Witter, I. E. Fernandez, K. Milger, M. Frankenberger, L. Nowak, K. Heinig-Menhard, I. Koch, M. G. Stoleriu, A. Hilgendorff, J. Behr, A. Pichlmair, B. Schubert*, F. J. Theis*, D. H. Busch*, H. B. Schiller*, K. Schober*, Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through “reverse
phenotyping.” Nature Communications (2021), doi:10.1038/s41467-021-24730-4

K. Schober*, F. Voit*, S. Grassmann, T. R. Müller, J. Eggert, S. Jarosch, B. Weißbrich, P. Hoffmann, L. Borkner, E. Nio, L. Fanchi, C. R. Clouser, A. Radhakrishnan, L. Mihatsch, P. Lückemeier, J. Leube, G. Dössinger, L. Klein, M. Neuenhahn, J. D. Oduro, L. Cicin-Sain, V. R. Buchholz, D. H. Busch, Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection. Nature Immunology 21, 434–441 (2020), doi:10.1038/s41590-020-0628-2

K. Schober*, T. R. Müller*, F. Gökmen, S. Grassmann, M. Effenberger, M. Poltorak, C. Stemberger, K. Schumann, T. L. Roth, A. Marson, D. H. Busch, Orthotopic replacement of T-cell receptor α- and β-chains with preservation of near-physiological T-cell function. Nature Biomedical Engineering 3, 974–984 (2019), doi:10.1038/s41551-019-0409-0.

  • Prof. Dr. med Kilian Schober
    Microbiology Institute – Clinical Microbiology, Immunology and Hygiene
    University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg
    T: 09131 85-46930
    kilian.schober@uk-erlangen.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
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