The central focus of Professor Poeck’s laboratory work is to identify the molecular mechanisms behind successful cancer therapies, as well as those found in therapy resistance. He and his team also look at tissue homeostatic responses during immunotherapeutic treatments such as allogeneic hematopoietic stem-cell transplantation (allo-HSCT), cellular therapies (chimeric antigen receptor [CAR] T cells or macrophages), immune checkpoint blockade (ICB), and certain chemotherapies. The specific aim is to understand how the innate immune system’s pattern recognition receptors (PRRs) can promote or inhibit these homeostatic responses in the tissues. Additionally they are investigating to what extent this is impacted by cellular engineering and environmental or cell-derived factors, such as the microbiome or extracellular vesicles.

The goal is then to develop new combinatorial strategies by gaining a deeper understanding of the modulation of anti-tumor and regenerative responses. These strategies will improve on existing cancer immunotherapies as they address the unsolved clinical problem of significant inter-individual response variability. At the same time they will ameliorate the damage done by unwanted immune-mediated tissue inflammation in conditions such as graft-versus-host disease (GvHD), cytokine-release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS by CAR T), and ICB-mediated autoinflammation.

A number of collaborations have been established here to promote further investigation. Close local cooperation with the following research groups has also been established: Meedt/Wer/Holler (translational GvHD and microbiome research); Edinger/Hoffmann (Treg cells); the Institutes of Pathology (Andreas Mamilos, Matthias Evert) and Microbiology and Hygiene (André Gessner, Andreas Hiergeist); Leibniz Institute for Immunotherapy (Hinrich Abken, Markus Feuerer, Christian Schmidl, Luca Gattinoni); as well as the Fraunhofer Institute ITEM (Melanie Werner Klein, Christian Werno).

Colon biopsy samples using ChipCytometry. Epithelial markers include: Pan-cytokeratin, E-Cadherin, Vimentin, Vinculin. Lymphocytic markers include: CD3, CD4, CD8, Foxp3.

Recent focus: Modulation of CAR T-cell function by the microbiome

Cancer immunotherapy using CAR T cells has proved to be extraordinarily effective in treating hematological malignancies. Two such CAR T therapeutics, Kymriah (Tisagenlecleucel) and Yescarta (Axicabtagene ciloleucel), are now used to treat B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). However, relapse rates of around 35% mean only a subgroup of patients will maintain long-term remission. In addition, challenges still remain for the use of CAR T-cell therapy in solid tumors.

The local microbial communities found in specific locations in the body are known as the bacterial microbiota. Recent studies have demonstrated that signals from the bacterial microbiota in the gastrointestinal (GI) tract, which indicate their composition, are linked to the outcome of patients receiving allo-HSCT as an immunotherapy against leukemias or lymphomas, as well as those receiving ICB treatment such as anti-CTLA-4 or PD1 inhibitors. Yet, the specific contribution of microbiota-mediated factors (e.g. metabolites) in CAR T-cell efficacy in hematologic and solid neoplasms remains unknown. In this project, Professor Poeck will analyze the role of microbiota-associated metabolites during CAR T-cell therapy in both mice and humans.

To this end, the team will utilize:

genetically engineered tumor cell lines, specifically A20 (target: CD19), Nalm6 (target: CD19), CT26 (target: CEA or Cldn-6), and LL/2-LLc1 (target: CEA or Cldn-6) in syngeneic or humanized mouse models
antimicrobial regimens (antibacterial/antifungal/antiviral)
gnotobiotic mice as respective tumor recipients
genetically modified immune cell (CAR T cells) transfer
unbiased next-generation sequencing approaches
targeted metabolomic profiling of stool samples, serum and intestinal tissues

Simultaneously, the team will investigate the relevance of microbiota-associated metabolites as potential biomarkers and predictors for developing anti-tumor responses, as well as for adverse events in human CAR T-cell recipients. This research will initially focus on hematologic cancers—such as ALL and lymphoma—and later on solid cancers—such as CEA+ colorectal carcinomas or Claudin-6 positive tumors.

Discover more by visiting Professor Poeck’s dedicated UKR page!

Visit the complete list of Prof. Poeck’s publications on PubMed:

https://pubmed.ncbi.nlm.nih.gov/?term=Poeck+H

Here is a selection of the most important publications from the last few years:

Heidegger S, Stritzke F, Dahl S, Daßler-Plenker J, Joachim L, Buschmann D, Winter C, Fan K, Enßle S, Li S, Perl M, Görgens A, Haas T, Thiele Orberg E, Göttert S, Wölfel C, Engleitner T, Rad R, Herr W, Giebel B, Ruland J, Bassermann F, Coch C, Hartmann G and Poeck H. Harnessing 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 Sep 19;4(9):101171. PMID: 37657445

2. Joachim L, Göttert S, Sax A, Steiger K, Neuhaus K, Heinrich P, Fan K, Thiele-Orberg E, 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. Volume 97, 2023, 104834, ISSN 2352-3964, https://doi.org/10.1016/j.ebiom.2023.104834. [IF: 9.2]. PMID: 37865045

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. Bacterial and Bacteriophage Consortia are Associated with Protective Intestinal Immuno-modulatory Metabolites in Allogeneic Stem Cell Transplantation Patients [https://doi.org/10.21203/rs.3.rs-1504704/v1] (Nat Cancer 2023, in press) PMID: 38172339

Heidegger S*^#, Wintges A *, Stritzke F, Bek S, Steiger K, Koenig PA, Göttert S, Engleitner T, Öllinger R, Nedelko T, Fischer JC, Makarov V, Winter C, Rad R, van den Brink MRM, Ruland J, Bassermann F, Chan TA, Haas T*, Poeck H*^#. RIG-I activation is critical for responsiveness to checkpoint blockade. Sci Immunol., 2019 Sep 13;4(39). PMID: 31519811

Heidegger S*^#, Kreppel D*, Bscheider M, Stritzke F, Nedelko T, Wintges A, Bek S,Fischer JC, Graalman T, Kalinke U, Bassermann F, Haas T*, Poeck H*^#. RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes withcheckpoint blockade. EBioMedicine. 2019 Mar6. pii: S2352-3964(19)30135 [IF: 9.2] PMID: 30852164

Fischer JC*, M Bscheider*, Gabriel Eisenkolb*, Lin CC, Wintges A, Otten V, Lindemans CA, Heidegger S, Rudelius M, Monette S, Porosnicu Rodriguez K, Calafiore M, Liebermann S, Liu C, Lienenklaus S, Weiss S, Kalinke U, Ruland J, Peschel C, Shono Y, Docampo M, Velardi E, Jenq R, Hanash A, Dudakov JA, Haas T, van den Brink MR *^# and Poeck H*^#. RIG-I/MAVS and STING signaling promote epithelial integrity during irradiation and immune-medited tissue injury. Sci Transl Med. 2017 Apr 19;9(386). PMID: 28424327

Jankovic D, Ganesan J, Bscheider M, Stickel N, Weber FC, Guarda G, Follo M, Pfeifer D, Tardivel A, Ludigs K, Bouazzaoui A, Kerl K, Fischer JC, Haas T, Schmitt-Gräff A, Manoharan A, Müller L, Finke J, Martin SF, Gorka O, Peschel C, Ruland J, Idzko M, Duyster J, Holler E, French LE, Poeck H*^#, Contassot E*^#, Zeiser R*^#.The Nlrp3 inflammasome regulates acute graft-versus-host disease. J Exp Med. 2013 Sep 23;210(10):1899-910. [IF: 14.2]. PMID: 23980097

Poeck H*, Bscheider M*, Gross O*, Roth S, Finger K, Hannesschläger N, Schlee M, Rebsamen M, Rothenfusser S, Barchet W, Akira S, Inoue S, Endres S, Peschel C, Hartmann G*, Hornung V* and Ruland J*. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1beta production. Nat Immunol. 2010 Jan;11(1):63-9. [IF: 28.4] PMID: 19915568

Poeck H*, Besch R*, Maihoefer C, Renn M, Tormo D, Morskaya S, Kirschnek S, Gaffal E, Landsberg J, Hellmuth J, Schmidt A, Anz D, Bscheider M, Schwerd T, Berking C, Bourquin C, Kalinke U, Kremmer E, Kato H, Akira S, Meyers R, Häcker G, Neuenhahn M, Busch D, Ruland J, Rothenfusser S, Prinz M, Hornung V, Endres S, Tüting T & Hartmann G. 5’-triphosphate siRNA: turning gene-silencing and RIG-I activation against melanoma. Nat Med. 2008 Nov;14 (11):1256-63 [IF: 59.2] PMID: 18978796

Gross O*, Poeck H*, Bscheider M, Dostert C, Hannesschläger N, Endres S, Hartmann G, Tardivel A, Schweighoffer E, Tybulewicz V, Mocsai A, Tschopp J, Ruland J. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009 May 21;459(7245):433-6. [IF: 54.4]. PMID: 19339971