SYMPATHY

Systems medicine approach to establish individualized treatment of lymphoma and leukemia

We aim to establish a systems medicine program that integrates systematic functional assays, multi-omic profiling, bioinformatic analysis, mathematical modeling and setup towards a clinical exploitation. The basis of the program is a platform to map patient specific pathway activity and drug sensitivity of their primary tumor cells ex- vivo. Signals provided by the microenvironment modify pathway activities, including those targeted by drugs, and thereby can mediate resistance or sensitivity to these drugs. We generate a systems-level understanding of how the microenvironment and the individual genetic and molecular make-up of a tumor interact and modify drug response using a high throughput automated microscopy platform mimicking microenvironment conditions. By comparing drug responses across patients with detailed molecular characterization and the clinical parameters, we obtain a rich set of associations of drug sensitivity with biology, biomarkers and outcome. The long-term aim of this work is to bring biology-based individualized treatment of lymphoma and leukemia into clinical practice.

Publications

^{Brinkmann, B. J., A. Floerchinger, C. Schniederjohann, T. Roider, M. Coelho, N. Mack, P.-M. Bruch, N. Liebers, S. Dötsch, D. H. Busch, M. Schmitt, F. Neumann, P. M. Roessner, M. Seiffert, and S. Dietrich (2024). "CD20-bispecific antibodies improve response to CD19-CAR T-cells in lymphoma in-vitro and CLL in-vivo models." Blood. doi.org/10.1182/blood.2023022682.}

^{Bruch, P.-M., H. A. Giles, C. Kolb, S. A. Herbst, T. Becirovic, T. Roider, J. Lu, S. Scheinost, L. Wagner, J. Huellein, I. Berest, M. Kriegsmann, K. Kriegsmann, C. Zgorzelski, P. Dreger, J. B. Zaugg, C. Müller-Tidow, T. Zenz, W. Huber, and S. Dietrich (2022). "Drug-microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL." Mol Syst Biol 18(8): e10855. doi.org/10.15252/msb.202110855.}

^{Dietrich, S., M. Oleś, J. Lu, L. Sellner, S. Anders, B. Velten, B. Wu, J. Hüllein, M. da Silva Liberio, T. Walther, L. Wagner, S. Rabe, S. Ghidelli-Disse, M. Bantscheff, A. K. Oleś, M. Słabicki, A. Mock, C. C. Oakes, S. Wang, S. Oppermann, M. Lukas, V. Kim, M. Sill, A. Benner, A. Jauch, L. A. Sutton, E. Young, R. Rosenquist, X. Liu, A. Jethwa, K. S. Lee, J. Lewis, K. Putzker, C. Lutz, D. Rossi, A. Mokhir, T. Oellerich, K. Zirlik, M. Herling, F. Nguyen-Khac, C. Plass, E. Andersson, S. Mustjoki, C. von Kalle, A. D. Ho, M. Hensel, J. Dürig, I. Ringshausen, M. Zapatka, W. Huber, and T. Zenz (2018). "Drug-perturbation-based stratification of blood cancer." The Journal of Clinical Investigation 128(1): 427-445. www.ncbi.nlm.nih.gov/pubmed/29227286.}

^{Herbst, S. A., V. Kim, T. Roider, E. C. Schitter, P.-M. Bruch, N. Liebers, C. Kolb, M. Knoll, J. Lu, P. Dreger, C. Müller-Tidow, T. Zenz, W. Huber, and S. Dietrich (2023). "Comparing the value of mono- vs coculture for high-throughput compound screening in hematological malignancies." Blood Adv. 7(19): 5925–5936. doi.org/10.1182/bloodadvances.2022009652.}

^{Herbst, S. A., M. Stolarczyk, T. Becirovic, F. Czernilofsky, Y. Liu, C. Kolb, M. Knoll, M. Herling, C. Muller-Tidow, and S. Dietrich (2021). "Phagocytosis by stroma confounds coculture studies." iScience 24(9): 103062. www.ncbi.nlm.nih.gov/pubmed/34585113.}

^{Herbst, S. A., M. Vesterlund, A. J. Helmboldt, R. Jafari, I. Siavelis, M. Stahl, E. C. Schitter, N. Liebers, B. J. Brinkmann, F. Czernilofsky, T. Roider, P.-M. Bruch, M. Iskar, A. Kittai, Y. Huang, J. Lu, S. Richter, G. Mermelekas, H. M. Umer, M. Knoll, C. Kolb, A. Lenze, X. Cao, C. Österholm, L. Wahnschaffe, C. Herling, S. Scheinost, M. Ganzinger, L. Mansouri, K. Kriegsmann, M. Kriegsmann, S. Anders, M. Zapatka, G. Del Poeta, A. Zucchetto, R. Bomben, V. Gattei, P. Dreger, J. Woyach, M. Herling, C. Müller-Tidow, R. Rosenquist, S. Stilgenbauer, T. Zenz, W. Huber, E. Tausch, J. Lehtiö, and S. Dietrich (2022). "Proteogenomics refines the molecular classification of chronic lymphocytic leukemia." Nat Commun 13(6226): 1–18. doi.org/10.1038/s41467-022-33385-8.}

^{Janssen, M., C. Schmidt, P.-M. Bruch, M. F. Blank, C. Rohde, A. Waclawiczek, D. Heid, S. Renders, S. Göllner, L. Vierbaum, B. Besenbeck, S. A. Herbst, M. Knoll, C. Kolb, A. Przybylla, K. Weidenauer, A. K. Ludwig, M. Fabre, M. Gu, R. F. Schlenk, F. Stölzel, M. Bornhäuser, C. Röllig, U. Platzbecker, C. Baldus, H. Serve, T. Sauer, S. Raffel, C. Pabst, G. Vassiliou, B. Vick, I. Jeremias, A. Trumpp, J. Krijgsveld, C. Müller-Tidow, and S. Dietrich (2022). "Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1." Blood 140(24): 2594–2610. doi.org/10.1182/blood.2021014241.}

^{Liebers, N., A. Boumendil, H. Finel, D. Edelmann, G. Kobbe, B.-N. Baermann, Y. Serroukh, D. Blaise, D. W. Beelen, C. Solano, M. Itälä-Remes, T. van Meerten, G. Choi, S. A. C. Schmidt, N. Kröger, J. Byrne, J.-J. Tudesq, A. Ossami Saidy, A. Nunes, R. Siddiqi, E. Baro, D. Zheng, I. Kloos, P. Dreger, A. Sureda, B. Glass, and S. Dietrich (2025). "Brexucabtagene autoleucel versus allogeneic hematopoietic cell transplantation in relapsed and refractory mantle cell lymphoma." Blood Cancer Discovery doi.org/10.1158/2643-3230.BCD-24-0178.}

^{Liebers, N., P.-M. Bruch, T. Terzer, M. Hernandez-Hernandez, N. Paramasivam, D. Fitzgerald, H. Altmann, T. Roider, C. Kolb, M. Knoll, A. Lenze, U. Platzbecker, C. Röllig, C. Baldus, H. Serve, M. Bornhäuser, D. Hübschmann, C. Müller-Tidow, F. Stölzel, W. Huber, A. Benner, T. Zenz, J. Lu, and S. Dietrich (2023). "Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial." Nat. Cancer 4: 1648–1659. doi.org/10.1038/s43018-023-00645-5.}

^{Liebers, N., J. Duell, D. Fitzgerald, A. Kerkhoff, D. Noerenberg, E. Kaebisch, F. Acker, S. Fuhrmann, C. Leng, M. Welslau, J. Chemnitz, J. M. Middeke, T. Weber, U. Holtick, R. Trappe, R. Pfannes, R. Liersch, C. Spoer, S. Fuxius, N. Gebauer, L. Caille, T. Geer, C. Koenecke, U. Keller, R. Claus, D. Mougiakakos, S. Mayer, A. Huettmann, C. Pott, A. Trummer, G. Wulf, U. Brunnberg, L. Bullinger, G. Hess, C. Mueller-Tidow, B. Glass, G. Lenz, P. Dreger, and S. Dietrich (2021). "Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas." Blood Adv 5(13): 2707-2716. www.ncbi.nlm.nih.gov/pubmed/34196677.}

^{Liebers, N., T. Roider, J. P. Bohn, I. Haberbosch, A. Pircher, B. Ferstl, M. Ebnother, C. M. Wendtner, C. Dearden, G. A. Follows, A. D. Ho, C. Muller-Tidow, P. Dreger, X. Troussard, T. Zenz, and S. Dietrich (2019). "BRAF inhibitor treatment in classic hairy cell leukemia: a long-term follow-up study of patients treated outside clinical trials." Leukemia. www.ncbi.nlm.nih.gov/pubmed/31740808.}

^{Liebers, N., S. O. Schonland, C. Speer, D. Edelmann, P. Schnitzler, H. G. Krausslich, C. Mueller-Tidow, U. Hegenbart, and S. Dietrich (2022). "Seroconversion Rates After the Second COVID-19 Vaccination in Patients With Systemic Light Chain (AL) amyloidosis." Hemasphere 6(3): e688. www.ncbi.nlm.nih.gov/pubmed/35187406.}

^{Liebers, N., C. Speer, L. Benning, P.-M. Bruch, I. Kraemer, J. Meissner, P. Schnitzler, H.-G. Kräusslich, P. Dreger, C. Mueller-Tidow, I. Poschke, and S. Dietrich (2022). "Humoral and cellular responses after COVID-19 vaccination in anti-CD20-treated lymphoma patients." Blood 139(1): 142–147. doi.org/10.1182/blood.2021013445.}

^{Roessner, P. M., L. Llaó Cid, E. Lupar, T. Roider, M. Bordas, C. Schifflers, L. Arseni, A.-C. Gaupel, F. Kilpert, M. Krötschel, S. J. Arnold, L. Sellner, D. Colomer, S. Stilgenbauer, S. Dietrich, P. Lichter, A. Izcue, and M. Seiffert (2021). "EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia." Leukemia: 1–14. doi.org/10.1038/s41375-021-01136-1.}

^{Roider, T., B. J. Brinkmann, and S. Dietrich (2021). "Processing human lymph node samples for single-cell assays." STAR Protocols. doi.org/10.1016/j.xpro.2021.100914.}

^{Roider, T., B. J. Brinkmann, V. Kim, M. Knoll, C. Kolb, P. M. Roessner, M. Bordas, P. Dreger, C. Muller-Tidow, W. Huber, M. Seiffert, and S. Dietrich (2021). "An autologous culture model of nodal B-cell lymphoma identifies ex vivo determinants of response to bispecific antibodies." Blood Adv 5(23): 5060-5071. www.ncbi.nlm.nih.gov/pubmed/34587238.}

^{Roider, T., J. Seufert, A. Uvarovskii, F. Frauhammer, M. Bordas, N. Abedpour, M. Stolarczyk, J.-P. Mallm, S. A. Herbst, P.-M. Bruch, H. Balke-Want, M. Hundemer, K. Rippe, B. Goeppert, M. Seiffert, B. Brors, G. Mechtersheimer, T. Zenz, M. Peifer, B. Chapuy, M. Schlesner, C. Müller-Tidow, S. Fröhling, W. Huber, S. Anders, and S. Dietrich (2020). "Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels." Nat Cell Biol: 1–11. doi.org/10.1038/s41556-020-0532-x.}