Our
Science

GDF-15 - a key modulator of
antitumoral immune responses

Growth Differentiation Factor-15 (GDF-15) is a remote member of the multifunctional transforming growth factor β cytokine superfamily. This cytokine is associated with a poor clinical outcome for cancer patients and reduced overall survival in various cancer indications. Tumors express and release high amounts of GDF-15 in its microenvironment, which allows them to avoid recognition by the circulating immune cells and mount an antitumoral immune response.

GDF-15 acts via the following mechanisms:

  • interfering with DC activation and maturation
  • reducing T-cell priming and activation by dendritic cells
  • blocking the effective immune cell extravasation and tumor infiltration
  • inhibiting T-cell and NK-cell-based killing of tumor cells
  • inducing immunosuppression in the tumor tissue by generation and
    function enhancement of regulatory T-cells

Catalym Corporate Video

How we neutralize GDF-15 within the tumor microenvironment

Click to see the movie.

Neutralization of GDF-15
as a therapeutic concept to reverse tumor-mediated immunosuppression

GDF-15 is also an important tool for tumors to build up resistance against checkpoint inhibitor therapy. As GDF-15 overexpression can easily be detected in blood samples from patients, high GDF-15 titers can be used to identify patients with a high likelihood of response .

By neutralizing GDF-15, CatalYm aims to reverse this tumor-derived immunosuppression and make tumors accessible and susceptible again to the patient’s own immune system. Our preclinical data demonstrated that neutralizing GDF-15 can restore the ability of T cells to enter the tumor and could therefore improve responses to antitumoral therapies depending on high immune cell presence in the tumor as anti-PD1 therapy in patients with high GDF-15 levels.

To find out how our therapeutic candidate can neutralize GDF-15 to expand the treatment horizon for immunotherapy-refractory cancer patients, check out the mechanism of action video above.

Our Scientific &
Clinical Advisors

On our path to expand the horizon of current immunotherapies, we are supported by an international team of seasoned experts in the immuno-oncology field.

Professor Alexander Eggermont is General Director of Gustave Roussy Cancer Institute, Professor of Oncology at the Paris-Sud University, and Professor of Oncological Surgery at the Erasmus University of Rotterdam in Holland. He also holds the Honorary Joseph Maisin Honorary Chair of Oncological Surgery (...)

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Professor Melero is Professor of Immunology at the Clinic of the University of Navarra and at the Center for Applied Medical Research of the University of Navarra, Pamplona, Spain. His current areas of research are focused on translational research with cell, gene and monoclonal antibody-mediated (...)

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Professor Wischhusen is scientific co-founder of CatalYm. He is also the Head of the Section of Experimental Tumor Immunology at the University of Würzburg Medical School, Germany. Prof. Wischhusen’s current research is directed towards tumor-host interactions in ovarian and breast cancer, with (...)

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Professor Ralf C. Bargou is Director of the Mainfranken Comprehensive Cancer Center and Chair of the Translational Oncology Department at Würzburg University. He also serves as member of the Board of Directors of the newly formed Bavarian Cancer Research Center. He has a long-standing and successful (...)

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Professor Reinhard Dummer is Professor of the University of Zürich and Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switzerland and is a key thought leader in worldwide cutaneous oncology. Currently, he is heading the Skin Cancer Unit and the Clinical Trial (...)

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Dr. F. Stephen Hodi is the Director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber / Brigham and Women’s Cancer Center, the Sharon Crowley Martin Chair in Melanoma at Dana- Farber Cancer Institute and Professor of Medicine at Harvard Medical School. His internationally (...)

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Professor Thomas Gajewski is Professor in the Departments of Pathology and Medicine at the University of Chicago.  He oversees the melanoma oncology clinic and is the leader of the Immunology and Cancer Program at the University of Chicago Comprehensive Cancer Center. Prof. Gajewski is committed (...)

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Professor Wolf H. Fridman is Professor Emeritus of Immunology at the Paris Descartes University Medical School in Paris, France. He received his MD and PhD degrees from the University of Paris. He has been the founder and first Director of the Cordeliers Research Centre, a joint research structure (...)

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Publications

Scientific validation for GDF-15 as a central key player in the immune resistance of cancer
list of publications, including link to each paper

catalym
Posted by catalym
November 15, 2021

Tumor-derived GDF-15 prevents therapy success of checkpoint inhibitors by blocking T-lymphocyte recruitment

Markus Haake, Tina Schäfer, Beatrice Haack, Neha Vashist, Sabrina Genßler, Patrick Harter, Alexander Martens, Kilian Wistuba-Hamprecht, Florian Wedekink, Birgitt Fischer, Michel Mittelbronn, Mitchell Levesque, Phil Cheng, Reinhard Dummer, Benjamin Weide, Kathrin Klar, Eugen Leo, Falk Nimmerjahn, Christine Schuberth-Wagner and Jörg Wischhusen J Immunother Cancer 2021;9(Suppl 2):A597

catalym
Posted by catalym
November 15, 2021

A phase I, first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in subjects with advanced stage solid tumors (Acronym: GDFATHER)

Ignacio Melero, Emiliano Calvo, Maria-Elisabeth Goebeler, Elena Garralda, Reinhard Dummer, María Rodríguez-Ruiz, Maria de Miguel, Cyrus Michael Sayehli, Guzman Alonso Casal, Egle Ramelyte, Martin Schuler, Tanja Gromke, Miguel Sanmamed, Irene Moreno, Ralf Bargou, Maria Lostes, Julia-Tatjana Maul, Corinne Eggenschwiler, Heike Richly, Petra Fettes, Kathrin Klar, Christine Schuberth-Wagner, Markus Haake, Jörg Wischhusen and Eugen Leo J Immunother Cancer 2021;9(Suppl 2):A536

piomat
Posted by piomat
August 30, 2021

Tumor-derived GDF-15 to suppress T-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.

Joerg Wischhusen, Markus Haake, Neha Vashist, Sabrina Genßler, Kilian Wistuba-Hamprecht, Patrick Harter, Alexander Martens, Michel Mittelbronn, Mitchell P. Levesque, Reinhard Dummer, Benjamin Weide, Marij JP Welters, Sjoerd H van der Burg, Manfred Ruediger, Eugen Leo, Falk Nimmerjahn, and Christine Schuberth-Wagner Journal of Clinical Oncology 2021 39:15_suppl, e14532-e14532

piomat
Posted by piomat
August 30, 2021

Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation

Jui-Hsia Weng, Peter David Koch, Harding H. Luan, Ho-Chou Tu, Kenichi Shimada, Iris Ngan, Richard Ventura, Ruomu Jiang and Timothy J. Mitchison Nat Metab 3, 513–522 (2021).

piomat
Posted by piomat
August 30, 2021

GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma

Zhaowei Wang, Lei He, Weina Li, Chuanyang Xu, Jieyu Zhang, Desheng Wang, Kefeng Dou, Ran Zhuang, Boquan Jin, Wei Zhang, Qiang Hao, Kuo Zhang, Wangqian Zhang, Shuning Wang, Yuan Gao, Jintao Gu, Lei Shang, Zhijun Tan, Haichuan Su, Yingqi Zhang, Cun Zhang, Meng Li Immunother Cancer. 2021 Sep;9(9):e002787. doi: 10.1136/jitc-2021-002787. PMID: 34489334.

piomat
Posted by piomat
August 30, 2021

Tumor-derived GDF-15 suppresses T-lymphocyte recruitment to the tumor microenvironment

Markus Haake, Neha Vashist, Sabrina Genssler, Kristin H. Eichler, Birgitt Fischer, Jessica Kammer, Paula S. Romer, Manfred Rudiger, Eugen Leo, Falk Nimmerjahn, Christine Schuberth-Wagner and Joerg Wischhusen Cancer Res August 15 2020 (80) (16 Supplement) 5597; DOI: 10.1158/1538-7445.AM2020-5597

ante
Posted by ante
August 29, 2021

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

Joerg Wischhusen J, Ignacio Melero,Wolf Herman Fridman Front Immunol. 2020 May 19;11:951. doi: 10.3389/fimmu.2020.00951. PMID: 32508832; PMCID: PMC7248355.

ante
Posted by ante
August 28, 2021

Circulating growth/differentiation factor 15 is associated with human CD56bright natural killer cell dysfunction and nosocomial infection in severe systemic inflammation

Holger Kleinertz, Monika Hepner-Schefczyk, Sabrina Ehnert, Maren Claus, Rebecca Halbgebauer, Lea Boller, Markus Huber-Lang, Paolo Cinelli, Carsten Kirschning, Sascha Flohé, André Sander, Christian Waydhas, Sonja Vonderhagen, Marcus Jäger, Marcel Dudda, Carsten Watzl, Stefanie B. Flohé EBioMedicine. 2019 May;43:380-391. doi: 10.1016/j.ebiom.2019.04.018. PMID: 30992245; PMCID: PMC6557805.

ante
Posted by ante
August 27, 2021

High GDF-15 Serum Levels Independently Correlate with Poorer Overall Survival of Patients with Tumor-Free Stage III and Unresectable Stage IV Melanoma

BenjaminWeide, Tina Schäfer, Alexander Martens, Anastasia Kuzkina, Laura Uder, Seema Noor, Claus Garbe, Patrick N. Harter, Michel Mittelbronn and Jörg Wischhusen J Invest Dermatol. 2016 Dec;136(12):2444-2452. doi: 10.1016/j.jid.2016.07.016. PMID: 27705749.

ante
Posted by ante
August 26, 2021

GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice

Tibor Kempf, Alexander Zarbock, Christian Widera, Stefan Butz, Anika Stadtmann, Jan Rossaint , Matteo Bolomini-Vittori, Mortimer Korf-Klingebiel, L Christian Napp, Birte Hansen, Anna Kanwischer, Udo Bavendiek, Gernot Beutel, Martin Hapke, Martin G Sauer, Carlo Laudanna, Nancy Hogg, Dietmar Vestweber & Kai C Wollert. Nat Med. 2011 May;17(5):581-8. doi: 10.1038/nm.2354. PMID: 21516086.

trophic
Posted by trophic
August 25, 2021

GDF-15 contributes to proliferation and immune escape of malignant gliomas

P. Roth, M. Junker, I. Tritschler, M. Mittelbronn, Y. Dombrowski, S. N. Breit, G. Tabatabai, W. Wick, M. Weller, J. Wischhusen, Clin Cancer Res 16, 3851-3859 (2010)

ante
Posted by ante
August 24, 2021

MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma

D. A. Brown, R. L. Ward, P. Buckhaults, T. Liu, K. E. Romans, N. J. Hawkins, A. R. Bauskin, K. W. Kinzler, B. Vogelstein, S. N. Breit, Clin Cancer Res 9, 2642-2650 (2003)

ante
Posted by ante
August 23, 2021

MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily

M. R. Bootcov, A. R. Bauskin, S. M. Valenzuela, A. G. Moore, M. Bansal, X. Y. He, H. P. Zhang, M. Donnellan, S. Mahler, K. Pryor, B. J. Walsh, R. C. Nicholson, W. D. Fairlie, S. B. Por, J. M. Robbins, S. N. Breit, Proc Natl Acad Sci U S A 94, 11514-11519 (1997).