Our
Science

GDF-15 - a key modulator of
antitumoral immune responses

Growth Differentiation Factor-15 (GDF-15) is a remote member of the transforming growth factor β cytokine superfamily. It acts as an immunosuppressant and is known for its important role in feto-maternal tolerance, a crucial mechanism during pregnancy that protects the embryo from the mother’s immune system. This protective function is often hijacked by tumor cells to evade being recognized and attacked by the immune system, and the majority of solid tumors show overexpression of GDF-15.

CatalYm and its collaborators have identified GDF-15 as a key regulator in cancer therapy resistance by unraveling the underlying pathways contributing to immune evasion, such as inhibition of T cell infiltration into the tumor site or blocking the activation of immune cells such as M1 macrophages critical for the initiation of anti-tumoral immune responses and destruction of cancer cells.

GDF-15 reduces tolerability of anti-cancer therapies

GDF-15 is known to be overexpressed in various cancer types. In addition, its expression can be induced by different anti-cancer treatments, including chemotherapy, antibody-drug conjugates (ADCs) and irradiation, leading to symptoms that impair a patient’s tolerability of these therapeutic regimen. This includes nausea and emesis, suppressed appetite and food intake, as well as exacerbated weight loss.

Neutralization of GDF-15
as a therapeutic concept to reverse tumor-mediated immunotherapy resistance and increase quality of life

As GDF-15 inhibits the initiation of an immune response at several critical steps, it is an important tool for tumors to create an immunosuppressive microenvironment, a key factor in the development of resistance against a range of cancer therapies, including immunotherapies such as checkpoint inhibitors.

By neutralizing GDF-15 with our monoclonal antibody candidate visugromab, CatalYm aims to reverse this tumor-mediated immunosuppression to reinstate an efficient anti-tumor response, e. g. by reenabling immune cell activation and tumor infiltration with effector cells. In addition, visugromab offers the potential to mitigate the GDF-15-induced symptoms of nausea, emesis, loss of appetite and weight loss, thereby enhancing the patient’s health-related quality of life, and potentially improving the effectiveness of cancer therapies by prolonging treatment duration and tolerance of clinical treatment doses.

Data from our completed Phase 1 and ongoing Phase 2 clinical trials with visugromab in combination with the checkpoint inhibitor nivolumab demonstrate increased T cell infiltration and promising durable responses in major cancer indications. Together with our insights into the underlying mechanistic details of GDF-15’s immunosuppressive effects, the clinical data highlight the potential of GDF-15 neutralizing approaches as a critical component for treatment success in a broad range of anti-cancer regimens.

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 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 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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Dr. Roy S. Herbst is widely recognized for his leadership and expertise in lung cancer treatment and research, particularly for the successful development of novel (immuno)therapies, including gefitinib, cetuximab, bevacizumab and axitinib. He and his Yale colleagues were among the first to describe (...)

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Professor Andrea Necchi is a medical oncologist specializing in the treatment of urological malignancies. In November 2020, he was appointed Associate Professor of Oncology at Vita-Salute San Raffaele University and Director of Genitourinary Medical Oncology at IRCCS San Raffaele Hospital and Scientific (...)

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Dr. Petros Grivas is board-certified medical oncologist with vast experience and high expertise in genitourinary (GU) cancers. He has had a main role in several clinical trials leading to FDA approval of new drugs for urothelial cancer, including avelumab and Trodelvy®. Dr. Grivas is considered (...)

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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 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 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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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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Publications

We are expanding the understanding of GDF-15’s role in establishing tumor resistance to current immunotherapy and are leading the development of a therapeutic approach to neutralize its effect.

trophic
Posted by trophic
November 8, 2023

GDF-15 neutralizing antibody visugromab increases intratumoral immune cell infiltration to support bispecific T-cell engagers

Sabrina Genssler, Daniel Schaetzlein, Eugen Leo, Markus Haake and Christine Schuberth-Wagner /

trophic
Posted by trophic
November 8, 2023

SHP-1 is a central mediator of GDF-15 mediated adhesion inhibition in T-cells

Markus Haake, Neha Vashist, Beatrice Haack, Birgitt Fischer, Kristin Eichler, Matthias Kist, Sabrina Genssler, Joerg Wischhusen, Eugen Leo and Christine Schuberth-Wagner /

catalym
Posted by catalym
October 27, 2023

12P Immuno-suppressive role of tumour-derived GDF-15 on myeloid cells

Schuberth-Wagner, C., Giese, I., Kist, M., Vashist, N., Genßler, S., Haack, B., Weigandt, J., Auer, M., Wischhusen, J., Klar, K., Leo, E., & Haake, M. /  Annals of Oncology, 34, S190 (2023)

catalym
Posted by catalym
October 12, 2023

Cancer immunotherapy: GDF-15’s role in Anti-PD-1 resistance

Interview with Christine Schuberth-Wagner, Chief Scientific Officer at CatalYm  /  Drug Target Review 24Aug2023

catalym
Posted by catalym
October 12, 2023

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Markus Haake, Beatrice Haack, Tina Schäfer, Patrick N. Harter, Greta Mattavelli, Patrick Eiring, Neha Vashist, Florian Wedekink, Sabrina Genssler, Birgitt Fischer, Julia Dahlhoff, Fatemeh Mokhtari, Anastasia Kuzkina, Marij J. P. Welters, Tamara M. Benz, Lena Sorger, Vincent Thiemann, Giovanni Almanzar, Martina Selle, Klara Thein, Jacob Späth, Maria Cecilia Gonzalez, Carmen Reitinger, Andrea Ipsen-Escobedo, Kilian Wistuba-Hamprecht, Kristin Eichler, Katharina Filipski, Pia S. Zeiner, Rudi Beschorner, Renske Goedemans, Falk Hagen Gogolla, Hubert Hackl, Rogier W. Rooswinkel, Alexander Thiem, Paula Romer Roche, Hemant Joshi, Dirk Pühringer, Achim Wöckel, Joachim E. Diessner, Manfred Rüdiger, Eugen Leo, Phil F. Cheng, Mitchell P. Levesque, Matthias Goebeler, Markus Sauer, Falk Nimmerjahn, Christine Schuberth-Wagner, Stefanie von Felten, Michel Mittelbronn, Matthias Mehling, Andreas Beilhack, Sjoerd H. van der Burg, Angela Riedel, Benjamin Weide, Reinhard Dummer and Jörg Wischhusen  /  Nature Communications volume 14, Article number: 4253 (2023)

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).

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