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 &
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.
Alexander EggermontMD, PhD
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 at the Louvain Catholic University in Belgium, and an Honorary Doctorate at the University of Essen-Duisburg, Germany. In addition, he serves as the President of the European Academy of Cancer Sciences, and the President of the Cancer Core Europe consortium. In 2015, Prof. Eggermont was elevated to the status of Chevalier of the Légion d’Honneur by the French Ministry of Foreign Affairs and International Development. His research specialty is in immunotherapy, the treatment of melanomas and sarcomas in addition to fundamental research in pathogenesis and immunology of tumors.
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 (...)
Ignacio MeleroMD, PhD
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 strategies for cancer immunotherapies. Dr. Melero has been awarded the BIAL Prize of Medicine, the Conde de Cartagena Award from the Royal Academy of Medicine, Doctor Durantez LAIR Foundation Award and a Cancer Research Institute research award. He has served on the advisory boards of Bristol Myers-Squibb, Roche-Genentech, AstraZeneca, Merck Serono and Boehringer Ingelheim.
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 (...)
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 a strong focus on tumor-initiating cells and their ability to evade immunosurveillance. Previously, he was a research group leader at the Interdisciplinary Center for Clinical Research in Würzburg. He received his PhD from the University of Tübingen, Germany in the field of molecular neuro-oncology.
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 (...)
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 Unit of the Department of Dermatology. Prof. Dummer’s principal research interests are molecular biology, immunology and immunotherapy of cutaneous malignancies, including cutaneous lymphomas and melanomas and has published more than 741 scientific publications. He is a founding and Board Member of the European Association of Dermato-Oncology, ESMO, URPP and a member of the German National Academy of Sciences (Leopoldina). Prof. Dummer began his medical education in hematology and oncology before successfully completing his dermatology residency in Würzburg, Germany, and Zürich, Switzerland.
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 (...)
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 recognized research focuses on gene therapy, the development of immune therapies, and first into human studies for malignant melanoma. Dr. Hodi is a member of ASCO, AACR, the ECOG Melanoma Committee, SITC, the European Academy of Tumor Immunology and a founding member of the Society for Melanoma Research. His clinical investigation efforts have pioneered the use of immune checkpoint blockade and combinatorial approaches to treat cancer. He has published over 300 peer-reviewed scientific publications including articles in the Proceedings of the National Academy of Sciences, Journal of Clinical Oncology and the New England Journal of Medicine.
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 (...)
Thomas GajewskiMD, PhD
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 to investigating and developing new treatments for patients with melanoma, with a special interest in the development of immunotherapies, and is an author/co-author of over 270 scientific publications in the field. He serves as an editor for Cancer Discovery, Journal for Experimental Medicine, and the Journal for Immunotherapy of Cancer, is on the Program Committees for the American Society for Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR), and is past President of the Society for Immunotherapy of Cancer.
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 (...)
Wolf H. FridmanMD, PhD
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 between INSERM, University Paris Descartes, and University Pierre et Marie Curie.
He was also the Head of the Immunology Laboratory of European Hospital Georges Pompidou in Paris. Prof. Fridman’s current research is focused on the immune response in the tumor microenvironment to control clinical outcomes in cervical cancer. He is a world leader in the field of human tumor immunology and has authored over 480 scientific publications in the field.
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 (...)
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.
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 /
Markus Haake, Neha Vashist, Beatrice Haack, Birgitt Fischer, Kristin Eichler, Matthias Kist, Sabrina Genssler, Joerg Wischhusen, Eugen Leo and Christine Schuberth-Wagner /
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)
Interview with Christine Schuberth-Wagner, Chief Scientific Officer at CatalYm / Drug Target Review 24Aug2023
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)
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
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
Tumor-derived GDF-15 to suppress T-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.
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