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.
Andrea Necchi
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 Institute in Milan, Italy. Prof. Necchi currently serves as a board member of the EAU Research Foundation and is an associate member of the ASCO-EAU penile cancer guidelines panel. His team pioneered the use of neoadjuvant immunotherapy in muscle-invasive bladder cancer with the PURE-01 trial. He is the principal investigator of our ongoing GDFATHER-2 trial and several other academic phase 1-2 trials of immuno-oncology combinations in urological malignancies. Prof. Necchi received his MD degree from the University of Milan
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 (...)
Petros Grivas
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 a key opinion, thought leader and international expert, giving lectures in several countries, educating oncologists and other healthcare providers, mentoring numerous trainees, leading large innovative clinical trials, reviewing grant proposals and manuscripts, and publishing novel and important research. He is dedicated to personalized and outstanding patient care, efficient clinical operations, and believes in optimal patient-physician relationship as well as community outreach. Dr. Grivas is the Clinical Director of the GU Cancers Program and Professor at the Dept. of Medicine, Division of Hematology Oncology, University of Washington and at the Clinical Research Division at Fred Hutchinson Cancer Center. He received his MD and PhD in Greece in 2005 and 2009, respectively. He completed his Internal Medicine Residency at the Hahnemann University Hospital/Drexel University College of Medicine (Philadelphia) in 2010, and a Hematology/Oncology Fellowship at the University of Michigan (Ann Arbor) in 2013. Dr. Grivas was Clinical Lecturer before he was recruited as Assistant Professor at the Cleveland Clinic (Cleveland)
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 (...)
Alexander Eggermont
MD, PhDProfessor 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 (...)
Reinhard Dummer
MDProfessor 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 (...)
Stephen Hodi
MDDr. 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 (...)
Wolf H. Fridman
MD, PhDProfessor 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 (...)
Jörg Wischhusen
PhDProfessor 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 (...)
Thomas Gajewski
MD, PhDProfessor 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 (...)
Ignacio Melero
MD, PhDProfessor 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 (...)
Roy Herbst
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 the PD-1/PD-L1 adaptive immune response in early phase trials and to offer trials of PD-L1 inhibitors atezolizumab and pembrolizumab to lung cancer patients. He currently holds the positions of Ensign Professor of Medicine (Medical Oncology), Chief of Medical Oncology, Deputy Director, and Associate Director of Translational Research at the Yale Cancer Center. He previously served on the boards of the American Association for Cancer Research (AACR) and the International Association for the Study of Lung Cancer (IASLC), and has been involved with the National Cancer Institute’s Thoracic Malignancy Steering Committee since 2012. Before joining Yale, he was the Barnhart Distinguished Professor and Chief of the Section of Thoracic Medical Oncology at The University of Texas MD Anderson Cancer Center (UT-MDACC). Dr. Herbst holds a PhD from The Rockefeller University and a MS from Harvard University. He completed his fellowships at Brigham and Women’s Hospital and the Dana Farber Cancer Institute, and a residency at Brigham and Women’s Hospital. Dr. Herbst received his MD from Cornell University Medical College and earned a MS and BS degree from Yale University
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 (...)
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.
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 /
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 /
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)
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
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.
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
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).
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.
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
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.
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.
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.
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.
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)
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)
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).