Melero et al. report the safety and efficacy of visugromab, an antibody blocking the immunosuppressive cytokine GDF-15, in combination with anti-PD-1 in patients with advanced cancers refractory to anti-PD-1/L1 therapy. GDF15 expression correlated with immune exclusion in TCGA datasets and at baseline in all enrolled patients. Visugromab was well tolerated across all dose levels, and in combination with nivolumab, induced durable responses in a fraction of patients with non-squamous NSCLC and urothelial cancer. Treatment induced CD8+ T cell tumor infiltration, proliferation, IFNγ-related signaling, and granzyme B expression in responders.
Contributed by Shishir Pant
ABSTRACT: Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment(1). Yet, response rates are still limited, and tumour progression commonly occurs(2). Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition(3). In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-_-related signalling and granzyme_B expression by cytotoxic T_cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.
Author Info: (1) Clnica Universidad de Navarra, CIMA, IDISNA and CIBERONC, Pamplona, Spain. imelero@unav.es. Nuffield Department of Medicine, University of Oxford, Oxford, UK. imelero@unav.es.
Author Info: (1) Clnica Universidad de Navarra, CIMA, IDISNA and CIBERONC, Pamplona, Spain. imelero@unav.es. Nuffield Department of Medicine, University of Oxford, Oxford, UK. imelero@unav.es. (2) START Madrid-CIOCC, Centro Integral Oncolgico Clara Campal, Madrid, Spain. (3) Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain. (4) Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain. (5) Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Spain. (6) Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland. (7) NEXT Oncology Phase I Unit/IOB - Hospital Quirnsalud Barcelona, Barcelona, Spain. (8) Medizinische Klinik 2, Early Clinical Trial Unit, University Hospital Wrzburg, Wrzburg, Germany. (9) West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany. National Center for Tumor Diseases (NCT) West, Essen, Germany. (10) Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. (11) Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. (12) Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS) & Liver Oncology Unit, Liver Unit, Hospital Clnic, Barcelona, Spain. Centro de Investigacin Biomdica en Red en Enfermedades Hepticas y Digestivas (CIBEREHD), Madrid, Spain. (13) Department of Immunology and Oncology, Clnica Universidad de Navarra, Pamplona, Spain. (14) START Madrid-CIOCC, Centro Integral Oncolgico Clara Campal, Madrid, Spain. (15) Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain. (16) Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain. (17) Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Spain. (18) Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Spain. (19) Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland. (20) NEXT Oncology Phase I Unit/IOB - Hospital Quirnsalud Barcelona, Barcelona, Spain. (21) Medizinische Klinik 2, Early Clinical Trial Unit, University Hospital Wrzburg, Wrzburg, Germany. (22) West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany. National Center for Tumor Diseases (NCT) West, Essen, Germany. (23) Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. (24) Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. (25) Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS) & Liver Oncology Unit, Liver Unit, Hospital Clnic, Barcelona, Spain. Centro de Investigacin Biomdica en Red en Enfermedades Hepticas y Digestivas (CIBEREHD), Madrid, Spain. (26) Department of Immunology and Oncology, Clnica Universidad de Navarra, Pamplona, Spain. (27) START Madrid-CIOCC, Centro Integral Oncolgico Clara Campal, Madrid, Spain. (28) Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain. (29) Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain. (30) Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland. (31) NEXT Oncology Phase I Unit/IOB - Hospital Quirnsalud Barcelona, Barcelona, Spain. (32) West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany. National Center for Tumor Diseases (NCT) West, Essen, Germany. (33) Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. (34) Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. (35) Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS) & Liver Oncology Unit, Liver Unit, Hospital Clnic, Barcelona, Spain. Centro de Investigacin Biomdica en Red en Enfermedades Hepticas y Digestivas (CIBEREHD), Madrid, Spain. (36) Department of Immunology and Oncology, Clnica Universidad de Navarra, Pamplona, Spain. (37) Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt, Germany. (38) Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt, Germany. (39) Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (40) Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (41) Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. (42) Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. (43) Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. (44) Department of Urology, Hospital of the Goethe University Frankfurt, Frankfurt am Main, Germany. (45) Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany. (46) Department of Urology, Hospital of the Goethe University Frankfurt, Frankfurt am Main, Germany. (47) Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany. (48) KinDyn Consulting, Warnham, UK. (49) LYO-X AG, Basel, Switzerland. (50) The University of Chicago Medical Center, Chicago, IL, USA. (51) Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Universit, Universit Paris Cit, Paris, France. (52) University Medical Center Utrecht and Princess Mxima Center, Utrecht, The Netherlands. Comprehensive Cancer Center Munich of the Technical University Munich and the Ludwig-Maximilian University, Munich, Germany. (53) Medizinische Klinik 2, Early Clinical Trial Unit, University Hospital Wrzburg, Wrzburg, Germany. (54) Discovery Life Sciences Biomarker Services, Kassel, Germany. (55) Discovery Life Sciences Biomarker Services, Kassel, Germany. (56) Discovery Life Sciences Biomarker Services, Kassel, Germany. (57) Metronomia Clinical Research, Munich, Germany. (58) da Silva Consulting Services, Munich, Germany. (59) CatalYm, Munich, Germany. (60) CatalYm, Munich, Germany. (61) CatalYm, Munich, Germany. (62) CatalYm, Munich, Germany. (63) CatalYm, Munich, Germany. (64) CatalYm, Munich, Germany. (65) CatalYm, Munich, Germany. (66) CatalYm, Munich, Germany. (67) CatalYm, Munich, Germany. (68) CatalYm, Munich, Germany. (69) CatalYm, Munich, Germany. (70) CatalYm, Munich, Germany. (71) CatalYm, Munich, Germany. (72) Department of Gynecology, University Hospital Wrzburg, Wrzburg, Germany. (73) CatalYm, Munich, Germany. (74) CatalYm, Munich, Germany. (75) CatalYm, Munich, Germany. (76) CatalYm, Munich, Germany. eugen.leo@catalym.com.
