CatalYm Presents Data at ESMO 2023 Expanding GDF-15’s Role in Checkpoint Therapy Resistance by Inhibition of Myeloid Immune Cell Activation
- First comprehensive demonstration that GDF-15 exhibits an inhibitory effect on the activation of M1 macrophages as well as effector functions as chemokine release
- New findings expand and underline the role of tumor-secreted GDF-15 as an important driver of therapy resistance in cancer by inhibiting both activation and relocation of important players of antitumoral immune responses
- Data highlight the potential of GDF-15 neutralizing approaches as a critical component for treatment success in a broad range of anti-cancer regimens
Munich, Germany, October 16, 2023 – CatalYm today announced new preclinical data expanding the mechanistic understanding of how GDF-15 plays a key role in cancer therapy resistance. The results will be presented in a poster session at the European Society for Medical Oncology (ESMO) Congress 2023 in Madrid, Spain on Sunday, October 22nd by CatalYm’s CSO, Dr. Christine Schuberth-Wagner. The data are the first to show that GDF-15 has an inhibitory effect on the activation of M1 macrophages. These specific myeloid lineage immune cells are central to the initiation of immune responses, including the secretion of pro-inflammatory cytokines and chemokines, presentation of antigens as well as direct antitumor cytotoxicity.
The results support and expand on initial findings, recently published in Nature Communications, on pathways involved in the development of GDF-15 mediated therapy resistance in cancer cells. These data were the first to demonstrate a mechanistic link between GDF-15 and inhibition of the LFA-1/ICAM-1 cell adhesion axis in cancer, resulting in impaired infiltration of T cells into the tumor microenvironment.
“The ESMO data add to recently discovered mechanistic effects of GDF-15 impairing T cell infiltration into tumors and show the impairment of another important immune cell compartment by GDF-15, thereby expanding our understanding of its role in establishing tumor resistance to current cancer therapies. Interestingly, M1 macrophages are crucial for initiation of anti-tumoral immune responses and in parallel are active in tumor cell destruction by phagocytosis and oxidative stress,” said Dr. Christine Schuberth-Wagner, Chief Scientific Officer at CatalYm. “The findings, therefore, provide additional support for the potential of GDF-15 neutralizing approaches as a critical component for treatment success in a broad range of anti-cancer regimens.”
The preclinical data comprise in vitro analyses demonstrating that GDF-15 inhibits the polarization of M0 to M1 macrophages, indicated by a reduction of activation marker expression as well as MHC-II and Fcg-receptors. These phenotypic changes are accompanied by an altered cytokine expression and secretion profile. The activation was restored when GDF-15 was neutralized with CatalYm’s anti-GDF-15 antibody candidate, visugromab. In in vivo melanoma models, knock-out of GDF-15 led to an increase of counts and activation status of macrophages and antigen-presenting dendritic cells in tumor tissue. Overall, the results indicate that GDF-15 counteracts myeloid immune cell activation, supporting the generation of an immune-evasive tumor microenvironment, an important feature in therapy resistance.
CatalYm is investigating its GDF-15-neutralizing antibody visugromab in the GDFather (GDF-15 Antibody-mediaTed Human Effector Cell Relocation) trials in combination with the anti-PD-1 inhibitor nivolumab in patients with advanced solid tumors. Interim data from the Phase 2 (NCT04725474) trial recently presented at ASCO continue to demonstrate a very good safety and tolerability profile and promising durable, confirmed responses in major cancer indications, including non-small cell lung cancer (NSCLC), bladder cancer and hepatocellular carcinoma (HCC). The company expects to report mature data readouts for efficacy and safety from the core Phase 2a program as well as main biomarker-correlations before the end of 2023.
About Visugromab (CTL-002)
Visugromab is a monoclonal antibody that neutralizes the tumor-derived Growth Differentiation Factor-15 (GDF-15), a locally acting immunosuppressant fostering immunotherapy resistance. Neutralizing GDF-15 with visugromab reverses key cancer resistance mechanisms to reinstate an efficient anti-tumor response by reenabling immune cell activation and tumor infiltration. Visugromab has already demonstrated a good safety profile and potent and durable anti-tumor efficacy in combination with anti-PD-1 treatment in advanced cancer patients The antibody is currently being investigated in ongoing Phase 2 studies in multiple solid tumor indications.
CatalYm has identified GDF-15 as a key cancer therapy resistance mechanism and is developing a safe and efficacious immune therapy for solid tumors. GDF-15, an immunosuppressant important for feto-maternal tolerance, is hijacked by cancer cells to evade immune system attack. Visugromab, CatalYm’s lead antibody, has demonstrated durable anti-tumor efficacy with long-lasting objective responses in relapsed and refractory metastatic solid tumor patients in combination with anti-PD-1. CatalYm is now advancing to Phase 2b studies to confirm visugromab as a new class of cancer immunotherapy in a broad range of anti-cancer regimens.
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