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GDF-15 - a critical driver of
therapy resistance and cancer cachexia

GDF-15 is emerging as a central driver of treatment resistance and cachexia in cancer patients. Elevated levels of GDF-15 enable tumors to evade the immune system while simultaneously driving the debilitating metabolic syndromes of cachexia.

Growth Differentiation Factor 15 (GDF-15) is a distant and atypical member of the transforming growth factor β (TGF-β) superfamily.

It is highly overexpressed in the majority of human solid cancers and high levels of circulating GDF-15 are generally associated with poor clinical outcomes. GDF-15 is a key driver of resistance to cancer immunotherapy and a central driver of cachexia.

Under physiological conditions, GDF-15 functions primarily as a stress-induced signal that helps the body to metabolically adapt to stress and prevent excessive tissue damage induced by stressors such as infections or inflammatory processes. GDF-15 can regulate appetite, nutrient intake, lipid and glucose metabolism, and contributes to nausea and emesis through signaling via the brainstem-restricted receptor GFRAL. High levels of GDF-15 restrain immune cell recruitment and activation, and typically restrict excessive immune responses.

During pregnancy, GDF-15 is highly expressed by the placenta and is thought to contribute to feto-maternal tolerance by promoting a locally immunosuppressive environment that protects the semi-allogeneic fetus from maternal immune attack.

Tumors overexpress and hijack GDF-15’s normal stress-response functions, which allows them to evade immune surveillance and promote disease progression.

GDF-15 molecule

The dual role of elevated GDF-15 in cancer:
Driver of immune suppression and cancer cachexia

Immune suppression

GDF-15 establishes and maintains an immunosuppressive tumor microenvironment insensitive to immune checkpoint inhibitors and other forms of immunotherapies.

Cancer cachexia

GDF-15 drives cancer cachexia, a severe muscle-wasting syndrome characterized by involuntary weight and muscle mass loss, nausea and emesis that impacts patients’ quality of life, treatment tolerance and survival.

How does GDF-15
mediate treatment resistance to immune checkpoint inhibitors and induce cachexia?

GDF-15 local immune evasion and treatment resistance

GDF-15 mediates immune evasion and treatment resistance

CatalYm and its collaborators have identified GDF-15 as a central regulator of resistance to cancer immunotherapy by elucidating its role in local tumor immune evasion.

GDF-15 suppresses anti-tumor immunity at multiple levels, including by limiting T-cell infiltration into tumors, impairing the activation and function of antigen-presenting cells and myeloid effector cells, and enhancing regulatory T-cell-mediated immune suppression.

Through these coordinated effects, GDF-15 promotes the formation of an immunosuppressive tumor microenvironment that undermines effective anti-tumor immune responses and contributes to resistance to checkpoint inhibitor therapy.

GDF-15 systemic cachexia biology through GFRAL RET signaling

GDF-15 drives cancer cachexia through GFRAL–RET signaling

Cancer cachexia is a complex and debilitating syndrome that affects a large proportion of patients with advanced cancer and is associated with poor clinical outcomes, reduced quality of life, and impaired tolerance to anticancer therapy.

Elevated levels of GDF-15 are a key driver of this syndrome. Through activation of the GFRAL–RET receptor complex in the brainstem, GDF-15 not only suppresses appetite and promotes nausea, but also engages the HPA axis and sympathetic nervous system to trigger broader systemic effects across adipose tissue, skeletal muscle, liver, pancreas, and the gastrointestinal tract.

These downstream signals drive metabolic dysfunction, increased energy expenditure, and progressive loss of fat and lean body mass.

GDF-15 self-reinforcing tumor-promoting cycle

Local and systemic effects reinforce disease progression

In addition to its broad general overexpression across solid tumors, GDF-15 can be further induced by tumor stress and by multiple anti-cancer therapies, including chemotherapy, radiation, and antibody-drug conjugates.

This treatment-associated increase may further reinforce immune escape and therapy resistance while also worsening systemic effects such as cachexia and reduced treatment tolerance.

Together, these local and systemic actions can create a self-reinforcing vicious cycle that supports continued tumor progression and is associated with poorer clinical outcomes.

Neutralization of GDF-15
A new concept to restore anti-tumor immunity and counteract cachexia

Based on growing evidence for its complex role in immune suppression and cachexia, GDF-15 is emerging as a promising novel target with the potential to address both challenges through one synergistic approach.

Visugromab: CatalYm’s anti-GDF-15 antibody

Visugromab is a first-in-class monoclonal antibody candidate designed to neutralize GDF-15, simultaneously targeting tumor immune evasion and cancer cachexia through a single mechanism. By blocking GDF-15 activity, visugromab reverses GDF-15-mediated immunosuppression at the tumor site to reinstate an efficient anti-tumor response and mitigate its systemic effects of cachexia to enhance the patient’s health-related quality of life and treatment tolerance. Through this multi-pronged approach, CatalYm aims to interrupt the vicious tumor-promoting cycle and significantly improve outcomes for patients with a range of difficult-to-treat solid tumors, who urgently need new therapeutic options.

Visugromab blocks local and systemic functions of GDF-15 in cancer
Visugromab blocks local and systemic functions of GDF-15 in cancer

Top section: Local immunosuppressive effects: GDF-15 blocks adhesion of T cells to endothelial cells in blood vessels close to the tumor site, preventing T cell infiltration into the tumor microenvironment. Neutralization of GDF-15 in therapy resistant/refractory tumors can help to improve T cell infiltration and immune cell activity, thereby enhancing the effectiveness of the therapy regimen. Bottom section: Systemic metabolic effects: Tumor-secreted GDF-15 acts systemically to increase cachectic symptoms including appetite suppression, adipose tissue catabolism and muscle wasting. Blocking these effects can help to increase patients’ quality of life, physical condition and their ability to tolerate treatment.

Clinical evidence
supporting GDF-15 blockade

Building on promising preclinical proof-of-concept data across multiple solid tumor models, we are expanding our advanced-stage clinical evidence base for visugromab to unlock the full potential of GDF-15 neutralization for patients with high-need cancer indications, including early-line settings.

Data from our first-in-human Phase 1/2 trial, GDFATHER, provided clinical proof-of-concept that GDF-15 inhibition with visugromab in combination with the PD-1-inhibitor nivolumab was generally well tolerated and showed deep and durable responses in anti-PD-(L)1 relapsed/refractory solid tumor patients, particularly in three indication cohorts comprising late- to last-line metastatic non-small cell lung cancer (NSCLC), urothelial cancer (UCC) and hepatocellular cancer (HCC) patients.

Long-term follow-up supported these findings, with the majority of responders experiencing deeper and longer-lasting responses when compared to their prior anti-PD-(L)1 treatment. Retrospective analyses also demonstrated clinically meaningful weight gain in cachectic patients, supporting a dual benefit of visugromab to improve tumor control and quality of life.

The results from the Phase 1/2 GDFATHER trial in heavily pretreated patients with solid tumors also included a wealth of translational research data that demonstrated the detailed proof-of-mechanism for visugromab, which induced T-cell influx, T-cell proliferation, and an immunostimulatory Interferon-γ signature induction in the tumor microenvironment both in monotherapy and in combination with nivolumab.

Furthermore, pan-cancer immunogenomic analyses demonstrated the immunosuppressive impact of GDF-15 on the tumor microenvironment and its immune cell landscape, which could be reversed by visugromab.

Overall, the GDFATHER Phase 1/2a data underscore the potential of GDF-15 neutralization by visugromab to (re)establish immune checkpoint inhibitor sensitivity in resistant tumors and mitigate cancer-associated cachexia.

In addition, encouraging proof-of-concept data from the GDFATHER-NEO Phase 2 trial in muscle-invasive bladder cancer, where neoadjuvant treatment with visugromab plus nivolumab substantially increased anti-tumor activity, highlight visugromab’s potential in earlier treatment lines. Building on this strong basis, CatalYm is now extending the later-stage clinical development of visugromab into earlier treatment lines and cancer cachexia.

Learn more about CatalYm’s ongoing late-stage trials here:

Phase 2b GDFATHER-NSCLC-01

A Phase 2b trial in 1L NSCLC

Learn more → Phase 2b GDFATHER-NSCLC-02

A Phase 2b trial in 2L NSCLC

Learn more → Phase 2b GDFATHER-HCC-01

A Phase 2b trial in 2L HCC

Learn more → Phase 2/3 VINCIT

A Phase 2/3 trial in 1L+ cancer cachexia

Learn more →

Publications

CatalYm’s deep scientific insights into GDF-15’s role in cancer resistance and cachexia forms the basis for our differentiated therapeutic approach with visugromab. Browse our scientific publications for a deep dive into our preclinical foundation and continuously growing clinical proof-of-concept data in high-need tumor indications.

Cancer Immunotherapy

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