GDF-15 blockade: A multi-directional approach to potentiate cancer immunotherapy and alleviate cancer cachexia

Abstract

Metastatic solid tumours remain a major challenge in clinical medicine, demanding innovation with novel treatment approaches and new synergistic combinations. Immunotherapy with immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 has improved the treatment outcome for numerous tumour types in a groundbreaking way. However, resistance to immunotherapy is very frequent and ultimately impacts the vast majority of patients treated, often resulting in fatal outcome. Similarly, in advanced cancer patients cachexia is a frequent event. This is a serious debilitating syndrome characterized by severe muscle wasting, weight loss and systemic metabolic dysfunction which associates with a dismal prognosis. Cachexia further worsens clinical outcome in cancer patients and can prevent ability to continue on therapy. In this context, our recent study published in Nature, titled “Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours,” demonstrates the multifaceted roles growth differentiation factor 15 (GDF-15) plays and provides initial data on a promising novel therapeutic strategy to counteract immunotherapy resistance and cachexia.¹ Here, we discuss the potential benefits of GDF-15 blockade as an emerging approach to both potentiate cancer immunotherapy and simultaneously mitigate cancer cachexia, highlighting recent advancements and their potential future clinical implications (Figure 1).

I. Melero, K. Klar and E. Leo prepared jointly the manuscript.

I. Melero is principal investigator of the trial 1 and has served as a consultant to Catalym GmbH. K. Klar and E. Leo are employees of Catalym GmbH, Martinsried, Germany, a biotechnology company developing the anti-GDF15 antibody visugromab.

The authors declare human ethics approval does not apply for this manuscript.